Pancreatic cancer Treatment

What is the pancreas?

The pancreas is a large gland, which is situated behind the stomach, in the back of the abdomen. It is part of the digestive system and has two main functions. It produces hormones, including insulin which controls the sugar levels in the blood. It also produces pancreatic juices which contain important enzymes. These enzymes help to break down food in the bowel so the body can absorb the nutrients.

The pancreas has three parts from right to left: the head, the body and the tail. It has a duct which, together with the duct from the liver (bile duct), empties into the first part of the bowel after the stomach, which is called duodenum. Around the pancreas, there are big blood vessels that carry the blood into the liver, stomach and spleen; in and out of the bowel and from the lower part of the body into the heart.

What is pancreatic cancer?

Normally the cells in the body grow in a controlled way. Sometimes this control is lost and the uncontrolled growing of the cells creates a lump which we call cancer. These cells can also survive in the lymphatic vessels or in the blood and create colonies in areas of the body far away from the lump. These colonies are called metastasis and can also grow without control.

There are different types of pancreatic cancer. The majority of them (about 80%) are made from cells in the lining of the pancreatic duct and are called pancreatic ductal adenocarcinoma. These are the ones most commonly referred to as “cancer of the pancreas”.

”There are also other types of pancreatic cancer, such as the neuroendocrine tumours, however, they behaved differently and have different treatment options.

What causes pancreatic cancer?

At the moment about 7600 people in the UK get pancreatic cancer every year. About half of them are over 70 years old.

We do not know the exact causes of pancreatic cancer. However, we know a few things that can increase the risk, such as smoking, age, being overweight, hereditary or chronic pancreatitis (inflammation of the pancreas) and a family history of pancreatic cancer.

What are the symptoms of pancreatic cancer?

Pancreatic cancer can be difficult to diagnose, as it often does not cause many specific symptoms in the early stages. Symptoms may include:

loss of appetite
indigestion
unintentional loss of weight
feeling or being sick
pain in the abdomen or back
problems with the bowel such as constipation, yellowy or greasy stool that float in the toilet (steoatorrhoea) and loose stool (diarrhoea).
Yellow skin or eyes (jaundice) and itchy skin
New onset problems with blood sugar levels (diabetes) or problems regulating sugar levels in patients with existing diabetes

What are the tests to diagnose pancreatic cancer?

When a patient sees a doctor with symptoms that are worrying for pancreatic cancer, the usual initial tests are blood tests. These may be followed in the community by an ultrasound scan. The best test to diagnose pancreatic cancer is a CT scan with contrast via a cannula in the arm. This will also help your cancer specialists determine the stage of the cancer. Other tests like MRI scans or PET scans (radionucleotide scan) may be requested to help in the diagnosis and staging. Sometimes, if the diagnosis is uncertain an endoscopic ultrasound (a camera test down the throat and into the stomach with an ultrasound probe) and biopsy of the lump will be required.

What are the stages of pancreatic cancer?

Categorising cancers at the time of diagnosis into stages is very important. From data around the world, cancer specialists have developed optimal pathways for the treatment of patients based on the stage of cancer.

There are various staging systems for pancreatic cancer. The most commonly used in order to explain to patients, categorises the disease in 4 stages. Stage 1 is the earliest stage of pancreatic cancer, when the cancer is contained inside the pancreas and is 4 cm or smaller. In stage 2, the pancreatic cancer has grown to 4 cm or larger or has spread to a small number (1-3) of lymph nodes around the pancreas. The lymph nodes are small glands found throughout the body which are part of the immune system. In stage 3, the cancer has grown through the pancreas and is involving the large blood vessels around the pancreas or has spread to 4 or more lymph nodes. In stage 4 the cancer has spread in distant parts of the body (metastases). The most common areas for metastasis are the liver, the lungs and the lining of the abdomen.

Stage 1 Stage 2

Stage 3 Stage 4

Another staging system that is mainly used by specialists is the TNM (tumour – node – metastasis). Based on the scans at diagnosis a radiological TNM stage can be provided. However, the most accurate TNM stage comes only after an operation to remove the cancer and examine it under the microscope.

