Confronting Pancreatic Cancer
Pancreatic Cancer Frequently Asked Questions
Last Reviewed: 2/2/09
Introduction to the FAQ
(answers to frequently asked questions)
This section consists of our version of "answers" to very general pre-selected questions about pancreatic cancer. This task is not easy, as there are controversies in virtually every aspect of its related diagnosis and treatment. Also, information regarding such treatment is in a constant state of flux, with the results of new studies often challenging assumptions 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.
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, 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 pancreas cancer so that patients can bring more to the table when speaking with members of their own health care team. These answers are generally about conventional approaches, and are primarily based on standard written bibliographic references. The main sources that we used for these purposes are listed below.
In addition, some of the answers contain hypertext links to other Internet sites. In supplying these links, we are not necessarily vouching for the accuracy of the information contained on these other linked sites. We are rather trying to round out the information a bit AND to give visitors a sense of what other related information exists on the Internet (and how and where other sites might be found for further self-directed research on the part of visitors).
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 (islet-cell) tumors. Please send any notice of mistakes, corrections or suggested additions (including other recommended questions) to us at email@example.com.
1. 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 rivlets eventually coalesce into 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.
A site which has detailed information about the matters as discussed in this answer is the NCI Booklet "What You Need To Know About Cancer of the Pancreas".
Malignant cancer is a tumor (or growth) in which an aggregation of individual cells begin 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 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 tumors of the pancreas arise 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 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 the mutations of a gene 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. 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.
It has been approximated that about 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 adenocarcinoma 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 adenocarcinoma are the liver, the peritoneum (the thin lining which contains many structure in the abdominal cavity) and the lungs. Cancers of the endocrine portion of the pancreas 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 (or islet-cell) tumors. 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. They tend to be slower growing and have a better prognosis. 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 exist a 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 30,000 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 ï¿½ months; with good treatment this increases to about six months. Perhaps in concluding, we might draw attention (in the midst of delivering this difficult news) to an interesting paper about one man's struggle to not be the median.
2. What are the Stages of Pancreatic Cancer?
On the surface this would seem to be a fairly straight forward question, but as there exists the controversy of competing nomenclatures, 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 staging 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 in the field. 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 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 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 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 includes pancreatic tumors of any kind with node status of any kind AND with evidence of distal metastasis.
Leaving aside that fact that this classification may not completely comport with similar nomenclature 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 or even patient prognosis, and very often the true lymph-node status cannot be fully determined without surgery (which most people do not receive).
For doctors and patients then, staging is based on sophisticated radiologic studies. And for these cases, a clinical/radiographic staging classification for pancreatic cancer has been proposed which attempts to more closely follow prognosis and clinical decision making in regard to treatment. This three stage classification (potentially resectable, locally advanced and metastatic), is based on radiological findings, and is not directly referent to the TNM status.
In this proposed classification, potentially resectable pancreatic cancer 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 ("encasment") by the tumor on the arterial celiac axis or the superior mesenteric artery. Locally advanced includes evidence of arterial encroachment (celiac axis or superior mesenteric artery) or venous occlusion (superior mesenteric / portal veins). And the metastatic stage includes evidence of metastatic spread (typically to the liver, peritoneum or lung).
There are other terms in use and still other 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 classifications from their strictly surgical origins and enable a more uniformly agreed upon staging nomenclature.
3. How is Pancreatic Cancer Diagnosed?
Signs and Symptoms
Generally, the most common symptoms of adenocarcinoma 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. Preceding to a medical evaluation often requires a high index of suspicion by the patient or by medical personnel.
Often lab results show a high bibirubin (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 adenocarcinoma of the pancreas, but its use in the screening for or diagnosis of the cancer is presently not an accepted practice. High CA 19-9 results 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, to help reflect the stability or the progression of the cancer.
The main reason for the 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; there are institutional and even geographical variations in considered opinions as to the correct approaches in regard to these staging techniques. Also, there may be great variability in the experience level of the operators and evaluators of a given procedure-thus (perhaps rightfully) coloring the institution's approach at recommending which 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 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 staging of pancreatic cancer. With the latest equipment and with experienced operators and evaluators, this approach can detect up to 90-95% of pancreatic ductal adenocarcinomas. Tumors greater than ï¿½ to one inch can usually be detected. These CTs can predict unresectability about 90% of the time; but are less accurate at predicting surgical resectabilty. Its 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 small liver metastasis or to pick up lymph node involvement.
Transabdominal ultrasound is a more popular procedure 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 pick up smaller 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, without having to resort to full surgery.
