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Information Resource for Pancreatic Cancer
This section consists of our version of “answers” to very general pre-selected questions about pancreatic cancer. The task is not easy, as there are controversies in virtually every aspect of the diagnosis and treatment of pancreatic cancer. Also, information regarding such treatment is in a constant state of flux, with the results of new studies often challenging assumptions about pancreatic cancer or pushing our understandings just a little further along. Additionally, general guidelines frequently do not apply to individual circumstances. Each person’s situation is unique. If a cookbook-approach could work well in these circumstances, doctors would not be needed. And make no mistake about it, in our view a strong bond with a compassionate and knowledgeable physician-specialist is mandatory in cancer of the pancreas.
Our brief answers are attempts to give a sense of overview to these very complicated subjects. There are whole books dedicated to many of these individual subjects in pancreatic cancer, so our answers are (at best) summaries. Because they are designed as summaries, it is possible that whole areas of controversy are inadvertently (or intentionally) ignored or not given proper weight. So be careful when reading these answers–all of the information given here needs to be checked out with your own doctor. And do not base any action or lack of action on these answers, they are meant for educational purposes only! Please read the disclaimer to this site.
We hope that these answers give a balanced sense of some of the underlying issues about pancreatic cancer so that patients can bring more to the table when speaking with members of their own health care team.
These answers were generally written with adenocarcinoma of the pancreas in mind, as this is the most frequently occurring malignant tumor of the pancreas. But there is one answer which briefly addresses various other types of pancreatic cancer, and another answer which specifically addresses neuroendocrine tumors, islet-cell tumors, and carcinoid tumors. Please send on any notice of mistakes, corrections or suggested additions.
WHAT IS PANCREATIC CANCER?
The pancreas is a small, spongy organ which lies just under the curvature of the stomach and deep within the abdomen. The function of the pancreas is a complicated, but one could say that it primarily does two things. It produces enzymes which are useful for the digestion of food AND it secretes hormones which, among other things, help maintain and regulate body sugar levels.
The pancreatic enzymes are produced in cells which are called acinar cells; this part of the pancreas is called the EXOCRINE part of the pancreas. The clumps of acinar cells are found gathered throughout the pancreas; these cells release salts and enzymes into small tributaries which collect and transport this pancreatic fluid. These small creeks eventually gather and coalesce into the river known as the pancreatic duct. This sixteenth-of-an inch wide duct runs from left-to-right along the length of the pancreas, eventually (usually) joining up with the bile duct and emptying its combined digestive contents into the first part of the small bowel (called the duodenum).
Additionally, the pancreas has an ENDOCRINE or hormonal function. For example, inside of specialized groupings of cells called the Islets of Langerhans, the pancreas produces hormones which are secreted directly into the blood stream. These hormones have numerous effects, and will be addressed in a simplistic fashion here. Insulin (produced by so-called beta cells) has effects, among which it lowers the level of glucose in the blood. Glucagon (produced by alpha cells) tends to increase the level of blood sugar. Other hormones, as well as various peptides, are produced by the endocrine pancreas–including also somatostatin, a hormone which inhibits the secretion of insulin.
Malignant cancer is a tumor (or growth) in which an aggregation of individual cells begins to grow in a rapid, uncontrolled and abnormal manner; and which may spread by aggressive local extension or by the seeding of other organs through blood vessel channels or via the lymphatic system. There also exist benign tumors which tend to be (but are not always) less serious, which tend to grow more slowly and orderly, and which tend not to spread by colonizing into other parts of the body (this process known as metastasis). Cancer can arise from virtually any kind of cell in the body.
In up to 95% of cases, pancreatic cancer arises from the exocrine portion of the organ. The least common exocrine pancreatic cancer comes from acinar cells. Most of the exocrine tumors (~90%) are from ductal cells–those which line the pancreatic ducts. These tumors are classified as carcinomas, a word that refers to tumors arising from a lining cell. Further, under the microscope, the appearance and arrangement of these carcinoma cells can appear as duct-like (or “adeno”) giving the term adenocarcinoma to this most common form of pancreatic cancer.
About three-quarters of exocrine pancreatic cancer arises in the head and neck of the pancreas (the anatomic parts through which the pancreatic duct runs just before it meets the duodenum). Some of these carcinomas arise in the body of the pancreatic organ, and less than ten percent arise in the tail of the pancreas (the tapering smaller “left” area, closest to the spleen).
It is now understood that cancer is caused by genetic mutations or other processes related to DNA which confer increased abnormal growth potential to cells. Genes in which this potential is directly conferred are called oncogenes. Other kinds of genes whose role includes that of preventing this phenomenon from happening are called tumor-suppressor genes. And finally there is a third kind of gene, called DNA-repair genes, the loss of function through mutation which may allow both activated oncogenes and thwarted tumor-suppressor genes to lead to cancer. It is generally believed that more than one mutation, modifying more than one regulatory pathway, is necessary for cancer to occur.
An oncogene called K-ras is found to be altered in up to 95% of ductal adenocarcinomas of the pancreas (what we usually refer to as pancreatic cancer. Common known tumor-suppressor genes which are inactivated by mutation in this kind of pancreatic cancer are the p53 and p16 genes. For example, p53 is inactivated in about 70% of adenocarcinoms of the pancreas. Still other genetic mutations have been found. This area of inquiry is currently a source of a great deal of interest and research, with an eye toward finding effective treatment or earlier diagnosis of pancreatic cancer.
It has been approximated that up to 30% of the changes which initiate cancer of the pancreas are caused by smoking; and that about 10% are secondary to hereditary genetic predisposition. There appears to be a mild correlation between the onset of diabetes and pancreatic cancer, but it is not entirely clear if this is fully a cause or perhaps an effect of the cancer. There does not appear to be a strong correlation between the onset of pancreatic cancer and the drinking of alcohol or of coffee (though these have been issues of some controversy).
Metastasis and endocrine tumors are two topics which are addressed in more detail in later questions. The most common sites of metastasis of pancreatic cancer (adenocarcinoma) are the liver, the peritoneum – which is the thin lining which contains many structures in the abdominal cavity, and the lungs. Cancers of the endocrine portion of the pancreas (neuroendocrine tumors) are less common than exocrine cancer of the pancreas – about two to three thousand cases are diagnosed each year in the U.S.. They are typically referred to as neuroendocrine tumors – or otherwise known as islet cell tumors. Carcinoid tumors are a typically slow growing type of neuroendocrine tumor. Although they arise from the hormone producing area of the organ, neuroendocrine tumors can be either functioning (demonstrating excess hormone secretion which produces symptoms) or non-functioning. Endocrine tumors have a different natural history than the exocrine tumors. As a whole, they tend to be slower growing and have a better prognosis than standard pancreatic cancer. The treatment of neuroendocrine tumors of the pancreas is distinct from that of adenocarcinoma of the pancreas.
This above description of tumor types is somewhat superficial as there really exists a large number of types of pancreatic cancer (many of these are very rare), some of which have shared characteristics and which may be very difficult to classify. The U.S. Armed Forces Institute of Pathology histological classification of pancreatic cancer outlines several kinds of malignant tumors of the exocrine pancreas (including “miscellaneous carcinomas”), further offering a number of sub-classifications of ductal adenocarcinoma alone and even sub-classifications of acinar cell carcinoma. They identify other forms of benign tumors and multiple “borderline” tumor types, described as having uncertain malignant potential. From this, one can perhaps get a better sense of the complexity of the subject.
