Treatment of pancreatic cancer can be tricky. The pancreas is located in an area of the abdomen that also houses other vital organs, such as major blood vessels and the liver.

Tumors from the pancreas can quickly spread to these areas, making surgical resection difficult, even when the primary tumor is not very large. In addition, as noted in Signs and Symptoms, diagnosis of pancreatic cancer is most often made after the tumor has become unresectable.

Finally, the average age of pancreatic cancer diagnoses is in the seventh and eighth decades of life. Many elderly patients have co-morbid disease states that make giving potentially toxic treatments such as chemotherapy and radiation therapy difficult. Given the generally poor outcomes associated with treatment of pancreatic cancer with standard approaches, all patients should be considered for participation in a clinical trial.

Common Treatment Options

SURGERY

Surgery is currently the only curative treatment for pancreatic cancer. Unfortunately, only 20% of patients are diagnosed with disease that can potentially be cured with surgical resection. The most common surgical strategy is called the Whipple procedure, which is resection of the pancreas and duodenum. Select patients may be candidates for resection of the distal pancreas only, depending upon the location of the tumor. Preoperative biliary drainage with stent placement may be done in patients who present with bile duct obstruction and jaundice. This improves liver function prior to surgery and may lead to a better surgical outcome.

The goal of surgery is an R0 resection, defined as surgical margins negative for tumor. An R0 resection leads to the lowest chance of local recurrence after surgery. Five-year survival rates for all patients undergoing surgery for pancreatic cancer are less than 5%; however, patients who achieve an R0 resection have a 20% chance of living five years.

Pancreatic resection is not a minor surgery. Complications include pancreatic leaks, abscesses and fistulas (an abnormal connection between two otherwise unconnected organs). These can be fatal. Mortality from pancreatic resection ranged from 10 to 20% prior to the 1990s. Since then, surgical techniques have improved. However, surgical resections of pancreatic tumors should still be done at institutions with experienced surgeons, who perform large numbers of these resections, preferably more than twenty cases per year. Mortality rates at these types of institutions are as low as 1 to 4%, compared to more than 15% at institutions that perform less than five procedures a year.

RADIATION THERAPY

Pancreatic cancer is very sensitive to treatment with radiation. This modality is almost always used in combination with chemotherapy (so-called chemoradiotherapy), usually with fluorouracil or gemcitabine. These agents are radiation sensitizers, leading to a synergistic effect when the two modalities are given together. Fluorouracil may be given as an intermittent intravenous bolus or as a continuous infusion, the latter being more effective but more cumbersome for patients. Other radiation sensitizers under investigation include paclitaxel and cisplatin. Chemoradiotherapy does lead to more side effects than chemotherapy alone.

CHEMOTHERAPY

Chemotherapy for pancreatic cancer may be used in a variety of ways:

• Adjuvant therapy after surgical resection
• Neoadjuvant therapy prior to surgery, for patients with potentially resectable disease
• Primary management of locally advanced unresectable or metastatic disease

ADJUVANT CHEMOTHERAPY

The goals of adjuvant chemotherapy are to improve survival and prevent or delay relapse. The rationale for studying this approach is that most patients experience pancreatic cancer recurrence, even after surgical resection. Adjuvant chemotherapy is delayed until adequate recovery from surgery, but it should ideally be started within four to eight weeks of resection.

Although the rationale for adjuvant chemotherapy is sound, this approach remains controversial for most pancreatic cancer patients. Large, well-designed trials to date have reported conflicting results. The first trial showing a benefit of adjuvant therapy was performed in the 1980s and used fluorouracil combined with radiation therapy. Survival improved from 11 months with surgery alone to 20 months. However, this was a very small trial with only a few dozen patients.

More recent trials involving hundreds of patients have generally failed to reproduce these results. In fact, chemotherapy alone (without radiation therapy) seems to be a more beneficial approach. Because so many questions remain, patients who are potential candidates for adjuvant chemotherapy should be encouraged to participate in a clinical trial.

There is currently no standard for adjuvant therapy. Options include the following:

• Chemoradiotherapy with fluorouracil, with or without sequential gemcitabine
• Gemcitabine monotherapy (preferred if monotherapy is chosen)
• Fluorouracil monotherapy
• Capecitabine monotherapy

Note that chemoradiotherapy should NOT be given to patients who received radiation therapy as part of neoadjuvant treatment. In these patients, chemotherapy alone should be used.