Pre-operative angiography (viewing contrast dye placed in select arteries) is recommended by some surgeons, 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 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 diagnosis and staging toward pancreatic cancer. For example, a spiral CT procedure might be done first. If it appears that there is a tumor and that it might be resectable, the next step might be a laparoscopy (for direct visualization)--with perhaps a peritoneal wash (to check for malignant 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 and to help with medical treatment planing. If no evidence of unresectability is found, then a full abdominal surgery might typically ensue to further evaluate the clinical status--and if finally so indicated to proceed with the most appropriate surgical procedure.
4. What is the surgical treatment of pancreatic cancer?
Surgery for adenocarcinoma of the pancreas is only offered to patients whose tumor is localized and meets other criteria (please note earlier FAQ answers). 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 select surrounding tissues) gives the best chance for a cure and generally confers a better overall prognosis in contrast to medical therapy. This is one reason why so much effort is given in pre-operative testing to try to identify those patients who may be good candidates for surgery. Another reason for such care is to avoid the offering of 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 cancer--to verify if the patient is a true candidate for resection. If the 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. General information on this procedure exists at the University of South Carolina website. And please note the extensive section on the Whipple procedure at the Beth Israel website. 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. The Johns Hopkins site has an illustrative site in this regard.
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 radical procedures.
If the pancreatic tumor is located in the tail of the pancreas, usually 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 cancer of the pancreas 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 affect 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 cancer is too advanced to make surgical resection a viable option, then certain palliative procedures may be offered. These are typically targeted at the primary symptoms or causes of symptoms in pancreatic cancer: pain, duodenal obstruction and jaundice due to obstruction of the bile duct. Thus a nerve block of the celiac nerve plexus may be done, and/or a gastrojejunostomy (stomach bypass) and/or a bile duct bypass. Stents (inner wall supports) may be used 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 radio therapy after surgery to help augment the effects of surgery. And neoadjuvant is the term that describes the practice of giving such therapy prior to surgery for potentially resectable pancreatic cancer disease. For the past fifteen years, it has been fairly common practice in the U.S. to give chemoradiation (chemotherapy-typically the chemotherapy drug 5-FU-plus radiation) as adjuvant treatment after the Whipple procedure. 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. This practice has recently been challenged (as offering no statistical survival advantage), but a number of experts in the field doubt the conclusions of this challenge and it is too early to know if the challenge will hold up to long-term scrutiny.
The use of neoadjuvant therapy is an area of research. According to some studies, chemoradiation may push back the cancer enough to allow some patients (a minority) with apparent unresectable adenocarcinoma of the pancreas who otherwise might not be candidates--to be eligible for surgical resection.
5. What is the medical treatment of pancreatic cancer?
There are no universally agreed upon firm guidelines for medical treatment for those patients with adenocarcinoma of the pancreas 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 treatment approaches which may be more or less appropriate, given certain variables. Also, therapy offerings are often tailored to patient circumstance and wishes--which are highly individual.
In the discussion to follow, very broad 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, as there is no single exceptionally superior treatment, thoughtful and creative physician-guided therapeutic regimens may be appropriate, and clinical trials may offer options to (or even act to augment) standard practice.
Generally, in locally advanced unresectable adenocarcinoma of the pancreas, chemotherapy plus radiation (in one form or another) is often prescribed as standard therapy. 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 had received both chemotherapy (5-FU) and radiation. This combination chemoradiation gave better outcomes than either chemotherapy or radiation alone.
There have been a wide range of studies involving the delivery mode, method and amount of radiation to the tumor area. These have included such approaches as external beam radiotherapy, intraoperative radiotherapy and the seeding of the 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 gemcitabine as an effective radiosensitizer for combination with radiation therapy in chemoradiation for locally advanced unresectable adenocarcinoma of the pancreas.
According to some studies, chemoradiation may push back the cancer enough to allow some patients (a minority) with apparent locally unresectable adenocarcinoma of the pancreas who otherwise might not be candidates--to be eligible for surgical resection.
The median survival duration from diagnosis with chemotherapy in unresectable locally advanced adenocarcinoma 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 are diminished. Thus, standard medical therapy for advanced adenocarcinoma of the pancreas typically involves chemotherapy-type agents alone.
The chemotherapy agent 5-FU (fluorouracil) which has been in use against cancer for about 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-which is important in DNA replication. The underlying principle in many standard chemotherapy agents has to do with interfering with the normal progression of the cell cycle. As cancer consists of uncontrolled cell growth, one if its weaknesses is inherent genetic instability. If an agent hurts the ability of the cell to progress through its normal cycle eventually to replicate itself, although this will tend to hurt all the cells in the body, its effect will be selectively severe on unstable and rapidly growing cells-the cancer itself.