The Toll of Pancreatic Cancer
Each year more than 50,000 people in the United States are diagnosed with adenocarcinoma of the pancreas and more than twice that in Europe. Most of these people will have passed away by the end of the first year. The incidence of pancreatic cancer increases with age; most people are between the ages of 60 to 80 when they receive the diagnosis. Men have tended to be over-represented, though in recent years the gap between men and women has shrunk, possibly due to increased cigarette smoking among women. In the U.S., pancreatic cancer is 9th or 10th most commonly diagnosed cancer (depending on gender), but the fourth leading cause of cancer death in men and women. The median survival period from the time of diagnosis until demise is arguably the worst of any of the cancers. The median survival for untreated advanced cancer of the pancreas is about 3 1/2 months; with good treatment this increases to about eight months, though many will live much longer.
James Abbruzzese, MD Chief, Medical Oncology Duke University
Markus Büchler, MD Chairman, Surgery Heidelberg University, Germany
Ralph Hruban, MD Director, GI / Liver Pathology Johns Hopkins University
Eileen O’Reilly, MD Associate Director for Clinical Research – Memorial Sloan-Kettering Cancer Center
Margaret Tempero, MD Chief, Medical Oncology University of California at San Francisco
You have likely found us either because you have pancreatic cancer, or care about someone who does.
Pancreatic cancer is a serious disease. Taking an aggressive rational stance at the earliest possible time, supported by the best medical team, and treated in the most appropriate manner gives the best chance for survival.
We believe in strong patient-physician bonds, scientifically-based treatment, and that comfort can come from knowing that everything that reasonably can be done – is being done.
That the best approach is meeting cancer of the pancreas head-on and armed with the best available information.
PANCREATIC CANCER STAGES
On the surface this would seem to be a fairly straight forward question, but as there exists the controversy of competing stage nomenclatures in pancreatic cancer, it is not as simple as one might think. In fact, in the U. S., universal agreement on a standardized staging system does not exist. The fundamental problem is that the stages system for exocrine cancer of the pancreas as put forth by, for example, the American Joint Committee on Cancer (“AJCC”) is felt to be somewhat impractical by certain experts. This classification rests on knowing the status of the TNM (that is Tumor, lymph Nodes and distal Metastasis).
Under this classification (roughly) Stage I pancreatic cancer includes tumors which have not spread into certain proscribed sensitive areas and which have no involved regional nodes or distal metastasis. Stage II pancreatic cancer includes tumors which have spread into the duodenum, bile duct, or “peripancreatic” tissues AND which have no involved regional nodes or distal metastasis. Stage III pancreatic cancer includes tumors which may have OR may not have spread into these aforementioned areas and which have involved regional nodes, but which show no evidence of distal metastasis. Stage IVA pancreatic cancer includes tumors which have spread into the stomach, spleen, large bowel OR the adjacent large vessels AND which have involved regional nodes, but show no evidence of distal metastasis. And Stage IVB pancreatic cancer includes pancreatic tumors of any kind with node status of any kind AND with evidence of distal metastasis.
Leaving aside that fact that this stage classification may not completely comport with similar nomenclature for pancreatic cancer by the International Union Against Cancer (Union Internationale Contre le Cancer), in practice, though referred to, this classification is rarely used in its pure form as the stages do not fully match treatment options for pancreatic cancer or even patient prognosis, and very often the true lymph-node status cannot be fully determined without surgery (which most people with pancreatic cancer do NOT receive).
For doctors and patients then, staging is USUALLY based on sophisticated radiologic studies or ultrasound. And for these cases, a clinical/radiographic stage classification for pancreatic cancer has been proposed which attempts to more closely follow prognosis and clinical decision making in regard to the actual treatment options for pancreatic cancer. This three stage classification (potentially resectable, locally advanced and advanced) of pancreatic cancer involvement, is based on radiological findings, and is not directly referent to the TNM status.
In this proposed classification, potentially “resectable pancreatic cancer” stage (or Local) is defined roughly as that including no evidence of extra-pancreatic involvement of the tumor, demonstration of fully patent superior mesenteric / portal veins and showing no evidence of encroachment (“encasement”) by the tumor on the arterial celiac axis or the superior mesenteric artery. The “locally advanced pancreatic cancer” stage is that which demonstrates evidence of arterial encroachment (celiac axis or superior mesenteric artery) or venous occlusion (superior mesenteric / portal veins). And the advanced “pancreatic cancer stage” includes evidence of metastatic spread (typically to the liver, peritoneum or lungs).
There are other terms in use and still other stage classifications. Of course, this makes for a messy kind of communication, although in practice oncologists seem to be able to speak with one another without apparent misunderstanding. It is possible and even likely perhaps, over time, assuming the great strides in the sophistication and power of radiographic techniques continue to move forward, the future will further free these staging classifications of pancreatic cancer from their strictly surgical origins and enable a more uniformly agreed upon stage nomenclature.
PANCREATIC CANCER DIAGNOSIS
Signs and Symptoms
Generally, the diagnosis of early pancreatic cancer is very difficult. The most common symptoms of cancer of the pancreas include loss-of-appetite, weight loss, abdominal discomfort and nausea. As these are all fairly non-specific symptoms, there is often delay in getting to the final diagnosis. The most common physical sign of pancreatic cancer is jaundice, with or without associated itching. Proceeding to a medical evaluation often requires a high index of suspicion by the patient or by medical personnel who are experienced with the presentation of early pancreatic cancer.
Often lab results in pancreatic cancer show a high bilirubin (yellowish bile pigment found in the serum) and elevated liver function enzymes. The CA 19-9 marker, a Lewis blood group-related mucin, is frequently elevated in pancreatic cancer, but its use as a sole agent in the screening for or diagnosis of cancer of the pancreas is not presently a fully accepted practice. High CA 19-9 levels may tend to be associated with (but do not always indicate) larger sized tumors and with a decreased likelihood of surgical resectability. The use of this marker is more universally accepted as a running measure within a particular individual (after diagnosis), to help reflect the stability, response, or progression of pancreatic cancer to treatment.
The main reason for the diagnostic staging of pancreatic cancer is to try to chart the best course for treatment, especially to help decide whether a patient is a candidate for surgical resection. There is a great deal of flux and controversy in these areas of diagnoses; there are institutional and even geographical variations in considered opinions as to the correct approaches in regard to these diagnosis / staging techniques. Also, there may be great variability in the experience level of the operators and evaluators of a given diagnostic procedure – thus (perhaps rightfully) coloring the institution’s approach at recommending which diagnostic studies are used. In the context of these understandings, the following brief overview will try and point out some strengths and weaknesses of certain of the current diagnosis staging procedures.
Generally, in the U.S., the dynamic spiral (or helical) CT scan with IV and oral contrast media enhancement is considered to be the procedure of choice for the diagnosis / staging of pancreatic cancer. With the latest equipment and with experienced operators and evaluators, this approach at diagnosis can detect up to 90-95% of cancer of the pancreas. Specific pancreatic cancer tumors that are greater than ½ to one inch in diameter can usually be detected. These CTs can predict unresectability about 90% of the time; but are less accurate at predicting surgical resectability. Its diagnostic strength in this regard is related to its ability to demonstrate pancreatic extension involving local arteries. This technique is less reliably able to show subtle local vein involvement, to detect or diagnose small liver metastasis or to pick up lymph node involvement in pancreatic cancer.
