Pancreatic cancer – Causes, Prevention, Prognosis, Diagnosis and Latest Treatment

Prevalence

Pancreatic cancer is the fourth most common cause of adult cancer death, accounting for an estimated 42,470 new cases and 35,240 deaths in USA for 2009.  The high mortality rate is due to the high incidence of metastatic disease at initial diagnosis, the aggressive clinical course and the failure of current therapies. 

Causes

It is not clear what causes pancreatic cancer, but some risk factors have been linked to the disease.  Modifiable risk factors that have been associated with pancreatic cancer include:

Smoking: Smokers have 2 to 3 times higher risk of getting pancreatic cancers.. About 2 to 3 out of 10 cases of pancreatic cancer are thought to be caused by smoking.

• Obesity and lack of exercise: Overweight people and those who don’t get much exercise are more likely to develop pancreatic cancer.
• Diabetes: Patients with type 2 diabetes have an increase risk of getting pancreatic cancer.
• Chronic pancreatitis: Some patients with chronic pancreatitis develop pancreatic cancer
• Cirrhosis of the liver: People with cirrhosis due to hepatitis and alcohol consumption seem to have an increased risk of pancreatic cancer.
• Work exposure: Heavy exposure to certain pesticides, dyes, and chemicals may increase the risk of getting pancreatic cancer.
• Stomach problems: Having too much stomach acid or having bacteria called H. pylori in the stomach may increase the risk of pancreatic cancer.

Prevention

At this moment, there is no way to prevent pancreatic cancer. Similar to the prevention of other cancer, stop smoking, having a healthy diet and exercise are important in keeping pancreatic cancer at bay.

Symptoms of pancreatic cancer

It is very difficult to find pancreatic cancer early in the course of the disease since the pancreas lies deep inside the body and it is not easy to fell the tumors during a routine physical exam. Currently, there are no blood tests or other tests that can find the pancreatic cancer early in patients without symptoms.

When a person has symptoms, the cancer is usually large and has spread to other organs. Thus, patients with pancreatic cancer usually have a poor outlook.

Symptoms of pancreatic cancer include jaundice, abdomen pain (belly area), pain in the middle of the back, weight loss, pale and greasy stools, swollen gallbladder, blood clots and increase in blood sugar level.

Physical exam

To confirm whether the tumor is cancerous, the physician will need to do a biopsy to confirm the cell types. 

The physician might also examine your lymph nodes and conduct imaging tests such as CT, MRI, PET, endoscopic ultrasound, ERCP (endoscopic retrograde cholangiopancreatography) to see whether the tumor has spread to lymph nodes or distant organs. 

Prognosis

Only 20% of the patients presenting with pancreatic cancer will the tumor be operable.  The median disease-free survival following complete resection of pancreatic cancer and adjuvant administration of gemcitabine is 13.4 months versus 6.9 months for untreated patients.  The longer disease-free survival after surgery and adjuvant chemotherapy, unfortunately, has not translated into any advantage in overall survival.

For the other patients who had locally advanced (40%) or metastatic (40%) disease at diagnosis, the median survival is 8-12 months and 3-6 months respectively.

Treatment

Surgery

Pancreatic cancer surgery is one of the hardest operations for surgeon and patients.  Surgery results in complications and may take many weeks for patients to recover.

There are 2 types of surgery used for pancreatic cancer:

1. Curative surgery when it looks like it is possible to remove all the cancer.  
2. Palliative surgery may be done if tests show that the tumor is too widespread to be completely removed.  In this case, surgery is done to relieve symptoms or to prevent the blockage of the bile ducts or the intestine by the cancer.

Studies have shown that palliative surgery does not help most patients to live longer.

Curative Surgery

If the cancer is contained within the pancreas, the surgeon might conduct a Whipple procedure. In this surgery, the surgeon remove parts of the pancreas, parts of the stomach and small intestine, the gallbladder, part of the common bile duct, and some nearby lymph nodes. It is a very complex operation that carries high risk of complications and might be fatal.  It is usually done by experienced surgeons who have done this many times.

For patients who have surgery, the 5-year survival rate is only 20%.  It is because a small number of cancer cells may already have spread to other parts of the body.  Only a small number of pancreatic cancer patients (about 10%) has their cancer contains within the pancreas.

Palliative surgery

When the surgeon discovers that the tumor has spread and it is impossible to cure the patients, the surgeon may continue the operation as a palliative procedure to relieve the symptoms. For example, the surgeon may relieve blockage of the bile duct to relieve the pain and the problems with digestion.

There are 2 options to relieve a bile duct blockage. One is to re-route the flow of bile from the common bile duct into the small intestine. This requires a large incision and it may take weeks for the patient to recover. An advantage is that during the surgery, the doctor may be able to cut the nerves leading to the pancreas and will reduce the pain for the patient.

The second and the most popular way to treat bile duct blockage is to use metal tubes called stents to keep the bile duct open. The doctor puts the stents in through an endoscope. Bigger stents are also used to keep the small intestine open, too.

Pharmacotherapy

First-line therapy

Gemcitabine (Gem)- Gemzar

Gemcitabine is the gold standard chemotherapy for pancreatic cancer since its approval in 1996.  The approval was based a phase III trial which involves 126 patients randomized either to gemcitabine or weekly injection of 5-fluorouracil (5-FU).  

