CANCER
June 20, 2012

Pancreatic Cancer

Parvin Peddi, M.D., and Andrea Wang-Gillam, M.D.
The death of Steve Jobs made more people aware of pancreatic cancer, but it remains tough to treat.
Dr. Peddi is a hematology/oncology fellow and Dr. Wang-Gillam is an Assistant Professor, Washington University School of Medicine, St. Louis, MO.

The death of Steve Jobs from a form of pancreatic cancer last year, and of Patrick Swayze and Michael Landon before him has brought this form of cancer into the public eye. Although pancreatic cancer is not one of the more common forms of cancer (it’s number 10 in the United States), its mortality rate is disproportionately high. In 2011, for example, an estimated 37,660 patients died of pancreatic cancer, making it the fourth most common cause of cancer death in men and women. The incidence and mortality rates for pancreatic cancer have unfortunately not changed much over the past several decades. The majority of these tumors (85%) are known as adenocarcinomas.

Tobacco use, obesity, and chronic pancreatitis have been associated with increased risk of pancreatic adenocarcinoma. Men and women have essentially equal risk for this form of pancreatic cancer, but African Americans have a higher incidence than white Americans.

One of the reasons that pancreatic cancer has such a high mortality rate is that patients often don’t have symptoms for a long time, and therefore it typically remains undiagnosed until late in the course of the disease.

Approximately 90% of pancreatic adenocarcinoma is sporadic, meaning that there is no family history of the disease. The other 10% of cases do seem to have a genetic link. The genes most commonly associated with familial cases of pancreatic adenocarcinoma are BRCA-1 and BRCA-2 (which are better known as the “breast cancer genes”), and the most commonly lost gene is the p16/CDKN2A gene on chromosome 9p.

In this article, we’ll discuss the causes, diagnosis, treatment methods, and palliative care options that are currently available for pancreatic cancer.

Symptoms and Diagnosis

One of the reasons that pancreatic cancer has such a high mortality rate is that patients often don’t have symptoms for a long time, and therefore it typically remains undiagnosed until late in the course of the disease. The symptoms that do, finally, occur include jaundice, abdominal pain, weight loss, and sometimes development of diabetes (due to disease of the insulin-secreting cells of the pancreas). Therefore, developing diabetes in adulthood along with weight loss should prompt one’s doctor to investigate pancreatic problems further.

There has been great interest in using blood tests to diagnose pancreatic cancer, although the test currently available (called CA 19-9) is not 100% accurate.

Doctors will typically order a CAT scan (CT) or right upper quadrant (RUQ) ultrasound if the patient has new onset jaundice. Diagnosis also requires tissue biopsy of the pancreatic cells. There has been great interest in using blood tests to diagnose pancreatic cancer, although the test currently available (called CA 19-9) is not 100% accurate. It can come back positive in response to benign conditions like pancreatitis, and, conversely, it can be falsely negative in people who do have pancreatic cancer. Therefore, CA 19-9 is not used to make a diagnosis of pancreatic cancer, but may help doctors learn more, in addition to the other methods mentioned above.

Staging
The American Joint Committee on Cancer (AJCC) has published TNM (Tumor, Lymph Nodes, Metastasis) staging criteria for pancreatic cancer, which is similar to staging systems for other solid tumors. However, in practice, a more simplified staging system, based on how “resectable” (operable) the tumor is, is used. Following imaging by CT or MRI, the disease is classified as: 1) resectable, 2) borderline resectable (tumors affecting nearby tissue and not clearly resectable or unresectable), 3) locally advanced (involving nearby tissues to the point of being clearly unresectable despite the absence of metastasis), and 4) metastatic.

Treatment

Surgical Resection
Surgery to remove the cancerous tissue is currently the only technique that can cure pancreatic cancer. However, by the time of diagnosis,, nearly 80% of patients with pancreatic cancer cannot proceed with surgery due to either involvement of the vascular system or to the fact that it has already spread to other organs. Hospitals differ in how likely they are to operate on pancreatic cancer that has spread locally. There are many important structures near the pancreas (like the hepatic artery and portal vein, going into and out of the liver), so doctors have to determine whether they have been affected by the cancer. Depending on this, surgeons will decide whether the tumor is operable or not.