Transabdominal ultrasound is a more popular diagnostic procedure for pancreatic cancer outside of the U.S. where operators are more experienced and generally the patient-population may be less obese – a big problem in imaging structures through the abdomen. In experienced hands, with a thin patient and with good equipment, this ultrasound approach can often diagnose or detect smaller pancreatic cancer tumors than are even found by the CT procedure.
Two other ultrasound procedures are of note. The endoscopic ultrasound (ultrasound through a tube which is placed down the esophagus) can be very good at finding small tumors in the pancreas. And laparoscopic ultrasound (ultrasound through a small tube placed through the abdomen into the region of the pancreas) is sensitive at finding liver and peritoneal involvement in pancreatic cancer, without having to resort to full surgery.
Pre-operative angiography (viewing contrast dye placed in select arteries) is recommended by some surgeons for pancreatic cancer diagnosis and staging, although the introduction of spiral CT has provided a competing option.
CT or ultrasound-guided percutaneous biopsy (via needle) can retrieve a bit of pancreatic tumor tissue for histologic (microscopic) viewing without requiring full pancreatic cancer surgery. There exists some concern about the risk of inadvertent “seeding” of the tumor into the peritoneum with this technique, but some experts feel that the potential risks outweigh the potential harm in selected cases.
Often an institution will have a coordinated approach at the diagnosis and staging of pancreatic cancer. For example, a spiral CT procedure might be done first. If it appears that there is a pancreatic cancer tumor and that it might be resectable, the next step might be a diagnostic laparoscopy (for direct visualization) – with perhaps a peritoneal wash (to check for malignant pancreatic cancer cells in the peritoneum) and with or without a laparoscopic ultrasound exam. If evidence of unresectability is found, a percutaneous biopsy might be done, to fully establish the diagnosis of the type of pancreatic cancer and to help with medical treatment planning. If no evidence of unresectability is found, then a full abdominal surgery might typically ensue to further evaluate the clinical status with an aim of the diagnosis of pancreatic cancer – and if finally so indicated to proceed with the most appropriate surgical procedure.
PANCREATIC CANCER SURGICAL TREATMENT
Surgery for adenocarcinoma of the pancreas is only offered to patients whose tumor is localized and meets other criteria (please note earlier FAQ topics). Only about 15-20% of those individuals with pancreatic cancer will be found to be eligible for surgery. In these cases, surgical resection (removal) of the tumor from the pancreas (and resection of the pancreas and select surrounding tissues) gives the best chance for a cure and generally confers a better overall prognosis in contrast to medical therapy for pancreatic cancer. This is one reason why so much effort is given in pre-operative testing for pancreatic cancer to try to identify those patients who may be good candidates for surgery. Another reason for such care is to avoid offering unnecessary surgery to patients who are already ill.
At surgery, the first job of the surgeon is to assess the nature and extent of the pancreatic cancer – to verify if the patient is a true candidate for surgical resection. If the pancreatic cancer has advanced further than the pre-operative testing has indicated (which is not uncommon), then certain palliative surgical measures as noted below (aimed at symptomatic relief) may be offered, but the resection would typically NOT proceed.
The resection, known as the Whipple operation / procedure (or pancreaticoduodenectomy) is typically done for patients who have tumors which are located in the head of the pancreas or which are located in regions adjacent to the head of the pancreas. There are a number of variations of the Whipple procedure. The classic procedure, a modification of the surgery described by A.O. Whipple and his colleagues in 1935, is a fairly extensive and somewhat complicated two-step process whereby certain key structures in the surrounding vicinity are removed (including that portion of the involved pancreas), followed by a kind of surgical bypass-reconstruction, in effect re-routing the digestive tube around the affected area.
One of the fundamental questions among researchers and surgeons relates to the necessary scope and extent of the pancreaticoduodenectomy surgery. Which tissues should be resected (and what are the optimal amounts to be taken) in order to get the best chance of survival, as balanced against quality-of-life issues. This topic is controversial and there has been a see-sawing back and forth over time between advocates of more radical procedures and those who advocate less extensive surgery.
If the pancreatic tumor is located in the tail of the pancreas, often that portion of the pancreas will be removed along with the nearby spleen.
The Whipple surgery itself can take several hours and is often grueling for the surgical team. The region of the body where the pancreas lies is very busy and complicated anatomically. Not only is the normal anatomy complex, but individual anomalies are frequent among the various blood vessels and ducts in the area. However, one of the great successes in the treatment of pancreatic cancer has been the improvement in mortality related to the Whipple surgery. The mortality was extremely high even a couple of decades back, but this has dramatically improved. Now, operative mortality related to the Whipple procedure is variously reported as 2-3%, but in some major U.S. institutions the more recent operative mortality has been reported at less than 1%.
Nevertheless, recovery can be an ordeal for the patient. Serious complications following surgery are still effect up to one-third of patients. These include the development of fistulas (false channels), and leakage from the site of the bowel reconnection. The judicious placement of surgical drains may tend to reduce the incidence of these kinds of complications. The survival of patients who received the Whipple procedure in one study (from a very experienced Johns Hopkins team) were reported out in 1995 as a 21% five-year survival rate, with a median survival of 15.5 months.
If it is determined that the pancreatic cancer is too advanced to make surgical resection a viable option, then certain palliative procedures or surgery may be offered. These are typically targeted at the primary symptoms or causes of symptoms in pancreatic cancer: pain, small bowel obstruction and jaundice due to physical compression of the bile duct. Thus a nerve block of the celiac nerve plexus may be done (for pain), and/or a gastrojejunostomy (stomach bypass) surgery, and/or bile duct bypass surgery. Stents (inner wall supports) may be placed for certain of these procedures.
There are two principles that need to be introduced at this time. Adjuvant therapy is a concept that connotes the practice of giving medical and/or radiotherapy after surgery for pancreatic cancer to help augment the effects of surgery. And neoadjuvant therapy is the term that describes the practice of giving such treatment prior to surgery for potentially resectable (surgical removal) pancreatic cancer disease. For long while it has been fairly common practice in the U.S. to give chemoradiation (chemotherapy plus radiation) as adjuvant treatment after the Whipple procedure surgery for pancreatic cancer. This practice is based on the results of a 1985 landmark study which demonstrated an almost double survival advantage for those who received such therapy. The radiation aspect of this practice has challenged in recent times as offering no statistical survival advantage in pancreatic cancer. But this issue remains a controversy as some experts doubt the challenge.
The use of neoadjuvant therapy is an intriguing area of research in pancreatic cancer. According to some studies, chemoradiation may push back the pancreatic cancer enough to allow some patients (a minority) with apparent unresectable cancer of the pancreas who otherwise might not be candidates – to be eligible for surgery, and thus may offer some survival advantage to select patients.
PANCREATIC CANCER MEDICAL TREATMENT
There are no universally agreed upon firm guidelines for medical treatment for those patients with pancreatic cancer who are not candidates for surgery or who have a recurrence of the cancer after surgical resection. In part, this is because there is no one great treatment option – there are a number of medical treatment approaches for cancer of the pancreas which may be more or less appropriate, given certain variables. Also, medical treatment offerings in pancreatic cancer are often highly tailored to patient circumstance and wishes, which can be exceptionally individual.