The most commonly used system by cancer specialists around the world to determine the optimal treatment pathways for patients with pancreatic cancer is that of the USA National Comprehensive Cancer Network. This system categorises the pancreatic cancers into those confined to the pancreas and those which are metastatic (spread to other organs far away from the pancreas). The cancers that have not created metastases, are further categorised into “resectable”, “borderline resectable” and “locally advanced”, depending mainly on the involvement of the big vessels around the pancreas by the tumour. Tumours that are not involving any vessels or only slightly touch the big veins are called “resectable”. If they involve the big vessels more than that and depending on how much more, they are called “borderline resectable” or “locally advanced”.

Can I be treated anywhere for pancreatic cancer?

Various investigations and treatment can be delivered in most of the UK hospitals. However, if surgery is an option, then patients are referred to a specialised centre. The reason for this is that from data around the world, pancreas cancer operations done in specialised centres have better outcomes for patients. Therefore pancreatic surgery has been centralised in the UK for more than 15 years now. You may not have to go to a specialist centre if surgery is not part of your treatment plan.

What are the treatment options?

Depending on the stage of the cancer, as well as the patient’s fitness and medical history, there are various treatment options, which can also be delivered in combination. These include surgery, chemotherapy and radiotherapy. There are also a number of clinical trials.

All cases of pancreatic cancer should be discussed in an MDT, which is a meeting of cancer specialist doctors of various specialties, including surgery, radiology and oncology, as well as other healthcare professionals, such as specialist nurses, dieticians etc. The MDT goes through each case and suggests an individualised plan.

Can I ask for a second opinion?

All cases of pancreatic cancer should be discussed in an MDT and a personalised plan should be produced for each patient. Patients may ask for a second opinion as suggested treatment pathways may vary depending on availability of the various treatments and the experience of the MDT teams and specialist centres.

I have stage 1 or stage 2 pancreatic cancer. What is the treatment?

Stage 1 and stage 2 tumours are by definition confined to the pancreas and usually do not involve major vessels. The most common pathway for the treatment of these tumours is surgery first followed by adjuvant chemotherapy. Some units around the world opt for their patients to have chemotherapy before surgery (neoadjuvant chemotherapy) even for these early stages of cancer.

In some cases (about 20% based on the literature), during the operation, some of these tumours are found to be stack on the portal or superior mesenteric veins (large veins that bring the blood from the bowel to the liver). In these cases removing part of the vein with the specimen is important for a good oncological operation. This increases somewhat the complexity of the operation, but it does not increase the peri-operative risks if performed by an experienced team and is now considered a standard of care for pancreatic cancer surgery.

I have stage 3 pancreatic cancer. What is the treatment?

In stage 3, the tumour is invovling major vessels around the pancreas. These are the tumours that are often inappropriately called "inoperable" or "unresectable". In reality though a substantial number of patients with these stages of the disease can have surgery after certain treatment requirements are met.

The standard of care for treatment of this stage is chemotherapy first for 3 or 6 months. Then after further scans and tests (which are called restaging investigations), an operation to remove the cancer should be considered. Depending on the amount of vessel involvement and response to treatment, surgery can be offered in about 30% to 50% of patients as explained further below.

I have stage 4 pancreatic cancer. What is the treatment?

In stage 4, the cancer has spread away from the pancreas to distant organs. In these cases, management is centered around systemic treatments, such as chemotherapy or immunotherapy. Radiotherapy may also have a role, however surgery is less likely to help in these cases.

Can I have surgery?

Surgery should be considered as a treatment option for all stages of localised pancreatic cancer (cancers that have not spread to far away organs creating metastasis). The earlier the stage the more likely is that surgery is possible.

For “resectable” stage pancreatic cancer, the usual approach around the world is surgery to be offered as the first line treatment. Then this is followed by chemotherapy. If chemotherapy is given after the surgery, then it is called “adjuvant chemotherapy”.