By the time of diagnosis, nearly 80% of patients with pancreatic cancer cannot proceed with surgery.

The most common procedure performed is the Whipple, which involves resection of the part of the pancreas, parts of the duodenum, the common bile duct, and the gallbladder. The distal (lower) portion of the stomach is also removed in the “classic” Whipple. (For those who are interested, this YouTube video provides an explanation of the procedure.) A different surgery is needed for pancreatic cancers in the pancreatic body or tail, which involves distal pancreatectomy, often along with splenectomy.

The Role for Adjuvant Therapy: Chemotherapy and Radiation
Even for patients with early stage pancreatic cancer who have had surgery, the median survival time ranges from only 15 to 19 months, with a 5-year survival rate of only 20%. Therefore, therapies like chemotherapy, radiation therapy or concurrent chemoradiation are sometimes used after surgery (i.e. adjuvant therapy) in attempts to kill cancerous cells that remain after surgery.

One study compared people who had a chemotherapeutic medicine called gemcitabine after surgery to those who did not receive it. At the end of about 53 months, 74% of the patients in the gemcitabine group and 92% of the control group had recurrence of their pancreatic cancer. The median length of time during which the patients were disease-free was significantly longer in those receiving gemcitabine (13.4 months vs. 6.9 months), but unfortunately, no overall survival difference was shown.

Given similar modest improvements seen in other trials, the NCCN (National Comprehensive Cancer Network) currently endorses the use of adjuvant chemotherapy with either gemcitabine or another drug called 5-FU/leucovorin, although gemcitabine is often preferred because it is less toxic. Concurrent chemotherapy and radiation are also accepted and commonly practiced in the United States. Studies comparing chemotherapy to chemotherapy combined with radiation are currently underway.

The Role for Neoadjuvant Therapy
There has also been interest in neoadjuvant therapy – therapy before surgery – in cases where surgery is deemed appropriate. Theoretically, neoadjuvant therapy for operable pancreatic cancer should shrink the size of the tumor and thereby increase the possibility that the tumor can be removed successfully. Furthermore, neoadjuvant therapy can buy some time, so that the doctor can determine more closely whether surgery would benefit the patient or not.

Unfortunately, most studies don’t show a survival benefit for neoadjuvant therapy compared to adjuvant therapy. Currently, researchers are recruiting for a phase III study that compares adjuvant therapy to a combination of neoadjuvant and adjuvant therapy for operable pancreatic cancer. This trial should help answer the question of the role of neoadjuvant therapy in resectable pancreatic cancer (for more information, visit clinicaltrials.gov).

For cases that are borderline operable, neoadjuvant therapy makes the most sense, as it would potentially push the case into the operable realm. No prospective phase III trials have addressed this scenario, however. The current approach varies by hospital, but it appears that most physicians prefer neoadjuvant therapy as opposed to immediate surgery. Fortunately, there are several ongoing trials that are looking at neoadjuvant chemotherapy in patients with borderline resectable disease to establish the possible benefits of this approach (for example, using folfirinox chemotherapy).

Chemotherapy for Cancer That Has Spread

Systemic chemotherapy is used for patients who are not eligible for surgery. It is mostly limited to patients who are in good overall health. Gemcitabine, mentioned earlier, is used as the first line option both for extending one’s lifespan, as well as for relief of symptoms. The combination of gemcitabine with other medications has not been shown to be of any greater benefit than gemcitabine alone. The only combination currently approved by the FDA is gemcitabine with a drug called erlotinib, which showed a very slight improvement in survival from 5.91 months to 6.24 months (compared to gemcitabine alone.)

Until recently, gemcitabine and the less commonly used combination with erlotinib were the only treatments for inoperable pancreatic cancer. Last year, one study found that a drug called folfirinox worked even better than gemcitabine in reducing the spread of the cancer and extending one’s lifespan survival (11.1 months vs. 6.8 months). However, it is more toxic than gemcitabine, with higher risk of neutropenia (low white blood cell count) and diarrhea, among other side effects. Therefore, only patients who are otherwise in good health should be offered this treatment.