In the discussion to follow, very broad medical standard treatment practices are outlined. The discussion does not touch upon general cancer therapy or the treatment of some of the more common symptoms of pancreatic cancer. Keep in mind while reviewing this information: there is no single exceptionally superior treatment; thoughtful and creative physician-guided therapeutic regimens may be appropriate; and clinical trials may offer options to standard practice.
A. Locally Advanced
Generally, in locally advanced unresectable pancreatic cancer, chemotherapy plus radiation is often prescribed as standard medical treatment. As early as 1981, a landmark report by the Gastrointestinal Tumor Study Group demonstrated significant survival advantage to those patients with locally unresectable adenocarcinoma of the pancreas who received both chemotherapy (5-FU) and radiation. This combination chemoradiation gave better medical outcomes for pancreatic cancer than either chemotherapy or radiation treatment alone.
There have been a wide range of studies involving the delivery mode, method and amount of radiation to the pancreatic cancer tumor area. These have included such approaches as external beam radiotherapy, intraoperative radiotherapy and the seeding of the actual tumor area with radioactive pellets or with radioactive colloidal solution (brachytherapy). 5-FU (sometimes with in combination with drugs which enhance its effect) has been perhaps the standard chemotherapy agent in many chemoradiation regimens, but the drug-agents mitomycin-C and cisplatin (a platinum-containing compound) are among the stable of chemotherapy agents which have also been utilized. Also, a number of studies have begun looking at the drug agent gemcitabine as an effective radiosensitizer for combination with radiation therapy in chemoradiation type medical treatment for locally advanced unresectable pancreatic cancer.
According to some studies, chemoradiation medical treatment may push back the cancer enough to allow some patients (a minority) with apparent locally unresectable pancreatic cancer who otherwise might not be candidates – to then be eligible for surgical resection.
The median survival duration from diagnosis with chemotherapy medical treatment in unresectable locally advanced cancer of the pancreas has been reported as 6-12 months.
As the pancreatic cancer becomes widespread, although there may be creative modalities by way of exception, the advantages of radiation (more of a field range) are increasingly diminished. Thus, standard medical treatment for advanced cancer of the pancreas typically involves chemotherapy type agents alone.
The chemotherapy agent 5-FU (fluorouracil) which has been in use as medical treatment against pancreatic cancer for more than 40 years, acts in several ways, but principally as a thymidylate synthase inhibitor, interrupting the action of an enzyme which is a critical factor in the synthesis of pyrimidine – a building block which is important in DNA replication. The underlying principle in many standard treatment agents has to do with interfering with the normal progression of the cell cycle. As cancer is caused by uncontrolled cell growth, one if its central weaknesses due to this rapid almost chaotic growth is inherent genetic instability. If a medical treatment agent hurts the ability of the cell to progress through its normal replication cycle, although this will tend to hurt ALL of the cells in the body, its effect will be selectively severe on unstable and rapidly growing cells – the cancer itself.
Gemcitabine is an approved medical treatment agent which tends to offer increased median survival duration (and increased one year survival rates) for pancreatic cancer as compared to 5-FU alone. It also appears in individual cases to confer improved quality-of-life measures over medical treatment with 5-FU and even over no medical treatment at all. Additionally, the targeted therapy Tarceva has been approved in the U.S. for the medical treatment of pancreatic cancer, although the minimal survival benefit has led to highly common usage. More recently, treatment for pancreatic cancer with four and five drug regimens that include 5-FU have shown themselves to offer comparable and perhaps even slightly superior results in comparison to gemcitabine alone, although side-effects may be limiting. A key example of this is the regimen known as FOLFIRINOX that includes leucovorin, fluorouracil (5-FU), irinotecan, and oxaliplatin. For use in advanced pancreatic cancer, the Phase III results of the FOLFIRINOX drug regimen were adjudged somewhat superior to gemcitabine alone as presented per a 2011 study in the New England Journal of Medicine.
There appear to be interesting and potentially promising combinations of several two or more conventional medical treatment drug agents (including gemcitabine) which are in practice and under study for the treatment of advanced pancreatic cancer. This includes combinations involving more conventional standard medical treatment drugs paired with some of the newer experimental more targeted agents. In 2013, gemcitabine plus Abraxane was found to be superior to gemcitabine alone in patients with metastatic pancreatic cancer. Subsequently, this regimen was approved by the U.S. Food and Drug Administration.
Additionally, there is a wide range of single-mode medical treatment approaches currently in clinical trials against pancreatic cancer (please note the FAQ on clinical trials). These include some of the newer experimental therapies which are aimed more at molecular targets and at interrupting genetic signaling pathways, newer chemotherapy drug agents, and even vaccines against pancreatic cancer.
In summary, in advanced pancreatic cancer, medical therapy is better than no therapy. Creative, intelligently-crafted and individualized medical treatment regimens as tailored by compassionate and thoughtful oncologists involving single agents or combination therapy for pancreatic cancer may be appropriate. And finally, clinical trials remain an option.
ALTERNATIVE, COMPLEMENTARY AND HOLISTIC TREATMENT
Although we understand the possible benefits of some alternative, complementary, or holistic treatment, this website is not strongly oriented this way. On an anecdotal basis, we have heard of positive experiences that patients have had with the treatment of symptoms related to pancreatic cancer (and chemotherapy) involving such approaches as visualization techniques, meditation, prayer, acupuncture, massage, biofeedback, relaxation therapy, hypnotherapy acupuncture, green tea and Chinese herbs.
We are not adverse to alternative, complementary, or holistic treatment modalities in which the downside risks are minimal (or better yet, nonexistent) and which do not appear likely to interfere with other more conventional medical therapies. For example, we strongly believe that faith and hope are the two most powerful allies at ones disposal.
The overriding concern of this website is the ancient admonition to physicians, “First do no harm.” This site is oriented to the scientific method and to scientifically-based treatment. If you have to take risks, our thought is at least do it under medical and scientific guidance. Nonetheless, we know that there are a large number of people who will not subscribe to this approach. To those people we would encourage thoughtful and cautious approaches to the more gentle of the alternative, complementary, and/or holistic treatments. And we would advise being careful.
With that warning, we note that there are sometimes clinic trials against pancreatic cancer involving unconventional alternative therapies. There are a number of researchers who are in support of these trials. Some perhaps because they think they will succeed. Others, who strongly feel that applying the scientific method to these kind of treatments will expose their weaknesses. The cutting edge of science and medicine is an odd place where today’s truth is replaced by new unexpected findings. Only time can tell us what the outcome of these studies will finally demonstrate. We would advise being careful.
There are many sites on the Internet about alternative, complementary, or holistic treatment practices. In our attempt to suggest tempering faith and hope with rationality and care, we would advise being careful.
NEUROENDOCRINE, ISLET-CELL AND CARCINOID TUMORS
Neuroendocrine tumors of the pancreas (islet cell tumors) are much less common than tumors arising from the exocrine pancreas. Reports often indicate that there are about two to three thousand cases diagnosed in the U.S. each year – although autopsy indicates that there may be a higher incidence of these islet cell tumors than are diagnosed.
The general term used tends to be “neuroendocrine” as these tumors may arise IN or ASSOCIATED WITH the hormone producing areas of the very complicated organ which is the pancreas. This hormone producing area is termed endocrine, and the other main area which tends to produce pancreatic “juice” that makes its way to the intestine to aid in digestion is called the exocrine pancreas. These different areas of the pancreas are somewhat jumbled up together anatomically – so rather than being like neighbors, the endocrine and exocrine areas of the pancreas are more like ethnicities all living together in the city known as the pancreas. The term “islet cell tumor” is another word for neuroendocrine tumor.
