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It is the most prevalent type of pancreatic neoplasm, and it is developed in the exocrine compartment and accounts for more than 90% of pancreatic cancer cases.
IThis year, an estimated 60,430 adults (31,950 men and 28,480 women) in the United States will be diagnosed with pancreatic cancer. The disease accounts for approximately 3% of all cancers. Pancreatic Cancer — Cancer Stat Facts
Male patients with pancreatic adenocarcinoma have a risk of suicide nearly 11 times that of the general population. Patients who undergo an operative intervention are more likely to commit suicide, generally in the early postoperative period. Suicide in patients with pancreatic cancer — Mayo Clinic
Common symptoms of pancreatic adenocarcinoma occurring before diagnosis include:
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.
Fewer than 25% of patients diagnosed with pancreatic cancer survive for 1 year, and only 5% of patients are alive after 5 years. For patients who are diagnosed before the tumor grows much or spreads, the average pancreatic cancer survival time is 3 to 3.5 years.
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.
In absence of metastatic disease, the most important factor for improving survival and possibly offering cure is to achieve a radical margin-negative resection. However, only 15% to 20% of patients have disease that is resectable at presentation.
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).
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.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy due to the lack of early diagnosis and limited response to treatments. It is the most prevalent type of pancreatic neoplasm, and it is developed in the exocrine compartment and accounts for more than 90% of pancreatic cancer cases. Despite scientific progress on the elucidation of PDAC tumor biology and the development of novel therapeutic regimes, it has an average 5-year survival rate of less than 10%[1] and is anticipated to become the second leading cause of cancer–related mortality by 2020. Almost 60%-70% of PDAC cases arise from the head of the pancreas, and these cases are usually diagnosed earlier than tumors arising from the body and tail, as the head of the pancreas contains the common bile duct[2].
Tumors of the body and tail are associated with a worse prognosis[3]. Weight loss, abdominal pain, and jaundice[4] are the most common symptoms observed in patients with PDAC, while less common symptoms include new-onset type 2 diabetes[5] and thromboembolic disease[6].
Classical treatments such as chemotherapy, surgery and radiation have been widely used, but they have not exhibited any significant improvements in clinical outcomes[7,8].
The overall survival for metastatic pancreatic cancer remains poor, and less than 20% of patients survive past the end of the first year[9]. Surgical resection and chemotherapy (gemcitabine and FOLFIRINOX, a combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin) have managed to improve survival of patients with early-stage pancreatic cancer, but these treatments are not sufficient for patients with late stages of the disease[10].
Novel immunotherapies have provided promising results in various solid tumors, such as melanoma or renal cell carcinoma, in a number of cases surpassing chemotherapy as a first-line therapeutic selection[11]. Although immunotherapy began a new era in the field of cancer treatment, it is challenging in the context of PDAC as this type of cancer has a nonimmunogenic, immune-suppressive and therapy-resistant microenvironment.
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)
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).
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.
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.
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.
Pancreatic Ductal Adenocarcinoma - Pancreapedia
1. Introduction
Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas. PDAC is an aggressive and difficult malignancy to treat. Complete surgical removal of the tumor remains the only chance for cure, however 80-90% of patients have disease that is surgically incurable at the time of clinical presentation (15). Despite our advancing knowledge of the tumor biology of PDAC, improvement in diagnosis and management, and the rise of centers specialized in the care of patients with PDAC, the prognosis remains strikingly poor (4,17). The following overview will discuss the epidemiology and tumor biology of PDAC, as well as important information for patients and family including diagnosis, treatment, and prognosis. This overview will not discuss cancer that arises in cystic lesions of the pancreas, nor will it discuss pancreatic neuroendocrine tumors, as these variants have a different biology and prognosis.