NEOADJUVANT CHEMOTHERAPY

This treatment approaches involves giving chemoradiotherapy prior to surgery. There are several potential advantages to neoadjuvant therapy for pancreatic cancer:

• Up to 25% of patients who might benefit from postoperative chemotherapy are unable to receive it due to surgical complications.
• Treatment before surgery allows earlier treatment of micrometastatic disease.
• Neoadjuvant therapy may lead to downsizing of tumors prior to surgery and improve resectability. This is the preferred strategy for patients with borderline resectable disease.

Unfortunately, the optimal neoadjuvant regimen has not been established. Fluorouracil-based therapy is most often used. It is also not known whether this approach is truly better than adjuvant chemotherapy, as there are no head-to-head trials. In addition, although a theoretical benefit, no study to date has clearly demonstrated improved resectability. As such, neoadjuvant therapy should only be employed as part of a clinical trial.

CHEMOTHERAPY FOR LOCALLY ADVANCED UNRESECTABLE PANCREATIC CANCER

The goals of treatment for unresectable pancreatic cancer are palliation of symptoms and (possibly) improved survival. The historical standard approach has been chemoradiotherapy with fluorouracil. Even this is somewhat controversial, however. Chemoradiotherapy has been shown to be superior to radiation therapy alone, with an average survival of 10 months. A recent trial, however, demonstrated that gemcitabine monotherapy resulted in longer average survival by 6 months compared to chemoradioatherapy. The choice of therapy is dependent upon anticipated side effects in individual patients, and the options include the following:

• Gemcitabine monotherapy (NO radiotherapy)
• Fluorouracil-based chemoradiotherapy
• Gemcitabine-based chemoradiotherapy
• Gemcitabine monotherapy followed by chemoradiotherapy with fluorouracil
• Gemcitabine chemotherapy combinations (usually with cisplatin or oxaliplatin)

CHEMOTHERAPY FOR METASTATIC PANCREATIC CANCER

The most important goal of therapy for metastatic pancreatic cancer is palliation of symptoms. Improved survival may be achieved, but it is usually measured in a few months only. Gemcitabine monotherapy given weekly for three weeks (every 28 days) is the current standard of care, especially in those with a poor performance status. The average survival is 6 months. More importantly, however, gemcitabine improves symptoms, including pain, and offers a modest survival advantage over fluorouracil. Combination chemotherapy with gemcitabine plus cisplatin, oxaliplatin, capecitabine, or irinotecan should be reserved for patients with a good performance status, due to the risk of side effects. These combinations have not shown a survival advantage when compared to gemcitabine alone.

The combination of gemcitabine plus erlotinib has recently received FDA-approval for first-line treatment of metastatic pancreatic cancer. Erlotinib is an oral tyrosine kinase inhibitor. It inhibits the effects of epidermal growth factor, which stimulates many pancreatic cancers. The combination offers a modest survival advantage (average of one month longer survival) over gemcitabine alone. Although erlotinib is generally well tolerated, it can lead to the additional side effects of rash and diarrhea. These can be severe. Erlotinib, although oral, is also very costly, upwards of several thousand dollars per month.

Clinicians and patients together must make the decision if the potential side effects and increased cost are worth the modest gains in survival. Patients who maintain a good performance status upon relapse may be treated with gemcitabine (if not previously used as first-line), oral capecitabine with or without oxaliplatin, or the FOLFOX regimen (fluorouracil, leucovorin, and oxaliplatin).

Other Treatment Options

BEST SUPPORTIVE CARE

This treatment approach should NOT be confused with lack of care. It is the treatment of choice for patients with metastatic pancreatic cancer who have a poor performance status or who experience side effects from chemotherapy. Aggressive pain control, stent placement as needed, and other symptom management are employed. Nausea/vomiting can be treated with antiemetics or octreotide, and itching from jaundice is often amenable to oral drugs such as doxepin. The average survival with best supportive care is 3 to 4 months.

CLINICAL TRIALS AND NOVEL TREATMENTS

Clinical trials of new treatments for pancreatic cancer currently involve new chemotherapy combinations (such as docetaxel plus irinotecan and gemcitabine plus pemetrexed) and the use of targeted treatments. For example, cetuximab is a monoclonal antibody that targets the epidermal growth factor receptor on tumor cells. It has activity in pancreatic cancer.

Drugs that inhibit blood vessel formation also show promise in treating pancreatic cancer. This includes bevacizumab, a monoclonal antibody, and sorafenib, a tyrosine kinase inhibitor like erlotinib.

Finally, there are many trials investigating the drug bortezomib. This is a proteosome inhibitor that disrupts cellular homeostasis and leads to cell death. All of these targeted treatments are most often given in combination with chemotherapy, usually gemcitabine. In addition, there are other agents being studied as treatments for pancreatic cancer. These may be reviewed at www.clinicaltrials.gov.