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Pancreatic Cancer Treatment

Advances in screening, preoperative care, chemotherapy, and radiotherapy have decreased the mortality of most cancers during the last 3 decades, but the impact of such advances on pancreatic cancer has been minimal. The only potential curative treatment offered to patients with pancreatic cancer is a combination of complete tumor removal and adjuvant (assisting) therapy, yet fewer than 15% of patients have resectable disease at the time of their diagnosis.

The Whipple procedure is the most commonly performed surgery in patients with pancreatic cancer, because, in about 75% of patients, the tumor is located in the head of the pancreas. In the standard Whipple procedure, the head of the pancreas, the gallbladder, the distal portion of the stomach, part of the duodenum, and the lymph nodes around the head of the pancreas are removed.

A distal pancreatectomy is performed if the tumor is located in the body of the pancreas or the tail of the pancreas. During this operation, the spleen is also commonly removed.

A total pancreatectomy is performed in patients with advanced cancer, when preservation of any part of the pancreas is impossible. This operation requires removal of the entire pancreas as well as the gallbladder, the distal portion of the stomach, part of the duodenum, the regional lymph nodes, and sometimes the spleen.
Pain Management:
Intractable pain, the major symptom in patients with pancreatic cancer, often necessitates the use of high-dose opioid analgesia. Complementary approaches include CT-guided or EUS celiac plexus block as well as bilateral or unilateral splanchnicectomy. However, the results have been disappointing, especially in patients with tumors of the body of the pancreas or of the tail of the pancreas.

Endoscopy is usually employed as a palliative measure for patients with pancreatic cancer. If the tumor is blocking the common bile duct, a stent (a small plastic or metal tube) is inserted into the duct to allow for the uninterrupted flow of bile into the duodenum. The stent can be put in either through the bottom of the bile duct (using ERCP) or through the skin and liver into the top of the bile duct (using a technique called a PTC, which stands for Percutaneous Transhepatic Cholangiography). Plastic stents are temporary, usually lasting for 3 to 4 months; they are easily replaced before, or when, they become blocked. Metal stents are much wider than the plastic stents and are considered permanent; they remain open much longer than the plastic ones. If metal stents become blocked, they are not removed; instead, a new stent is placed inside the old one.

Pancreatic cancer is highly resistant to conventional chemotherapy. Currently, only 2 drugs have been approved by the U.S. Food and Drug Administration (FDA ) for the treatment of patients with advanced pancreatic cancer: gemcitabine (Gemzar) and erlotinib (Tarceva).

Gemcitabine has been the standard for systemic therapy for patients with unresectable pancreatic cancer since the late 1990s. In a landmark study by Burris et al., patients with unresectable pancreatic cancer were randomized to receive either gemcitabine or 5-fluorouracil (5-FU). In terms of the primary outcome (namely, the clinical benefit) and the composite outcome (pain, weight, and performance status, as measured by the so-called Karnofsky performance scale), the gemcitabine patients fared significantly better (24% success rate) than the 5-FU patients (5%). Additionally, the gemcitabine patients saw a small but statistically significant improvement in their 1-year median survival rate (18%), as compared with the 5-FU patients (2%).

Gemcitabine inhibits DNA synthesis via competitive inhibition of DNA polymerase and via incorporation into replicating DNA. In addition to its antimetabolic effect, gemcitabine also has an antitumor effect by inducing apoptosis. In some solid tumor lines, including pancreatic cancer lines, gemcitabine induces apoptosis by activation of various caspases, such as caspase 8 and 3.

Gemcitabine is given intravenously 3 out of 4 weeks a month, at a dose of 1000 mg/m2 of body surface area. The major side effects are leukopenia (low white blood counts), fatigue, and rash.

Though still a fatal disease, advanced pancreatic cancer is no longer considered refractory (completely resistant) to treatment. Chemotherapy with gemcitabine can relieve a patient’s symptoms, improve the quality of life, and extend life expectancy, even though the survival advantage achieved with single-agent gemcitabine is quite modest. The median overall survival rate in patients on gemcitabine is 6 months.

The second-line regimens for patients with advanced pancreatic cancer include 5-FU and platinum-based compounds such as oxiplatin. Several studies have suggested that the combination of 5-FU with gemcitabine did not result in an improvement in the overall survival rate, as compared with gemcitabine alone. Nonetheless, gemcitabine-based combinations using platinum analogs were shown to be significantly superior to gemcitabine alone, with a higher patient survival rate and good functional status.