• Clinical response was experienced in 23.8% of gemcitabine-treated patients compared with 4.8% of 5-Fu-treated patients (p=0.004)
• The median overall survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients (p=0.003)
• The 1 year survival rate was 18% and 2% for the gemcitabine and the 5-FU group, respectively (p=0.0009)

Gemcitabine + Oxaliplatin (GemOx) – Gemzar and Eloxatin

For patients who like extend the time without disease progression and are willing to tolerate the adverse effects of chemotherapy may consider the GemOx regimen.  GemOx was evaluated in 313 patients with advanced pancreatic cancer.  Patients were randomly assigned to either GemOx or gemcitabine.

At the end of the study, GemOx was superior to gemcitabine in   

• Response rate (26.8% vs 17.3% for GemOx and Gem, respectively; p=0.04)
• Progression-free survival (5.8 vs 3.7 months for GemOx and Gem, respectively; p=0.04)
• Clinical benefit (5.8 vs. 3.7 months for GemOx and Gem, respectively; p=0.04)

However, there was no difference in median overall survival (9.0 and 7.1 months for GemOx and Gem, respectively; P=0.13)

Also, patients who were assigned to the GemOx arm had a higher incidence of grade 3 and 4 toxicity in platelets (14.0% for GemOx vs 3.2% for Gem), vomiting (8.9% for GemOx vs 3.2% for Gem) and neurosensory symptoms (19.1% for GemOx vs. 0% for Gem).

Gemcitabine + Capecitabine (GemCap) – Gemzar and Xeloda

GemCap is another alternative to gemcitabine for pancreatic cancer.  However, results of two phase III trials showed conflicting results.

The first trial randomized 319 patients to receive either GemCap or Gem. 

• There was no difference in median overall survival time between the two arms (8.4 and 7.2 months in the Gem Cap and Gem arms respectively; p=0.234).
• Frequency of grade 3 or 4 adverse events, including neutropenia, was similar in both arms.   
• Post hoc analysis reviewed that patients in the GemCap arm with good Karnofsky performance status experienced a significant prolongation of median overall survival time when compared with the Gem arm (10.1 vs 7.4 months, respectively; P=0.014)

Another phase III trial randomized 533 patients to receive gemcitabine plus capecitabine or gemictabine.  The trial demonstrated a statistically significant improvement in overall survival time in the GemCap arm (7.4 months vs 6 months, p =0.0014).  The result might be attributed to the prolonged administration of capecitabine.

Erlotinib + Gemcitabine – Tarceva + Gemzar

Beside chemotherapy, targeted therapy plus chemotherapy has also been shown to improved survival.  Erlotinib, a targeted therapy, has been approved as treatment for locally advanced and metastatic pancreatic cancer patients. 

In a randomized, double-blind, phase III trial, 569 patients were randomly assigned to receive gemcitabine plus erlotinib or gemcitabine plus placebo. 

• Overall median survival was significantly prolonged by 2 weeks in the erlotinbi/gemcitabine arm (6.2 months vs. 6.0 months, p=0.028). 
• One-year survival was also greater with erlotinib plus gemcitabine arm (24% vs. 19%; p =0.023). 
• Progression-free survival was significantly longer with erlotinib plus gemcitabine (3.75 months vs. 3.55 months, p = 0.004).
• Of the 282 patients who received erlotinib, 79 had no rash, 102 had grade 1 rash, and 101 had a grade 2 or higher skin rash.

• The occurrence of skin rash was associated with a significant and clinically meaningful difference in survival.  The median survival rates for patients with grade 0, 1, and 2 rash were 5.3, 5.8, and 10.5 months and the 1-year survival rate were 19%, 9% and 43%, respectively (p=0.001).

Bevacizumab + Erlotinib + Gemcitabine – Avastin + Tarceva + Gemzar

Another target regimen that has been tested is the bevacizumab plus erlotinib and gemcitabine.  This regimen, however, have only been shown to improve progression-free survival (4.6 months vs. 3.6 months, p = 0.0002), but not overall survival (7.1 months vs. 6 months, p =0.2) when compared with erlotinib plus gemcitabine.

Second-line therapy

Oxaliplatin plus 5-FU and folinic acid (OFF regimen)

Patients who failed first line gemcitabine can use the OFF regiment to control their disease.  The CONKO 003 trial have shown that metastatic pancreatic patients whose disease had progressed from the first-line gemcitabine treatment, had significant survival benefit with the OFF regimen than the FF regimen (5-FU plus folinic acid).

The progression-free survival was significantly different (p=0.012) and the median survival time from initiation of second-line therapy was 20 weeks for the OFF vs 13 weeks for the FF arms (p=0.014).

Table 1  Clinical trials in Locally Advanced and Metastatic Pancreatic Cancer Patients

P<0.05 means statistically significant difference

Conclusions

Pancreatic cancer remains a major challenge to the medical field.  Only 10% of the pancreatic cancer patients have their cancer contained with the pancreas.  This group of patients might be cured by surgery. The rest might need chemotherapy and targeted therapy to extend their survival.

Gemcitabine is the standard 1^st line therapy for pancreatic cancer.  Patients with good performance status can also consider oxaliplatin + capecitabine to achieve prolonged survival.

For patients who fail the first line treatment, oxaliplatin-5FU-folinic acid should be used to improve survival.

In the adjuvant setting, current studies have supported the role of gemcitabine, either as monotherapy or in combination with chemoradiotherapy with 5-FU.

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