Gemcitabine is a more recently approved chemotherapy drug which tends to offer a slightly increased median survival duration (and increased one year survival rates) as compared to 5-FU, and also appears confer substantially improved quality-of-life measures over treatment with 5-FU and over no treatment. Additionally, Tarceva has been approved in the U.S. for the treatment of pancreatic cancer. More information including data about side effects, gemcitabine, flourouracil and other cancer chemotherapy drugs is found at CancerSource.
There appear to be interesting and potentially promising combinations of two or more conventional chemotherapy agents in the same treatment regime which are in practice and under study, including combinations involving more conventional chemotherapy agents paired with some of the newer experimental agents.
Additionally, there is a wide range of single-mode 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 agents and even vaccines against pancreatic cancer.
In summary, in advanced adenocarcinoma of the pancreas, chemotherapy is better than no therapy. And gemcitabine, depending on circumstances, may confer advantages that 5-FU does not. Creative, intelligently-crafted and individualized treatment regimens as tailored by compassionate oncologists involving single agents or even combination therapy may be appropriate. And finally, clinical trials remain an option.
6. What are emerging therapies in regard to the treatment of pancreatic cancer?
The difficulty in discussing this topic is not because there are too few, but rather as there are so many creative experimental clinical trials which are occurring with newer agents and combinations against pancreatic cancer. However, it is important to note that many agents in that past have looked promising, only to show no advantage by the end of phase III clinical trials. These are experimental therapies, and can be highly risky.
In listing some of the categories and individual agents below, this is in no way meant or to be considered as an endorsement of that category of drug or mode-of-action (or of a particular drug agent). These examples are given for education and discussion purposes only. The categories are representative of some of these newer agents and this listing is not meant to be exhaustive.
As a better understanding is gained of the activity of the cell at the molecular level, more targeted approaches are being implemented to try and interrupt certain functions that are thought to play a role in cancer formation or of cancer support.
Some of these areas of interest include new combinations with accepted chemotherapy agents such as putting gemcitabine or 5-FU together with some of the newer agents (or with each other).
More recently discovered classes of chemotherapy drugs are in development such as those which inhibit topoisomerase, an enzyme which helps in cell replication. Also, platinum-containing compounds are in use and under study (often in combination with other agents) including such agents as cisplatin, carboplatin and oxaliplatin.
Trying to inhibiting angiogenesis (the tumor's ability to selectively redirect vascular nutrient channels to itself) has been another area of research. Agents such as Erbitux (and many other kinds of anti-angiogenesis compounds) have been under study against all solid tumors including cancer of the pancreas.
The inhibition of certain of the matrix metalloproteinase family of enzymes which have been found to be over-expressed in pancreatic cancer, has been explored, although the recent results of such drugs have been somewhat disappointing.
Several agents which are directed at inhibiting the signaling pathways which proceed from the ras oncogene have been studied. One group of these drugs is known as the farnesyl protein transferase inhibitors. Several of these have been under study.
More genetically directed approaches including anti-sense therapy and viral vectors which deliver specifically designed genetic material to tumor cells have been studied in clinical trials against pancreatic cancer.
There are a few vaccine trials against pancreatic cancer. These are all in early stages, but include one which marshals cellular factors in the body to enhance a boosted immune response against the tumor. And the clinical trials of anti-pancreatic cancer vaccines also include others which are directed more at certain antigens which tend to be over-expressed in all (or in select) pancreatic tumors-such antigens (or targets) as CEA, MUC-1, COX-2 and the ras pathway.
Also, there are a number of studies which are looking at more surgical oriented issues, especially at adjuvant and neoadjuvant augmentation.
7. What are alternative or complementary treatments of pancreatic cancer?
Although we understand the possible benefits of some alternative therapies, this website is not strongly oriented this way. On an anecdotal basis only, 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 therapy, prayer, acupuncture, green tea and Chinese herbs. We are not adverse to alternative 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. Playing the role of a scold is no fun, and it is not our aim to deprive anyone of hope. In fact, we strongly believe that faith and hope are the two most powerful allies that one can have.
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 clinical trials. 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 say, "be careful."
With that warning, we note that there are at least two ongoing trials against pancreatic cancer involving unconventional alternative therapies. The Kelly-Gonzalez regimen which involves nutritional support, high-dose vitamins, pancreatic enzymes and coffee enemas is being tested in a phase III clinical trial through Dr. Gonzalez and at the Columbia-Presbyterian hospital in New York City. And the Burzinski regimen in which oral "antineoplastons" are prescribed is in a phase II clinical trial at the Burzinski Research Institute in Houston, Texas. 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 kinds of treatments, will finally expose them as fraudulent. Only time will tell what the outcome will be. Our advice: "be careful."