If the pancreatic cancer is staged as “borderline resectable” or “locally advanced” (Stage 3) then the first line of treatment is chemotherapy. This is called “neoadjuvant chemotherapy”. After three or six months of chemotherapy (the cancer specialist team will decide on the duration) patients have more investigations. Based on these, the pancreatic cancer surgeon can decide if an operation is possible. For these cases, operations are more difficult and require significant experience in operating not only on the pancreas, but also on big blood vessels (as these cancers are involving big arteries and veins around the pancreas). Furthermore, neoadjuvant treatment can create inflammation (angry tissues) or fibrosis (significant scarring) around the area of the operation, which may increase the risks of the operation. In order to account for this, the surgery should be ideally performed within 4-6 weeks from the end of the neoadjuvant treatment.

Therefore, a surgical team with significant experience in operating on these stages of pancreatic cancer and close direct communication between the surgical and the oncology teams are extremely important for a good outcome.

Will I get surgery after neoadjuvant treatment?

This is a difficult question and depends on several factors. Some patients do not cope well with therapy and have many side effects. The oncology team will help them to get you through this, but for some patients the side effects may be so difficult that it’s not possible to complete the therapy. In these cases surgery is unlikely.

The complexity of surgery and the patient’s fitness is important as well. More extensive tumours that involve big blood vessels need more difficult surgery. A person would need to be fitter to have that surgery than a less difficult operation.

The response of the cancer to the therapy is also very important. This will be determined by radiological scans and a blood test to determine the tumour marker CA19-9. Around 1 in 8 people do not have the CA19-9 marker (that is normal for them) and so for those, we can only rely on the scans.

Our team in Birmingham is one of the most experienced teams and our programme for the treatment of patients with pancreatic cancer with neoadjuvant treatment is the largest in the UK and one of the largest in the world.

Our results over the last few years for the treatment of stage 3 pancreatic cancer, as presented in national and international meetings, have shown that, in our experience, for patients that start neoadjuvant treatment for “borderline resectable” tumours, about 1 in 2 (47%) are offered an operation to remove the cancer. These chances increase to 65% if the patients tolerate the chemotherapy. When a patient agrees to an operation and this is carried out by our team, the chance of removing the cancer is about 86%.

For “locally advanced” tumours, about 1 in 3 (32%) patients that start neoadjuvant treatment are offered an operation to remove the cancer. These chances increase slightly to 38% if the patients tolerate the chemotherapy. When a patient agrees to an operation and this is carried out by our team, the chance of removing the cancer is about 67%.

I have been told my cancer is “inoperable” or “unresectable”. What does this mean?

“Inoperable” pancreatic cancer means that the surgical team has advised that an operation is not possible in order to remove the cancer. In a large number of patients this is due to the fact that the cancer has already spread to far way areas of the body creating metastases (such as the liver or the lungs). However, in a number of patients that the tumour is still localised in the area of the pancreas, the term “inoperable” refers to the technicalities of an operation. Consequently the term also reflects the skill-set and experience of the surgical team and may not be the same among the various teams. For example, if a surgical team does not perform vein resections (needed to remove tumours that involve the big veins around the pancreas), then it will refer to “borderline resectable” and “locally advanced” tumours as “inoperable”. However, this is not the case with teams, such as our team, that are experienced in performing regularly pancreatic cancer operations and removing tumours from arteries and veins around the panreas.

The term “unresectable” pancreatic cancer means the same as “inoperable”.

Both terms, were sometimes used in the past to stage pancreatic cancers, epsecially stage 3 tumours. This is no longer appropriate. Due to the advancement of the surgical techniques and the successful outcomes that have been described around the world with surgery for advanced cases of pancreatic cancer, the international guidelines are now using the terms “resectable”, “borderline resectable”, “locally advanced” and “metastatic”.

What are the types of surgery?

There are 3 main types of operations for pancreatic cancer depending on the area of the pancreas that is affected and the involvement of adjacent organs or big vessels.

Pancreaticoduodenectomy (classical or pylorus preserving)

This is the usual operation for tumours in the head of the pancreas. The surgeon removes the head of the pancreas, the duodenum, 15-20 cm of small bowel, the gallbladder and part of the bile duct. In the classical operation the end part of the stomach is also removed, while in the pylorus preserving variation the end part of the stomach is not removed. Then the bowel is attached to the remaining pancreas, the remaining bile duct and the stomach.