Chemoradiation for Locally Advanced Disease
It is unclear whether chemoradiation offers benefits over chemotherapy alone in patients whose disease is beginning to spread locally but has not metastasized. It may be helpful for patients who have pain or symptoms from obstruction of the stomach, small intenstine or gallbladder drainage due an enlarging pancreatic mass [of the pancreas or surrounding organs] but it is not clear whether it lengthens lifespan.

Palliative Care for Advanced Cancer

Somewhat unique to pancreatic cancer is the need for considerable palliative procedures in the course of illness. Symptoms occurring from biliary obstruction, for example, occur in more than 65% of patients with pancreatic cancer. Cancer-related pain is also a major symptom that sometimes cannot be managed with oral pain medications alone. Therefore, one’s doctor must have a thorough understanding of the options that are currently available to manage these symptoms.

Biliary or Gastric Obstruction
The majority of patients who do not have surgery will eventually develop biliary obstruction, where bile cannot be carried away from the liver, due to growth of the tumor in the pancreatic head. In most cases, doctors may place a biliary stent to alleviate the obstruction, either metal or plastic (each has their pros and cons, but metal stents tend to last longer, although they are more expensive).

Sometimes a biliary stent cannot be placed, so a biliary drain may be used instead. A biliary bypass may also be used, usually for people who are having surgery but whose cancer is found to be inoperable during the operation.

Some patients may also have gastric (stomach) obstruction. In these cases, a doctor may place a stent to relieve the obstruction. Other options may also be possible depending on the nature of the disease, the overall health of the patient, and his or her life expectancy.

Relieving Pain
Most patients with pancreatic cancer experience cancer-related pain, often due to the cancer’s spread to surrounding nerves. When usual pain medications are not enough or when one is experiencing adverse side effects, one’s doctor may consider directly targeting the nerves causing pain by a procedure called celiac plexus neurolysis. The procedure involves injection of a combination of a local anesthetic, such as bupivacaine, and a neurolytic, a compound to damage the nerve (usually an alcohol). Patients who undergo the procedure generally have better pain management than others.

Pancreatic Insufficiency
Pancreatic insufficiency, in which the pancreas does not secrete enough digestive compounds, occurs in up to 94% of patients who have pancreatic surgery. It also occurs in patients who have not had surgery, simply as a result of tumor-induced damage to the pancreas or blockage of the pancreatic duct.

Symptoms of pancreatic insufficiency result in steatorrhea (fat being present in the feces), abdominal cramps, weight loss, and malnutrition. The treatment is based on the symptoms one has, rather than diagnostic testing, given the high prevalence of this problem in patients with pancreatic cancer. Pills containing pancreatic enzymes can be taken orally, with half of the dose taken at the start of the meal and half taken in the middle of the meal, to help the body digest food.

Thromboembolic Disease
The risk of a blood clot occurring inside a vein, known as venous thromboembolic (VTE) disease, is higher in all patients with cancer, and pancreatic cancer is a notorious culprit. The condition is generally treated with the anticoagulant medication heparin, which has the best effectiveness of any of the anticoagulants. One recent study suggested that it may also be used prophylactically, in other words as a preventative measure, to avoid blood clots occurring in the first place.

Summary

Despite some recent advances, pancreatic cancer continues to be one of the most lethal cancers in the twenty-first century. Surgery provides the only chance at curing the disease but even with surgery, pancreatic cancer is still highly fatal. Additional therapies are typically used to improve the results of surgery alone. When surgery is not an option, systemic chemotherapy with gemcitabine and more recently, folfirinox, is often used. Until more effective therapies are found, managing symptoms such as pain and biliary obstruction are key elements in the management of patients with pancreatic cancer. Getting good palliative care is important to help manage these symptoms as well as to arrange for hospice care in the later stages of the disease. Hopefully, the coming years will bring more treatment options and, perhaps more importantly, better screening methods, so that pancreatic cancer will become a more curable form of cancer.

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