About 75% of neuroendocrine tumors are “functioning.” That is they are found to be producing symptoms related to one or more of the hormone peptides that they secrete. About one quarter of islet cell tumors do not produce symptoms related to hormone secretion and thus are termed non-functioning. The predominant hormone peptide being secreted gives the functioning islet cell tumor its name. There are a surprising number of these hormonal peptides that islet cell tumors have been found to secrete; some are not even related to the pancreas. This array includes insulin, gastrin, glucagon, somatostatin, neurotensin, pancreatic polypeptide (“PP”), vasoactive intestinal peptide (“VIP”), growth hormone releasing factor (“GRF”), ACTH and others. Some of these are very rare.
Apart from producing no currently discernible hormone peptide, non-functioning tumors may include those which produce PP (“PPomas”) or neurotensin (“neurotensinomas”), as these hormones usually produce no symptoms. The most common functioning pancreatic endocrine tumors are insulinomas followed by gastrinomas, glucagonomas and VIPomas, respectively. Typically, the symptoms produced by the excess secretion of the predominant hormone in a given functioning endocrine tumor, drives the eventual diagnosis.
With the exception of insulinomas, most of the islet cell tumors have fairly similar characteristics, belying the apparent differences caused by the large range of symptom effects related to the secretion of such different hormones. Histologically (under the microscope) they tend to be quite similar. It is not possible to ascertain malignancy from the histological appearance; malignancy is seen primarily as a function of finding additional metastatic sites. Except for insulinomas, very roughly about 60% of islet cell tumors are malignant. This rate contrasts with about 10% of insulinomas which are eventually found to be malignant. The sites of metastasis of islet cell tumors most commonly are the liver and the lymph nodes in the vicinity of the pancreas.
Insulinomas are islet cell tumors which secrete an excess of (predominantly) insulin. These tumors will typically first present symptoms between the ages of 40 and 50, are more common among women and tend to be small, solitary tumors located in the pancreas itself. The clinical features of this tumor are related to the effects of insulin-and thus primarily demonstrate symptoms related to hypoglycemia which are relieved by food intake. Other general symptoms include episodic sweating, tremor and rapid heart rate, as well as hunger, nausea, weight gain, and sometimes even central nervous system symptoms (including rarely, seizures).
Gastrinomas over-secrete the hormone gastrin. The clinical effect of this circumstance is what has come to be called the Zollinger-Ellison syndrome, a triad of signs and symptoms including atypical peptic ulcer disease, gastric hyperacidity and hyper-secretion, and an associated islet cell pancreatic tumor. About 2% of patients with non-healing peptic ulcers (after receiving an appropriate therapy regimen) are found to have Z-E syndrome with its attendant tumor. Most patients are male (~60%) and the average age at diagnosis is about 60 years.
Patients with glucagonomas tend to present with mild diabetes and a severe dermatitis. These tumors are frequently fairly large by the time of diagnosis, sometimes greater than two inches in diameter. Approximately 70% of these tumors are malignant. About 80% of VIPomas are located in the pancreas itself-the rest elsewhere. Over-secretion of this vasoactive intestinal peptide causes watery diarrhea, and low serum potassium and chloride levels. Only about 200 cases of this kind of tumor have been described in the medical literature; the majority are malignant by the time of diagnosis.
Carcinoid cancer is the most common of the neuroendocrine tumors, with one-and-a-half diagnosed cases per 100,000 of population, although anatomy at autopsy demonstrates about 400 times those that are diagnosed clinically. They tend to be slow growing. The symptoms and signs of carcinoid tumors range widely, and depend on the location and size of the tumor, on the presence of metastases, and secretions. They can appear to the surgeon as firm nodules bulging into the intestinal lumen (can originate from pancreas, lungs, thymus, appendix, and ovaries, etc.), with possible local expansion, and possible metastases to mesenteric lymph nodes, liver, ovaries, peritoneum, testes, prostate, spleen and other anatomic locations. Carcinoid tumors can secrete any number of hormonal, growth and other factors. Symptoms related to the tumor and its factors may be intermittent and vague, but the most common presentation is periodic abdominal pain sometimes accompanied by malignant carcinoid syndrome, characterized by flushing of the face, severe diarrhea, and an asthma episode. The initial evaluation of patients often includes measurement of such factors as serotonin, 5-HT, catecholamines and histamine, and especially urinary 5-HIAA levels. In general, survival rates for patients with carcinoid cancers are related to the size of the primary tumor – and the degree of metastasis.
The natural history of islet cell and carcinoid tumors tends to be favorable as compared with pancreatic adenocarcinoma. For example, the median survival duration from the time of diagnosis for patients with non-functioning metastatic islet cell tumors approaches five years. The diagnosis of islet cell tumors is aided by the different abnormal biochemical profiles that they may present, which often leads to radiographic means to try and locate the tumor. It would be a mistake to generalize too much about attempts to locate these tumors. But generally, dynamic CT scans with radio-contrast dye, octreotide scintigraphy, transabdominal ultrasound, and selective visceral angiography are all methods employed to elicit radiographic information about the cancer, depending on individual circumstance.
Although they arise from similar cells, these different types of neuroendocrine cancers all behave somewhat differently. The standard treatments tend to be tumor-type specific, but some general observations can be made. Immediate treatment of the symptomatic conditions created by the over-secretion of the hormone(s) may be appropriate. (For example, the use of H2-blockers, omeprazole and even octreotide in gastrinomas). The treatment of choice for localized islet cell tumors is generally curative surgery. The treatment of metastatic islet cell cancer disease, depending on the tumor type, will often include chemotherapy involving such agents as streptozocin, everolimus, sunitinib, temozolomide, capecitabine, 5-FU, doxorubicin, dacarbazine and octreotide. Recently, there have been published in the medical literature promising studies of aggressive surgery benefiting select cases of metastatic neuroendocrine tumors.
Apparently isolated liver metastases have been treated with such creative approaches as hepatic artery embolization. This may reduce the nutrient blood supply to the metastatic liver tumor (which tend to be rather vascular), but this approach remains controversial. It is difficult per the limits of today’s radiographic methods (and even via direct inspection at surgery) to fully appreciate the presence of small tumors in the liver-thus there well may be more metastases that have been undetected. Currently, there are studies employing techniques of radioimmunotherapy to selected patients with metastatic islet cell cancer, wherein radioactive elements have been conjugated together with specific compounds (sometimes hormonal elements) which are chosen for their properties that tend to selectively target islet cell tissue. These are very interesting early studies which hold the virtue of biologic plausibility, but the final results of the efficacy of this approach is not yet fully known.
Some percentage of islet cell tumors may be a part of several well-defined hereditary syndromes in which the tendency exists for the development of tumors in various (typically multiple) endocrine glands in the body, and which are known as the multiple endocrine neoplasia (or “MEN”) syndromes.
PANCREATIC CANCER CLINICAL TRIALS
Pancreatic cancer clinical trials are offered in many parts of the word. These studies seek to establish the validity of new and possibly improved treatment options.
Clinical trials are, ideally, a part of a system in which a series of scientifically-controlled experiments shepherd a plausible medical agent, combination of agents or procedure through a process whereby the efficacy of the medical agent or procedure is established or not. In the U.S. this process is overseen by the Food and Drug Administration (“FDA”).