2. Distal pancreatectomy and splenectomy

This is the usual operation for tumours in the body and tail of the pancreas. In this operation the surgeon removes the tail and body of the pancreas with the surrounding tissues. The spleen is also removed. There are two reasons for this. The first one is that the vessels that go to the spleen travel next to the body and tail of the pancreas and the second is that the lymph nodes that have to be removed to clear any cancer are closely related to the spleen. The spleen helps our body to fight infection; therefore if it is removed the patients have prophylaxis against infections by antibiotic tablets and vaccines.

3. Total pancreatectomy and splenectomy

Sometimes in order to clear all the cancer the surgeons have to perform a total pancreatectomy. This is a combination of the pancreaticoduodenectomy and the distal pancreatectomy and splenectyomtomy.

My tumour is involving blood vessels. Is an operation still possible?

In many cases of tumours that involving blood vessels an operation is technically possible. However, in order for the operation to be successful, the surgical team that performs the operation or advises about the case should have substantial experience in operating on blood vessels around the pancreas.

In the vast majority if n0t in all cases of “borderline resectable” and “locally advanced” cases of pancreatic cancer, a resection of the portal and/or superior mesenteric veins would be needed. This may also be required in about 1 in 5 cases of early pancreatic cancer (“resectable” stage) even if scans have not showed this before teh operation. The superior mesenteric vein is a large vein that brings blood out of the bowel. It then connects with the vein that brings the blood out of the spleen (splenic vein) to form the portal vein behind the pancreas. The portal vein brings blood into the liver. We cannot live without the portal or superior mesenteric veins. Due to their position behind the pancreas these veins can be involved by the cancer. When doing the operation, the surgeon will need to control the veins, cut and remove part of them together with the cancer and then rejoin them. From data around the world, this is safe and feasible if performed by experienced teams.

There are also big arteries around the pancreas that may be involved by the tumour. Namely these are the artery that goes to the liver (hepatic artery), the artery that goes to the spleen (splenic artery), the left gastric artery, which is one of the arteries that feed the stomach, the coeliac artery (from which the hepatic, splenic and left gastric arteries arise) and the superior mesenteric artery that provides blood to a large portion of the bowel. In some people, there may also be extra or unusual arteries which we call “aberrant”. These are normal variations of the anatomy due to the fact that every person is different. If tumours involve arteries then they are staged as either “borderline resectable” if the involvement of the arteries is limited or “locally advanced” if there is extensive arterial involvement. The pancreatic cancer surgeon should identify this on the preoperative scans and prepare a surgical plan. There are two main ways of operating on the arteries around the pancreas. The first one is called peri-adventitial dissection or arterial divestment. With this technique the surgeon strips the artery from its sheath. The sheath is made of lymphatics and nerves and it is a very good substance for cancer to grow into. If this technique is successful the artery is naked and freed from the tumour. This is achievable in a good number of cases. In cases that this is not possible during the operation, there is an option is some cases to perform an arterial resection (second technique). In this case, the surgeon has to cut part of the artery and rejoin the remaining part of the artery back into the circulation. The later is an extremely highly demanding technique with substantially higher risks and offered only in a few centres around the world. Therefore the surgeon should discuss this with the patient before the operation and obtain consent. If the patient does not want to take the extra risks, then the operation may be aborted if an arterial resection is deemed necessary.

Our team in Birmingham has significant experience and consistently perfrms these complex procedures in a number of patients every year. Our results are comparable to other large units in Europe and the USA.

What are the benefits of having an operation?

Surgery to remove the cancer is the only option that may be possible to cure the patient or provide long survival. The best chance for cure is when patients receive all the chemotherapy needed, have surgery to remove the cancer, recover well and receives enzyme replacement therapy. Unfortunately, however, pancreatic cancer is usually a very aggressive disease and in the majority of the cases it may return.