2. Epidemiology and Demographics
It was estimated that 46,420 new cases and 39,590 deaths were attributable to pancreatic cancer in the United States in 2014, of which PDAC represents the vast majority. That the number of deaths per year nearly equals the number of new cases per year highlights the lethality of this disease. Pancreatic cancer was the 12th most common type of cancer in the US in 2014, representing just 2.8% of all new cancer cases. Despite this, pancreatic cancer was the 4th most common cause of cancer-related death (15). Furthermore, the incidence of pancreatic cancer is rising. It is estimated that in 2015 the above figures will rise to 48,960 new cases and 40,560 deaths attributable to pancreatic cancer. Approximately 96% of these cases will be PDAC (16). By 2030, researchers project that pancreatic cancer will become the 2nd leading cause of cancer related death in the US after lung cancer, surpassing colorectal, breast, and prostate cancer (14).
The median age for diagnosis of pancreatic cancer is 71, with 75% of cases diagnosed between the ages of 55 and 84. The median age for death as a result of pancreatic cancer is 73 years of age (4). Pancreatic cancer is slightly more common in men than women, but this gap has narrowed in recent years. Risk factors for pancreatic cancer are identifiable in approximately 40% of cases, and include (but are not limited to) the following:
3. Tumor Biology
PDAC is an epithelial tumor that arises from the cells of the pancreatic duct or ductules, for which it is named. In health, the pancreatic duct(s) serve as the conduit through which digestive enzymes and bicarbonate ion produced in acinar cells reach the small intestine. Ductal cells and acinar cells together represent the “exocrine” pancreas, from which the vast majority of pancreatic neoplasms arise.
It is now believed that the development of PDAC occurs over an extended period of time, and likely follows a stepwise progression similar to other carcinomas (colorectal carcinoma, in particular). This progression is characterized by the transition of a normal pancreatic duct to a pre-invasive precursor lesion known as pancreatic intraepithelial neoplasia (PanIN), which can ultimately develop into an invasive PDAC (5).
This progression is spurred on by the gradual accumulation of genetic mutations (Figure 1). A mutation in the K-ras oncogene is one of the most common and earliest found in PDAC, occurring in 90% of cases. Other common genetic mutations commonly found in PDAC include activation of oncogenic Her-2/neu, and loss of function in tumor suppressor genes such as p16, p53, and SMAD4 (5, 6). Advanced PanIN lesions develop increasing genetic variability, proliferate, and eventually acquire the means to invade and metastasize.
Figure 1: The “Progression Model” for Pancreatic Cancer. From Hruban et al, reused with permission (5). Progression is divided into morphological stages which are usually associated with mutation in the genes showed below.
4. Clinical Presentation- Signs and Symptoms
The most common symptoms of PDAC are pain and weight loss, and the most common clinical sign is jaundice. More specifically, one study has reported the following frequency of sign and symptoms in patients with PDAC, in descending order (13):
It is important to understand that the presenting signs and symptoms are often related to the location of the tumor. Grossly, the pancreas is divided into the following anatomic regions: the uncinate process, the head, the body, and the tail. In the context of PDAC, the anatomy may be simplified into two groups, namely the head of the pancreas (including the uncinate process) and the body/tail. Approximately 60-70% of PDAC arise from the head of the pancreas, whereas 20-25% arise from the body/tail (9). In general, tumors arising from the head of the pancreas come to clinical attention earlier than tumors arising from the body and tail, as the head of the pancreas contains the common bile duct. A tumor that obstructs the common bile duct leads to the phenomenon known as “painless jaundice” as bile constituents accumulate in the blood, often prompting an imaging study that will reveal the underlying tumor. In contrast, tumors of the body and tail do not produce jaundice, and therefore most often come to clinical attention later once weight loss and/or pain become apparent.
PDAC may occasionally be the cause of acute pancreatitis (caused by obstruction of the pancreatic duct), and come to clinical attention in that manner. New onset diabetes in an adult patient that is otherwise healthy is also an uncommon presentation of PDAC, and one that carries a poor prognosis. Finally, PDAC may be identified incidentally abdominal imaging for an unrelated issue, but this is exceedingly rare.
5. Diagnosis
The presenting symptoms and signs discussed above are not specific for the diagnosis of PDAC, and therefore a diagnosis of PDAC can only be made after further investigation. Laboratory investigation—particularly liver function tests—should be performed in all patients suspected to have a pancreatic malignancy, and especially if there are signs of jaundice on physical exam. The tumor marker carbohydrate antigen 19-9 (CA 19-9) may be increased in 75-85% of patients with PDAC. It is non-specific and may be elevated in benign biliary or pancreatic disease, nor is it perfectly sensitive.