Until more recently, when fast-tracking has become more possible, the process of taking a potential agent from the biochemical stage through clinical trials to final FDA approval could take as long as 15 years. This process begins long before human testing. Generally, moving the process into human testing is predicated on successful animal results. It is then that the three primary phases of human testing begins. A phase I clinical trial with human subjects seeks to answer questions about whether a drug-agent is reasonably safe for use by humans. It also may seek to learn something of the biokinetics of the drug. And finally tries to establish what the maximum tolerated dose of the drug is. These are the only real aims of a phase I clinical trial, although researchers will, of course, be looking for subtle indications that the drug may show future promise.
Some fraction of phase I clinical trials will move on to the phase II, which seeks to answer the question as to whether the drug has, in fact, an apparent effect against the cancer in question (in our case pancreatic cancer). Many potential drug therapies go no further than phase II – as they show no real effect against pancreatic cancer. Successful phase II candidates move on to phase III clinical trials which seek to determine how the new therapy compares to existing standard therapies. Phase III clinical trials are the core measure of a potential new drug. Phase III clinical trials are controlled experiments whereby patients with similar characteristics are assigned to receive either the existing therapy or to receive the new therapy. After a time, the results of the arms of test are then compared. If the new agent shows similar or improved results as compared to existing therapy, (after another step or two) it is often approved for release by the FDA. There is even a phase IV to this process which has to do with after-approval monitoring of the new drug for side-effects, etc. as it makes its way into wider use.
The decision to participate in a clinical trial for pancreatic cancer is a big one and should not be taken lightly. At its very heart a clinical trial is an experiment. Consequently, clinical trials contain inherent risk-both active risks and passive risks. An example of an active risk might be encountering an unexpected side-effect of the drug. An example of a passive risk might include the clinical trial protocol which may call for being off all standard medical treatment for 28 days (which is not uncommon) before beginning the clinical trial. More many diseases, this may not patter much. But with pancreatic cancer, this kind of a rule may matter a great deal.
On the other hand, the prognosis of certain stages of pancreatic cancer may not be great. Some of the emerging treatments may appear to hold more promise than existing ones. Approaching the possibility of participating in a clinical trial in a carefully reasoned, intelligent manner, depending on circumstance, may be a smart personal decision.
There are many issues to consider. Am I a good candidate for a clinical trial? What emerging drug or combination of drugs looks to be promising? Is the clinical trial really (realistically) more promising than existing therapy? Which phase of clinical trial am I comfortable participating in? Which institution is hosting the clinical trial? What is their reputation? What is their location relative to mine? Which physicians will be involved? What support do I have?
And there are other issues – many of them. Probably more than you can come up with on your own. This is when a strong bond with your personal physician can be of great service to you. Be sure to ask for aid and guidance from your physician (and other health professionals) in helping sort through these kinds of complicated decisions regarding pancreatic cancer clinical trials.
PANCREATIC CANCER TROUBLING SIGNS AND SYMPTOMS
The fear of pain is the leading concern of most patients with advanced pancreatic cancer. Often a vague mid-abdominal pain is one of the first symptoms of pancreatic cancer. There is no fixed pattern, but often, over time, the pain of pancreatic cancer may move or radiate more through the abdomen to the back area. Inadequately treated pain can have profound negative effects on the psychosocial and even physical well-being of pancreatic cancer patients, and may subject patients to unnecessary anxiety and even depression. On the positive side, there have never been more options for good pain relief, and in the vast majority of patients excellent pain control can be maintained by cooperative efforts with the help of an enlightened health-care team.
Since the publication of the World Health Organization’s suggested three-step analgesic “ladder” for pain control in 1986, pain is often classified as mild, moderate or severe. Mild pain is generally treated with a non-opioid analgesic agent (one which is not an opium-derived or opium-like narcotic) such as a non-steroidal anti-inflammatory drug like ibuprofen (Motrin). Moderate pain is treated with a “weak” opioid such as codeine with or without a non-opioid analgesic and with or without another adjuvant agent (such as an anti-anxiety drug). And severe pain is treated with a strong opioid such as morphine with or without a non-opioid analgesic and with or without another adjuvant agent (such as an anti-anxiety drug).
Examples of strong opioids include fentanyl, hydromorphone (Dilaudid), oxymorphone, meperidine (Demerol), methadone, and morphine. In addition to selecting the optimal agent(s), there are routes of administration to be considered. 70-90% of pain can be controlled by oral opioids. Other routes, for example, include those of injection (intravenous, subcutaneous or intramuscular), skin patches, rectal suppositories and pump-delivered (continuous or on-demand). The aim is to find an optimal agent(s) to be given at the optimal dose and via the optimal route of administration. The current concept among pain specialists is that the cancer patient should have around-the-clock pain relief. In addition, provisions are made to administer a fast-acting agent should the occasion occur of any “break-through” pain.
A specific palliative step in pancreatic cancer may include a nerve block of the celiac nerve plexus (located in the back/abdomen area where many patients feel pain with pancreatic cancer) via injection with alcohol or other agent. There are other possible interventions including subarachnoid or epidural blocks (both in the spinal space); and even further interventional and surgical measures which are available.
Alternative or non-invasive methods on the part of patients themselves exist, which may invoke mind-body control, including those of acupuncture, massage, biofeedback, relaxation, visualization techniques, hypnotherapy and others.
A thoughtful, integrated approach toward pain will result in very good pain control for almost all patients with pancreatic cancer.
B. Gastrointestinal symptoms
As the pancreas is an integral part of the digestive system, it would stand to reason that gastrointestinal symptoms would figure prominently in pancreatic cancer.
Nausea and vomiting may be a problem in up to 40% of pancreatic cancer patients. The cause of these symptoms are varied-and can range from, for example, a reaction to chemotherapy or radiotherapy – to being a sign of mechanical obstruction of the small bowel. Consequently, the reason for the nausea and vomiting (sometimes referred to as “emesis”) needs to be sought out–and the underlying cause dealt with appropriately. In addition, anti-emetic agents may be prescribed. High-activity anti-emetic agents work as an antagonists to type-3 serotonin receptors and include such drugs as granisetron (Kytril) and ondansetron (Zofran). The anti-emetic activity of metoclopramide (Reglan) is now thought to be as both a serotonin and dopamine antagonist. Corticosteroids (such as dexamethasone) are also potent anti-emetics and may be used selectively in combination with serotonin antagonists to good effect. Older agents with generally lower anti-emetic activity, including the phenothiazines (such as phenergan or compazine), butyrophenones (such as Haldol) and the cannabinoids (such as Marinol) and others may have their place in selected circumstances. The action of each of these agents is somewhat different, and they each have side-effects which must be considered.
Constipation is a frequent complication of opioid therapy, and its prevention should begin at the onset of opioid therapy. Other causes of constipation in pancreatic cancer patients may include such elements as a low fiber diet, diminished fluid intake, diminished physical activity and postural effects from bed rest. More serious causes may include various metabolic abnormalities and even bowel obstruction. The treatment is various, but should include evaluating and correcting any underlying problems, insuring adequate fluid intake, increasing physical activity if possible, giving laxative drug therapy where appropriate and providing enemas as needed. Laxatives include such agents, for example, as lactulose, Senokot, colace and dulcolax.