Almost 1 in 2 patients with pancreatic cancer that has not spread to far away organs is alive 1 year after the diagnosis. Between 15 and 25 out of 100 patients are alive 3 years after the diagnosis as per the Cancer Research UK statistics. In cases that the cancer has spread to distant organs (metastasis) 1 out of 10 patients will be alive 1 year after the diagnosis and only 1 out of 100 patients 3 year after the diagnosis.

For cancers that have not spread to distant organs dedicated treatment pathways and experience teams can increase significantly the chances for surviving longer. For “borderline resectable” and “locally advanced” tumours, patients that complete neoadjuvant chemotherapy and surgery, live longer compared to those who only have chemotherapy or those who receive no treatment (due to frailty or personal decision). Based on our teams results, patients that complete the pathway have overall survival almost 3 times longer (median around 30 months) compared to those that have received chemotherapy alone (median around 10 months) and almost 8 times longer compared to those without any treatment (median around 4 months). Surgery after neoadjuvant treatment is also the only treatment that can potentially result in someone being alive 5 years from diagnosis (about 1 in 3 for “borderline resectable” and about 1 in 10 for “locally advanced” cases).

What are the risks of having an operation?

Pancreatic cancer operations are major operations with substantial risks. These may include risks around the operation for up to 40% of the cases. There is also a risk for a patient dying after the operation between 1% and 8%, which depends not only on the extent and difficulty of the operation, but also equally importantly on the patient’s medical history and fitness. The less medical issues a patient has, the more likely is that an operation will be uneventful. Operations after neoadjuvant treatment are in general more challenging and therefore carry a higher risk. This is due to the extent of the tumour and the involvement of adjacent structures and big vessels (which is the reason to have the neoadjuvant treatment in the first place), as well as the effects of the treatment in the operative field. Appropriate timing of the operation and an experienced surgical team are crucial for a favourable outcome.

Furthermore, these operations may also cause significant changes in every day life after the surgery, even if everything goes well and without any complications. The patients will have to follow a specific diet and be on certain medication and supplements. They may become diabetic and insulin to control the blood sugar levels. If patients are frail before the operation they may require assistance upon discharge from the hospital.

The risks of the operation and the possible changes in the quality of life after an operation have to be carefully considered and weighed against the benefits.

Why selecting your surgeon is important for a good outcome?

Management of pancreatic cancer is complex and therefore better delivered by specialist multidisciplinary teams. With regards to surgery for pancreatic cancer, publised evidence and studies in the literature support that outcomes are better if the operation is performed in a high volume centre. This is why pancreatic surgery has been centralised in the UK for many years now. Even so, not all apsects of surgical treatment are offered everywhere. Within specialist centres and surgical teams, expertise and experience varies. These variations become more important in cases of "borderline resectable" and "locally advacned" tumours, when experience in operating after neoadjuvant chemotherapy and on major vessels is crucial for a successful outcome. Techniques to remove and replace or separate from the tumour large veins and arteries during these operations are usually required and are not widely practiced. Therefore, identifying and selecting a surgeon with substantial experience is highly recommended.

Surgery after neoadjuvant chemotherapy and radiotherapy was the focus of Mr Chatzizacharias' fellowship training in the USA, in one of the largest volume centres in the world, next to pioneers for the treamtent of pancreatic cancer. Mr Chatzizacharias has brought these expertise back in the UK and established the programme for the treatment of locally advanced pancreatic cancers in Queen Elizabeth Hospital, Birmingham, which is currently the largest in the UK and one of the largest in the world.

Am I fit to have an operation?

Due to the substantial risks of pancreas cancer operations as described above, any patient that can have an operation should go through an assessment of fitness. This starts with the clinical teams, oncology and surgical teams, and continues with a pre-assessment appointment. In that appointment the patient will be reviewed by an anaesthetic doctor. Various tests, such as heart and lung tests or an exercise tolerance test, may be required to help with the assessment of fitness and final decision. With all the information in hand the patient will be informed about specific risks and/or concerns; and after all questions are answered a decision is made. If a patient is not deemed fit for an operation or if he/she does not want to proceed with the operation, then they can be considered for other treatments.

Am I too old to have an operation?