Therefore while an elevated CA 19-9 in a patient with a pancreatic mass is highly suspicious for PDAC, it does not make the diagnosis. Rather, the role of CA 19-9 is predominantly one to assess for recurrence after surgery (21).
Because laboratory tests are not specific for PDAC, dedicated imaging studies are indicated. Abdominal computed tomography (CT) is the most common initial test performed to identify a pancreatic mass (Figure 2), but other imaging studies include abdominal magnetic resonance imaging (MRI) with or without cholangiopancreatography (MRCP), abdominal ultrasonography (US), and endoscopic ultrasound (EUS) with or without endoscopic cholangiopancreatography (ERCP).
EUS and ERCP are the most invasive of the above-mentioned tests, but are the only studies among those listed that allow for a biopsy that may provide the exact diagnosis.
Figure 2: Typical CT appearance of PDAC.(A) An axial CT scan demonstrating a “hypoattenuating” mass (yellow arrow) in the head of the pancreas with proximity to the superior mesenteric vein. (B) A coronal CT scan of same “hypoattenuating” mass (yellow arrow) in the head of the pancreas. Please note there is abnormal dilatation of the pancreatic duct (red arrow), indicating that the mass is obstructing the outflow of the pancreas.
Unless there are specific contraindications or extenuating clinical circumstances that favor performing an alternative test, abdominal CT is the recommended initial test of choice. CT is widely available and has a high degree of accuracy in identifying most tumors, and can determine whether a tumor is resectable in 90% of cases (10).
Unlike in most other solid malignancies, it remains controversial whether a biopsy should be attempted if PDAC is suspected, except in two particular situations. The majority of surgeons recommend proceeding directly to surgery when a mass suspected to be PDAC is causing obstructive jaundice—in this case surgery will be required to alleviate the obstruction regardless of the tissue diagnosis.
On the other hand, in cases where PDAC is suspected but there is evidence of metastasis or locally advanced disease that precludes an attempt at curative resection, tissue biopsy is universally required in order to guide chemotherapy. In the remainder of clinical situations, a multidisciplinary team may be necessary to determine whether a biopsy should be performed prior to surgery (19).
6. Staging
Once a diagnosis of PDAC is confirmed or highly suspected, an attempt to stage the tumor is made. This is achieved primarily through triphasic CT scan of the abdomen (19). Rarely, an investigation outside of the abdomen is performed to identify distant metastasis, usually with CT scan of the chest or whole body positron emission tomography (PET). The 7th edition of the American Joint Committee on Cancer (AJCC) Pancreas Cancer Staging follows the standard “TNM” (Tumor size, lymph Node status, Metastasis) format and is shown in Table 1 and Table 2 (1). The AJCC staging system is most commonly used to determine prognosis (see “Prognosis” section). Further information regarding staging is publically available through the website of the National Cancer Institute (http://www.cancer.gov/cancertopics/pdq/treatment/pancreatic/Patient/page2).
Preoperative surgical staging refers to the determination of whether a suspected PDAC is amenable for surgery. A tumor is considered potentially resectable, borderline resectable, or unresectable (7).
Although the criteria for calling a tumor resectable versus borderline resectable may change somewhat depending on the institution and the comfort level of the surgeon, in general, PDAC is considered resectable when the following criteria are met:
If patients are considered borderline resectable, it is generally related to questionable involvement of the arteries and/or veins that cannot be fully assessed preoperatively.
In these patients, preoperative chemotherapy and possibly radiation therapy may be beneficial (see above).
Figure 3: Diagram of Standard Whipple Procedure
.Figure and further detail can be found at Canadian Cancer Society. The tissue shown as dark is removed with the right panel showing the reconstruction.
7. Treatment
Surgery
Surgical resection remains the only definitive treatment for PDAC, and the only treatment that offers a chance for cure. Unfortunately, only approximately 10-20% of patients will have tumors that are amenable to surgical resection.