Indigestion, diarrhea and a change in bowel habits are not uncommon in pancreatic cancer. The causes can range from the more mundane to the serious – and may, for example, include laxative overuse, malabsorption, anxiety or stress, infection, medication side-effect, radiation therapy, the effect of the cancer itself, surgery, pancreatic enzyme deficiency — and can even represent a sign of bowel obstruction. The treatment is individual, but should include evaluating and correcting any underlying problems. Food and fluid regulation are likely required. And anti-diarrheal medication may be indicated.
C. Nutrition and weight loss
Weight loss and muscle wasting (cachexia) are common and occur in over 90% of patients with pancreatic cancer. These phenomena, apart from physiological disadvantage which contribute to fatigue and weakness, often have a pronounced deleterious effect on such factors as a patient’s sense of well-being. Contributors include anorexia, nausea, other gastrointestinal symptoms, depression, the side-effects of chemotherapy, surgery, new dietary constraints, early satiety (sense of stomach fullness), medical procedures and perhaps most importantly the metabolic effects of the pancreatic cancer itself. Some patients are unable to tolerate a diet which is high in fat and protein, and in others the onset of diabetes may occur.
These factors may have significant consequences on patients and their caregivers as, in the midst of these matters, a diet which is both palatable and effective is implemented. The help of a nutritionist is useful, almost mandatory. Adequate calories are required, including an adequate balance of protein, fat and carbohydrates. Some nutritionists recommend sources of omega-3 fatty acids. Vitamins and minerals may need augmentation. Pancreatic enzymes may be prescribed. Adequate fluid intake is important. The diabetes, if present, will need to be controlled. High-calorie liquid dietary supplements are often required. Intelligent experimentation with such measures as more frequent, smaller food portions can be helpful. The U.S. National Cancer Institute has provided access to an online guide entitled Eating Hints for Cancer Patients.
The use of appetite stimulants such as megestrol (Megace) and (according to some experts) corticosteroids (such as dexamethasone), as well as cannabinoids may be helpful in select patients.
D. Symptoms secondary to bile duct obstruction
Because the pancreatic tumor mass of ductal adenocarcinoma most commonly arises from the head of the pancreas (and in areas adjacent to the head of the pancreas) which are the sections where the bile duct joins with the pancreatic duct, the normal flow of the bile duct is often obstructed, thus disrupting the natural deposition of the bile fluid (including its bile salts and pigments) into the small bowel. This bile duct obstruction causes a back-up of the bile pigment into areas where it shouldn’t normally go – creating the clinical symptoms of jaundice with its attendant yellowish skin coloration and other associated changes, and which is often accompanied by a loss of appetite (anorexia) and by the symptom of unrelenting and often debilitating pruritis (itching) of the skin.
Additionally, the lack of bile salts which are now unavailable for normal digestive and other bowel processes, can result in complex physiological interactions leading to liver and immune dysfunction. This interruption of normal bile deposition may also disrupt the absorption of fat-soluble vitamins and the conjugation of endotoxins, thus leading to possible blood coagulation difficulties, malabsorption syndromes and even kidney failure. Also, up to ten percent of affected patients may develop cholangitis (an inflammatory condition of the biliary tree with often very serious consequences).
The treatment for this bile duct obstruction is some form of biliary bypass procedure. The majority of patients who receive such a procedure will experience relief of anorexia and jaundice, and will tend to live longer – in a more comfortable fashion. This bypass procedure is done via surgery and/or with the application of stents (inner wall prosthetic supports). The biliary stent prosthesis, in selected circumstances, may be placed via endoscopic route, without the necessity of resorting to full surgery. There are controversies in this area of treatment which are not yet resolved, none of these treatment options is without complication and it all is highly dependent on the individual situation. But progress has been made and options continue to improve, to the benefit of affected pancreatic cancer patients.
E. Ascites (increased abdominal fluid)
In some pancreatic cancer patients, there can be a troubling large collection of fluid in the abdominal cavity itself, which increases abdominal girth. This is called ascites (pronounced: as-site-ees), sometimes referred to as malignant ascites. The true cause of this fluid build-up is not fully understood, and may vary from person to person – but it is presumably often due in part to factors related to the existence of lymphatic or peritoneal metastases.
Some physicians will prescribe diuretic medication which may work well in select patients, but which also can give mixed results. Additionally, another approach is to offer patients with ascites an abdominal tap (or paracentesis), in which a special needle is inserted directly into the abdominal cavity and the fluid is drawn off. There are some risks to this procedure including the possible introduction of infection into the abdomen, but generally this procedure is surprising well-tolerated. Unfortunately – often – with progression over time, this abdominal tap procedure may need to be increasingly repeated. There do exist a number of very clever surgical shunting procedures which in select circumstances are employed, whereby through changes made to anatomic “plumbing,” the ascites fluid is internally re-routed back into the body’s own vascular system.
Fatigue can be an early symptom of pancreatic cancer, manifesting even before the diagnosis is made. Sooner or later, the majority of pancreatic cancer patients indicate fatigue as a significant symptom. Typically described as a loss of customary energy levels and even as effecting mental processes, the fatigue of pancreatic cancer can be debilitating.
The range of causes of fatigue under these circumstances is very large and can include such factors as the pancreatic cancer itself, sleeplessness (possibly due to pain or for other reasons), anemia, chemotherapy side-effect, anxiety or depression, medication side-effect (including pain medication), infection, electrolyte disturbance, or dehydration.
The treatment of fatigue is first directed at trying to eliminate any correctable medical or psychological underlying cause. This may include the adjustment of medications. Attention might be given to those factors which help promote adequate and restorative sleep. Short-term pharmaceutical aids to sleep may be prescribed. Hypnotic drugs such as Ambien (zolpidem tartrate) and Sonata (zaleplon) are sometimes used for these purposes.
Underlying psychological matters should be addressed. If possible, where appropriate, patients are encouraged to remain physically active, but not to overstep reasonable activity bounds. Some physicians will prescribe psychostimulant drugs in selected instances. But generally, the primary approach remains to take the symptom of fatigue seriously and to try to identify and remove specific underlying causes.
PANCREATIC CANCER SCREENING TESTS AND MARKERS
Presently, there is no agreed upon screening test to aid in the identification or earlier diagnosis of pancreatic cancer for the general population. There is the beginning of the establishment of protocols involving periodic testing procedures at certain academic institutions to follow persons at high risk for pancreatic cancer, but these measures have not been well studied yet.
The best known of the blood markers for pancreatic cancer is CA19-9, a “carbohydrate associated antigen” also known as a sialylated Lewis (a) antigen. This marker is somewhat uneven in the diagnosis of pancreatic cancer, but can be quite elevated in those with pancreatic cancer.
Approximately 10% of Caucasians lack the Lewis antigen, so in them the CA19-9 is not expressed. Currently, some oncologists appear to feel that the best use of the CA19-9 marker is as a guide to follow the disease and treatment process in a given individual patient.
There are mutations in specific DNA genes that are found commonly in pancreatic cancer. Some of these well-known genes are K-ras, p53 and p16. Because of the development of genetic micro-array tools (that allow for a huge number of tests all at once), in the past decade there has been a remarkable increase in research looking for genetic fingerprints to aid in the screening for and earlier diagnosis of pancreatic cancer. And although there has been a big increase in knowledge about DNA mutations and specific genes involved in pancreatic cancer, thus far this has not translated (yet) into screening tests or a diagnostic marker for pancreatic cancer. However, it remains an area of great interest.