Old age is not on its own precluding surgery. However, old age is related to frailty and medical conditions, such as heart and lung problems. Therefore, a careful assessment as described above and an open discussion with the patient about expectations and possible outcomes, including changes in every day life and its quality after an operation, are absolutely necessary.

What about chemotherapy?

Chemotherapy is one of the cornerstones in pancreatic cancer treatment. Essentially, all patients with pancreatic cancer benefit from chemotherapy if they are fit enough to receive it.

There are various types of drugs and combinations. The pancreatic oncologists will decide the best for each patient depending on various parameters. The most effective combination currently is called FOLFIRINOX (leucovorin, fluorouracil, irinotecan and oxaliplatin). However, FOLFIRINOX has also some serious adverse effects and may not be tolerated by all patients. Gemcitabine is another chemotherapy medication that can be used alone or in combination with other medications, such as capecitabine or nab-paclitaxel.

When the chemotherapy is given after an operation that removed the cancer, it is called “adjuvant” and its purpose is to eradicate any cancer cells that are circulating in the body.

In patients with “borderline resectable” or “locally advanced” pancreatic cancer, chemotherapy is given as the first line treatment and is called “neoadjuvant”. In these cases the intent is for patients to have an operation to remove the tumour after 3-6 months of neoadjuvant chemotherapy. This may not however be achieved in all the cases.

If the pancreatic cancer has moved to distant organs in the body (metastasis) then the intent of the chemotherapy is “palliative” and surgery to remove all the cancer is not possible.

Chemotherapy can cause side effects and every patient may be affected in different ways. Side effects may include being sick, extreme tiredness and low blood cell levels. How patients tolerate chemotherapy and how the adverse effects are managed are important parameters for their management.

What about immunotherapy?

Immunotherapy, also called biological therapy, biotherapy or biological response modifying therapy (BRM therapy), is a set of treatment techniques that boost the body’s natural defences to fight pancreatic cancer. Some immunotherapy treatments boost the immune system overall, while others try to teach it to attack specific types of cells found in tumours. Treatments may include the administration of vaccines, tablets or monoclonal antibodies (these are a type of protein that can attach to cancer cells in the body).

What about radiotherapy?

Radiotherapy is an option for cancers that remain localised in the pancreas (have not metastasised). It can be delivered alone or in combination with chemotherapy (chemoradiotherapy). The purpose of radiotherapy is to control the cancer as much as possible and provide some relief from symptoms, such as pain. However, it cannot kill the cancer completely.

Sometimes, in “locally advanced” pancreatic cancers, radiotherapy can be given with neoadjuvant intent. This means that it is given to control the tumour with a hope that after the radiotherapy an operation to remove it would be possible.

What about clinical trials?

Clinical trials are medical research studies that are trying to find better or new treatments for pancreatic cancer. There are pros and cons to taking part in a trial. For example, a trial may be an opportunity to receive a new treatment, however there is no guarantee that every patient will receive it. Interested patients should speak to their cancer specialist about the existing trials and whether any of these are an option. An online trial finder tool is also available in the Pancreatic Cancer UK website

What about nutrition?

Nutrition is very important in the management of all patients with pancreatic cancer. Patients may not have much appetite. This may also be affected by the various treatments. It is crucial though for enough and “good quality” calories with high protein content food to be taken every day. Utilising small frequent meals may help. If dietary requirements cannot be met with food, nutritional supplements can be used to increase the intake of calories and nutrients.

The use of pancreatic enzyme replacement therapy is also very important. As the functionality of the pancreas is affected by the cancer, the production of the enzymes that digest food is reduced. By supplementing these with capsules, the body receives the necessary help to digest food and absorb the nutrients. Pancreatic enzyme replacement therapy has been identifed by medical research as a prameter that helps in improving patient survival.

More information about nutrition and pancreatic cancer, including pancreatic enzyme replacement therapy and personalised advice and dietetic management at www.birminghamdietitian.co.uk.

Useful websites

Pancrearic cancer UK

Cancer research UK

National Comprehensive Cancer Network - guidelines for patients

European Society for Medical Oncology - a guide for patietns