There are many sites on the Internet about alternative therapy. In our attempt to suggest tempering faith and hope with rationality and care, we offer two links to a site that deals with treatments that are adjudged by them to involve quackery. Along with these links, we reiterate: "be careful."
Quackwatch 1 | Quackwatch 2
8. What about neuroendocrine (islet cell 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.
About 75% of these 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. 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 carcinoic 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, 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. There are at least three such syndromes as presently defined.
Recent Neuroendocrine Research Results
Carcinoid & Neuroendocrine Select Abstracts
Neuroendocrine and Carcinoid Clinical Trials
Neuroendocrine and Carcinoid Links
9. What about clinical trials?
Clinical trials are, ideally, a part of a system in which a series of scientifically-controlled experiments shepherd a plausible agent, combination of agents or procedure through a process whereby the efficacy of the 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 became more possible, the process of taking a potential agent from the biochemical stage through 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 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 seeks to try and 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. Many potential drug therapies go no further than phase II--as they show no real effect against tumor. Successful phase II candidates move on to phase III clinical trials that seek to determine how the new therapy compares to existing therapies. This is the real test 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 is a big one and should not be take 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 following a particular clinical trial protocol which may call for being off all standard therapy for 28 days (which is not uncommon) before beginning the trial.
On the other hand, the prognosis of certain stages of pancreatic cancer is not 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 it really (realistically) more promising than existing therapy? Which phase of clinical trial am I comfortable participating in? Which institution is hosting the 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.
We include here links which may cover more information about clinical trials.
DUNN | NCI 1
Pancreatica offers the largest listing of clinical trials for pancreatic cancer. Link to our clinical trials database.
10. How do I find the best doctor for me?
On the surface, one would idealize the perfect physician for oneself as a medical blend of Albert Einstein and Mother Theresa. But the truth is more complex because we are more complex. In fact, it is our contention in this brief summary that it is virtually impossible to generalize about what qualities that you should be looking for in a physician (of course that won't keep us from trying).
The primary reason for this is that each patient's circumstance is different. The range of variation in patients' situations is extremely large. For example, issues include the extent of disease, patient personality, desire-to-live, financial circumstance, the possible existence of a primary caregiver and the possible existence of a web of personal emotional support. Personal qualities include depression, acceptance, resignation, equanimity, spirituality, pugnacity, anger, a willingness to fight, etc. These are not general qualities-they are highly individual.
The specialist who deals with cancer is called an oncologist. Generally, an oncologist has specialized in the medical field of Internal Medicine, and has further become a sub-specialist in oncology. This training is long and arduous, and thus tends to indicate an extraordinary amount of dedication. And oncologists have chosen to work with people who have cancer; this tends to show an orientation to compassion. Often the oncologist is the leader or at least an integral part of a team which clusters around an individual patient, whose team members also may include a surgeon, a radiologist, oncology nurses, social workers, nutritionists and others. For the most part, we are addressing the assessment of oncologists in this portion of the answer.
First, you may already have a physician. And it may well be that this is the best person for you to work with for a variety of reasons: you are presumably already known, you may already have a sense of the character of this oncologist, practical considerations may have led you (in the context of the health-care system) to this person, they may have come well recommended, there may be issues of convenience, of location, etc. But apart from all this, here are some things to consider in evaluating a physician.
Is the physician's overall orientation congruent with your deepest wishes. For example, has the physician dismissed the idea of making extraordinary efforts, when you stand ready and willing to fight. Conversely, is the oncologist suggesting big efforts (for example, having you enroll in clinical trials) when you are more resigned to circumstance. Only you will know what your real desires are, but they should generally comport with the general orientation of your physician. Of course, this is one time for direct communication. It may be that, even though each of your individual personal orientations are not completely in sync, this gulf can be bridged by honest and forthright communication.
It is difficult for patients to evaluate the competence of their physicians. And there is not one good way to accomplish this. Word of mouth can be useful; but it also can deceiving. Our view is that though physician referral can be very useful, even physicians are often not in the best stance to evaluate the functioning competence of their fellow doctors. Sometimes nurses are in a good position to see how physicians function: how thorough is their hospital work, do they come in at 3 a.m. when needed, etc. Certain institutions tend to attract great physicians. These approaches can all give pieces to the puzzle, but they each have their drawbacks. So to a great extent you are on your own with this, using a variety of approaches to try to come to an understanding.