A related area is represented by the many proteins that emanate from genetic instruction. The whole of this array of proteins is called the proteome. There has been considerable research in this area to try to detect reliable protein patterns in pancreatic cancer that will allow for screening or earlier diagnosis. Thus far, much has been learned but no universally recognized markers have been established through the study of protein patterns.
Many other agents have been studied as screening and diagnostic markers without much success. Some of these include cell surface associated mucins (MUC), carcinoembryonic antigen (CEA), and heat shock proteins (HSP).
Apart from the genome and proteome, another area of great recent research interest in screening and diagnostic markers for pancreatic cancer has been in that of MicroRNAs. First characterized in the 1990s, MiRNAs are small (22 nucleotide) non-coding RNA molecules involved in genetic regulation. There have been many recent intriguing study results looking at patterns of various MiRNA types in pancreatic cancer.
Researchers have looked at many tissues and access points to study these potential markers including in stool, pancreatic juice, saliva and blood.
The amount of research into the area of finding a means of screening for or providing for the earlier diagnosis of pancreatic cancer has increased dramatically in the past decade. It is a promising arena, as finding pancreatic cancer earlier would likely enable many more patients to avail themselves of surgery, for example. Much more is known than in the past. And is seems likely that this big knowledge will eventually lead to practical results. But despite gains we are not there yet.
PANCREATIC CANCER PROGNOSIS
Each year more than 50,000 people in the United States (and double this number in Europe) are now diagnosed with pancreatic cancer (adenocarcinoma). The prognosis is such that most of these people will have passed by the end of the first year. In the U.S., pancreatic cancer is 9th or 10th most commonly diagnosed cancer (depending on gender), but the fourth leading cause of cancer death in men and women.
The prognosis of pancreatic cancer (adenocarcinoma of the pancreas) is a very tough, though the survival rates have been incrementally improving particularly over the past ten to fifteen years. It is important to realize that each person is individual; each cancer is different. Statistics can only indicate what tends to happen in the aggregate, and not in the case of an individual person.
The median survival duration from the time of diagnosis until demise is arguably the worst of any of the cancers – certainly of the major cancers. The median survival for untreated advanced pancreatic cancer is about 3 1/2 months; with good treatment this increases to about eight months, though many will live much longer. We have encountered eleven and twelve year survivors.
Perhaps it is a good place to discuss what the term median means. Simply put, the median is the time point that separates half of patients who live longer from the half who will live less. Thus, there are many patients who will live much longer than the median.
The American Cancer Society prognosis figures show that the stage at which pancreatic cancer is diagnosed is strongly correlated to survival; earlier obviously being better. But, the statistics are still pretty tough. The five year survival rate with good treatment is now considered to be about 8%. Again, it is imperative to understand that each person’s situation individual; each cancer is different. Statistics can only indicate what tends to happen in the aggregate, and not in the case of an individual person. Many people do better than average.
The prognosis for those who are able to have surgery is improved over those who are not able. Unfortunately, only about 15% of those individuals with pancreatic cancer will be found to be eligible for surgery – for most, the cancer will have been found to be too advanced. For example, patients with pancreatic cancer who received the Whipple surgical procedure in one study (from a very experienced Johns Hopkins team) were reported as having a 21% five-year survival rate, with a median survival of 15.5 months. In more recent studies this five-year median survival duration after surgery has been reported as high as twenty months.
The prognosis is also better for those whose pancreatic cancer is diagnosed at an earlier stage. The median survival duration from diagnosis with chemotherapy medical treatment in locally advanced cancer of the pancreas has been reported as 6 to 12 months.
Patients with neuroendocrine tumors tend to have a much more favorable prognosis than, for example, those with adenocarcinoma of the pancreas. The natural history of neuroendocrine tumors, islet cell tumors, and carcinoid tumors tends to be very different than that of pancreatic adenocarcinoma. For example, the median survival duration from the time of diagnosis for patients with non-functioning metastatic islet cell tumors approaches five years.
PANCREATIC CANCER RISK FACTORS
A risk factor is a variable that may tend to increase an individual’s risk of acquiring pancreatic cancer. Who we are and what we do has some effect on the diseases that we may contract. In this process, pancreatic cancer is no different from other diseases; although there is still a great deal that we do not understand about the cause and effect of risk factors to pancreatic cancer.
Having many risk factors does not necessarily mean that one will contract pancreatic cancer. And in many individuals, there is no fully understood reason why they may have acquired the disease. It is important to understand the limitation of this central idea of risk factors – they are perhaps useful but not definitive.
The incidence of pancreatic cancer increases with age; most people are between the ages of 60 to 80 when they receive the diagnosis. The median age at the diagnosis of pancreatic cancer is between 70 and 71 years old. Men tended to be over-represented, though in recent years the gap between men and women has shrunk, possibly due to increased cigarette smoking among women.
African Americans tend to be more likely to acquire cancer of the pancreas as compared to their Caucasian counterparts. The causes of this are not entirely clear, but may have to do with diet, smoking, diabetes rates, and obesity.
Cigarette smoking is a prominent risk factor. Between 20-30% of cases of pancreatic cancer are thought to be attributable to smoking. Other forms of tobacco use (including smokeless forms) can increase risk too. But it is also true that at about ten years after quitting smoking, the rate of pancreatic cancer moves about back to that of those who have never smoked.
Pancreatic cancer is more likely in those with diabetes, but the study results are a bit mixed. It is not entirely clear if diabetes is a cause or a result. This includes and may be especially true in those with type 2 diabetes. Similarly, those who are obese have an increased risk of acquiring pancreatic cancer, though some of this may be explained on the basis of the relationship between diabetes and obesity.
Certain published medical articles have associated diets rich in fat, with a high level of meat, and/or with processed meat to be linked to a higher rate of pancreatic cancer. Coffee is currently thought not to be a risk factor for pancreatic cancer. Moderate intake of alcohol appears relatively safe, but in recent studies the excessive and prolonged drinking of alcohol has been linked to an increased likelihood of pancreatic cancer.
Certain illnesses which may or may not appear to directly affect the pancreas appear to confer an increased possibility of contracting pancreatic cancer – and thus are risk factors. These include, for example, chronic pancreatitis, cirrhosis of the liver, peptic ulcer disease associated with the Helicobacter pylori (H. pylori) bacteria, and certain kinds of hepatitis.
Prolonged exposures to given metals, chemical and dyes may be risk factors for pancreatic cancer.
Pancreatic cancer can run in some families due to increased risk factors related to genetics. It is thought that having a genetic predisposition may be responsible for as much as 10% of pancreatic cancer.
Some of the genetic type syndromes or disease complexes that can dispose to a higher incidence of pancreatic cancer (adenocarcinoma) include familial mutations in the BRCA1 and BRCA2 genes, genetic melanoma, genetic chronic pancreatitis, genetic non-polyp colorectal tumor (Lynch syndrome), Peutz-Jeghers syndrome, and Von Hippel-Lindau syndrome.
Neuroendocrine tumors, islet cell tumors and carcinoid tumors can also, for example, be associated with hereditary predisposition tendency diseases such as neurofibromatosis, and with various “multiple endocrine neoplasia” (MEN) type syndromes.
Currently, only about 15% of those diagnosed with pancreatic cancer are eligible for potentially curative surgery. We need to find the disease earlier!
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HELP US SHINE A LIGHT ON PANCREATIC CANCER THIS NOVEMBER !
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