Erlotinib is a small-molecule inhibitor that binds to the ATP binding pocket of the EGFR, preventing phosphorylation, activation of the EGFR, and the downstream signaling cascade. In a mouse tumor xenograft model, erlotinib significantly inhibited EGFR phosphorylation, either as a single agent or in combination with gemcitabine. In human patients, in a large, randomized Phase II trial, the erlotinib and gemcitabine group saw a modest but statistically significant improvement in the progression-free and overall survival rates, as compared with the gemcitabine and placebo group. Given the results of that trial, the FDA approved erlotinib for use in combination with gemcitabine as first-line therapy for patients with advanced pancreatic cancer. The corresponding European regulatory agency (EMEA) has approved erlotinib for the treatment of metastatic pancreatic cancer.

Erlotinib is taken orally; the typical dose is 100 to 150 mg, independent of the body weight. Rash is the major side effect, usually appearing 8 to 10 days after treatment, most frequently on the patient’s head and upper body.

The limits of conventional cytotoxic (poisonous to cells) drugs for patients with pancreatic cancer have led to the development of immunotherapies, including cancer vaccination; however, the clinical results so far are quite disappointing. Phase II clinical trial showed some promising results with vaccines such as GV1001 that target telomerase (an important enzyme in DNA replication whose overexpression occurs early in the development of pancreatic cancer). A large phase III clinical trial in the UK is currently exploring the role of the vaccine TeloVac for patients with advanced pancreatic cancer.

Radiation Therapy:
The use of radiation therapy (also called radiotherapy) for patients with pancreatic cancer is a matter of debate. Results of the clinical trials have been controversial. Radiotherapy alone is rarely used for patients with advanced pancreatic cancer (when the tumor has invaded the surrounding blood and lymphatic vessels and nearby organs). Often, patients may receive low doses of chemotherapy along with radiation (chemoradiotherapy), because chemotherapy renders cancer cells more susceptible to radiation. The most common medications used in combination with radiotherapy are 5-FU and gemcitabine. The standard schedule for radiotherapy is Monday through Friday for 6 weeks. Radiotherapy alone may be used before a Whipple procedure or before a total pancreatectomy to reduce the size of the tumor.

Clinical Trials:
A Phase II study of R11577 (a farnesyl transferase inhibitor that, in preclinical studies, disrupted K-ras function) in patients with advanced pancreatic cancer showed no substantial activity of the compound. Another Phase III trial in patients with advanced pancreatic cancer demonstrated no significant survival advantage in patients receiving R115777 in combination with gemcitabine, as compared with gemcitabine alone.

More than 50% of pancreatic tumors overexpress EGF receptor and the level of EGFR positivity was shown to be associated with poor clinical outcomes. High levels of expression of EGFR make the molecule an attractive target for drug development. Two approaches have been taken to antagonize the EGFR signaling: antagonize ligand binding (with monoclonal antibodies) and compete with ATP binding (small molecules) therefore preventing downstream signaling. Monoclonal antibodies against EGFR include: Cetuximab, Matuzinab and small molecule inhibitors are Gefitinib, Erlotinib.

Cetuximab is a chimeric antibody of IG1 subclass that competes with natural ligands like EGF for binding to EGFR1 receptor. The compound has acceptable toxicities; the most common side effect of the compound is acne in 88% of patients.
A recent Phase III clinical trial failed to demonstrate a clinically significant increase in overall survival and in progression-free survival by adding cetuximab (a chimeric antibody of the IG1 subclass that competes with natural ligands like EGF for binding to EGFR1 receptors) to gemcitabine.

Angiogenesis provides the required substances for tumor growth and dissemination. The concept of targeting angiogenesis in cancer therapies is not novel and was suggested in 1970s by Folkman. VEGF is the most important factor inducing angiogenesis and an important target for the development of novel therapeutics. The most widely used compounds targeting the VEGF pathway are monoclonal antibodies such as Bevcizumab and Sorafenib. Bevacizumab is the only one that has been used in clinical trials on actual patients.

The results of Phase II clinical trials using a combination of bevacizumab and gemcitabine were promising, but the subsequent Phase III trial was interrupted early. The overall survival rate was lower in patients receiving both gemcitabine and bevacizumab group than in patients receiving gemcitabine alone.

Sorafenib is an orally available inhibitor of VEGF receptor-2 and also B-raf, a downstream signaling molecule of the VEGF pathway, which demonstrated in vitro activity in pancreatic cancer xenograft models. Despite promising in vitro results in xenograft models of pancreatic cancer, the results of a Phase II trial evaluating the efficacy of sorafenib in combination with gemcitabine were disappointing. The median overall survival time was only 4 months for the combination group, as compared with 6 months on gemcitabine alone.

Results of 2 randomized clinical trials comparing Marimastat (a novel MMP inhibitor) with a standard dose of gemcitabine were quite disappointing. Marimastat was shown to be inferior, in all parameters, to gemcitabine alone.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with all stages of pancreatic cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.



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