One approach, again with potential pitfalls, is to use aggregated data which exists about individual physicians on the Internet. For example, though it is possible to read too much into this data, the American Medical Association has physician profiles about most practicing physicians in the U.S., including their medical school and training institutions. The American Board of Medical Specialties provides information about certified specialists (in the U.S.) These are physicians who have generally undergone written specialty examinations after meeting certain training requirements, and are thus "board certified" in one or more specialties. And, with limitations, some U.S. states carry certain disciplinary information in regard to certain physicians.
Kindness and wisdom are invaluable qualities in a physician. At difficult points, a strong bond with a compassionate and trusted physician can make every difference.
One stands in awe of the surgeons who regularly perform the Whipple procedure and other operations related to pancreatic cancer, as these are among the most arduous of operations - requiring great stamina and skill. Increasingly, the site of the performance of these surgical procedures in regard to pancreatic cancer in the U.S. has tended to move to major medical centers. And even there, more and more of these procedures are increasingly being done by fewer surgeons -- who may tend to specialize in these kinds of oncology surgeries. This is not always true, and there are accomplished surgeons in U.S. private practice who are renown for their work in pancreatic cancer.
Each of the three "C's" as listed above in regard as to what one might look for in an oncologist also applies to surgeons: congruity, competence, and compassion. In additional we would add a fourth "C" for surgeons: Common. How commonly does the surgeon do this procedure. All things being equal (which they rarely are), you would generally be advised to work with a surgeon who performs these complicated procedures, for example, twice a month -- rather than twice a year. Of course, for any rule that one might make in areas like this, one can certainly find exceptions.
Finally, there is the issue of second opinions. There are a number of instances where second opinions are highly recommended. The microscopic histology of many pancreatic tumors is complex. There can be as much art as science in some of the diagnostic and therapeutic considerations in pancreatic cancer. If there is any thought of seeking a second opinion, do not hesitate to do so. Your physicians will (or should) understand. There exist sites on the Internet about this topic. We have selected a couple of representative links.
Cancer Second Opinions
The American Cancer Society
11. How do I locate the best institution for me?
This is a companion to the previous FAQ answer about finding the best physician "for me." Again, there is no simple answer to this question. If you have found a trusted oncologist at your local hospital, and are not interested in making rather extraordinary efforts, then your local hospital will probably be the best possible institution for you. On the other hand, it is true that there exist exceptional cancer referral institutions-and that exceptional physicians and researchers tend to cluster to these research institutions. It is also true that interesting clinical trials may be occurring at one or another institution-this too may be a stimulus for researching other institutions.
In a sense, this is a difficult topic to discuss, as the range and even perhaps quality of the treatment options which exist at some of these research-oriented comprehensive cancer centers is often much more sophisticated than that which can reasonable be expected from a community hospital. And, in saying this, we do not wish in any way to disparage the remarkable efforts and comfort which are routinely given to patients through the efforts of many under-appreciated professionals (and non-professionals) at local community hospitals.
It is important to realize that there are pros and cons related to moving beyond one's local hospital, and for many many people with pancreatic cancer, the disadvantages will truly be seen to outweigh the advantages. Perhaps the biggest disadvantage is the distance/location problem. The logistics alone can be a serious deterrent to seeking care outside of one's local community.
There are Internet resources which can help to perhaps gain a better sense of the geography of this topic. For a fairly full list of community centers, the Association of Community Cancer Centers has a searchable database. Often the cancer centers and oncology departments of the major teaching hospitals and medical schools in a U.S. State offer advanced care options. Here is a site which links to the medical schools in U.S. States and Canada.
The U.S. National Cancer Institute though the National Institute of Health identifies a small number of institutions in the U.S. as comprehensive cancer centers. Additionally, though there is some duplication with NIH-designates, the members of the National Comprehensive Cancer Network are identified in this map of the U.S.
The U.S. News and World Report (a news magazine) periodically ranks what it sees, according to its own criteria, as the best cancer institutions in the U.S.
Here are three links to cancer institutions from around the world.
World 1 | World 2 | World 3
These approaches which rank cancer centers have to be viewed with some caution and a little skepticism. The best institution for you will be the one which is consistent with your circumstance. And in many instances, it will turn out to be your local hospital with your trusted oncologist together with local resources.
12. What are some of the main troubling symptoms and their treatment?
A. Selected symptoms related to adenocarcinoma of the pancreas
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 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 (Actiq lozenges on a stick or duragesic transdermal patches), 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) 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. A couple of links to online sources of information regarding cancer pain management are provided. Pain control 1 | Pain control 2 .
2). 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 actions 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 can