In order to be eligible for surgery with curative intent, a tumor must be considered resectable (see above) by the operating surgeon. If that criterion is met, then the location of the tumor determines the type of operation that will be performed. Regardless of location, the goal of surgery is to achieve a complete removal of the tumor with negative margins—both macroscopically and microscopically (known as R0 resection).
Less adequate resections leave tumor behind, whether it is microscopic (an R1 resection) or macroscopic (R2 resection).
For PDAC located in the head of the pancreas, a pancreaticoduodenectomy (also known as a “Whipple” procedure) is the only surgery of choice (Figure 3).
Although historically plagued by high operative mortality, the Whipple procedure is now performed safely with perioperative mortality around 2% when performed by a surgeon in a high-volume center.
However, between 30-40% of patients will endure a major complication, most commonly pancreatic fistula or delayed gastric emptying (2).
For tumors of the body and tail, a distal pancreatectomy and splenectomy is performed. This has also become a safe procedure over the past three decades, with low operative mortality in high-volume centers. The complication rate also approaches 35%, with a leak from the transected pancreas being the most common (12).
Chemotherapy
Currently, chemotherapy is indicated in the treatment of PDAC in all cases, although the duration and type of chemotherapy depends on the goals of therapy.
For patients that have undergone surgery, adjuvant chemotherapy is given postoperatively and has been shown to impart a survival advantage when compared to surgery alone. The current agents that are the standard of care in this setting are gemcitabine, or a combination of 5-flurouracil plus leucovorin.
For patients with advanced PDAC—metastatic or unresectable—a survival benefit has been demonstrated with the administration of FOLFIRINOX (5-flurouracil, leucovorin, irinotecan, oxaliplatin) as induction chemotherapy, indicating that it is the primary treatment of the disease (8).
Finally, a recent development in the treatment of PDAC has been the increasing use of neoadjuvant chemotherapy for borderline resectable or locally advanced disease, meaning that chemotherapy is given prior to surgery.
The rationale for giving chemotherapy in borderline resectable PDAC is that the tumor becomes resectable as a result of treatment. Studies are ongoing to determine the ideal combination of agents with or without radiation therapy (20).
Radiation
The use of radiation in PDAC is somewhat controversial. Some studies have failed to show a significant survival benefit when radiation is added to chemotherapy in the adjuvant setting. There have even been some data to suggest that adding radiation may have a negative overall effect when used in the adjuvant or neoadjuvant setting.
However, there is also data that demonstrates radiation therapy imparts a significant advantage when used in the neoadjuvant setting, allowing for improved local control of the tumor and an increased chance of an R0 resection in tumors that are initially considered borderline resectable (3).
Palliation
A number of complications of PDAC may arise that require intervention, even in patients that are not candidates for surgery with curative intent. These include: malignant biliary obstruction, malignant gastric outlet obstruction, and intractable tumor-associated pain. Malignant biliary obstruction occurs as a result of tumor compression of the common bile duct, leading to severe jaundice. Malignant gastric outlet obstruction refers to tumor blockage of the outlet of the stomach, prohibiting the passage of food from the stomach into the small intestine, and causes severe nausea and vomiting, in addition to malnutrition. Both biliary and gastric outlet obstruction may be treated initially via endoscopy, but may require surgical bypass.
Severe pain related to PDAC that is refractory to oral pain medications is often related associated pain is often the result of local extension of the tumor into the nerves of the celiac plexus. Targeted therapies including ethanol ablation or anesthetic injection into the celiac plexus have been shown to reduce tumor-associated pain (18).
8. Prognosis
Currently, overall 5-year survival is 7.2% for patients with PDAC, meaning that 7.2% of all patients diagnosed with PDAC are expected to be alive 5 years after diagnosis.
The subset of patients that have “localized” disease (and therefore are surgical candidates) may expect a 27.1% 5-year survival. This discrepancy is a testament to the fact that surgery remains the only truly effective treatment modality. The prognosis by stage is summarized in Table 3, and is based on data from the National Cancer Data Base for patients diagnosed between 1992 and 1998.
9. References
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