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Pancreatic Cancer

Conventional Medical Treatments for Pancreatic Cancer

Pancreatic cancer is one of the most challenging cancers for oncologists. Typical conventional treatments for pancreatic cancer include chemotherapy, radiation therapy, immunotherapy, biologically-targeted therapies, and surgery. Chemotherapy and radiation therapy are typically not curative and provide only minor increases in survival rates in most cases. The median survival is only 10-12 months (Kim 2007). The 5-year survival of patients who undergo conventional treatment with surgery, chemotherapy, and radiation therapy is about 20%. However, the overall 5-year survival rate is 5%, as only 15% of patients are eligible for surgery (Fisher 2011). In those cases diagnosed with locally advanced unresectable or metastatic pancreatic cancer, palliative management is typically the goal (Gomez-Martin 2011).


Only 15% of pancreatic cancer patients may be eligible for complete surgical removal of their tumors, a procedure known as a Whipple resection. This is a high-risk procedure with a mortality rate of 15% and a five-year survival rate of only 10% (Snady 2000). The median survival time for the inoperable 85-90% of cases is often only a few months. Management of these cases is based on relieving symptoms (referred to as palliative care).

Various chemotherapy drugs may be used before or after surgery to remove most of the tumor. Chemotherapy combined with radiotherapy is often used in the standard treatment of pancreatic cancer (Snady 2000).


Radiation therapy, such as intensity modulated radiation therapy (IMRT) is used to provide symptom relief, improve pain and rarely prolongs survival (Gomez-Martin 2011). Refer to the Cancer Radiation protocol for information on supporting healthy tissues during radiation therapy.

Pancreatic tumor cells with mutant ras genes are more difficult to kill with radiation than are cells with normal ras genes (McKenna 2003). However, experiments showed that the FTI (farnesyl transferase inhibitor) tipifarnib (Zamestra™) made pancreatic cancer cells with a K-ras mutation more sensitive to the killing effects of radiation (Hussein 2009; Alcock 2002). Therefore, the combination of dietary-derived ras inhibitors and radiation may offer therapeutic advantages for those undergoing radiotherapy (Shi 2005).


Gemcitabine (Gemzar™) has been the standard chemotherapeutic agent for the past decade but it has not significantly improved the average survival rate. Furthermore, chemotherapy often causes intolerable levels of toxicity. Six months of chemotherapy with Gemzar™ after surgery improves 5-year survival from 9% to 21% (Neuhaus 2008). Even when Gemzar™ is combined with other chemotherapy drugs (Xeloda™ or cisplatin), or targeted-therapies such as EGFR inhibitors (Tarceva™ or Cetuximab™), there is minimal improvement in survival (Fisher 2011). Clinical trials with the favored, but aggressive FOLFIRINOX (chemotherapy cocktail) produced a median overall survival of 11.1 vs. 6.8 months (with Gemzar™) but with significantly worse side-effects (Conroy 2011).

Pancreatic cancer-gemcitabine chemoresistance is associated with enhanced NF-kB activation. The well-known capacity of omega-3 fatty acids to inhibit NF-kB (Ross 2003) and promote tumor cell death has the potential to restore or facilitate gemcitabine chemosensitivity (Hering 2007). Curcumin may also help circumvent chemoresistance via downregulation of NF-kB signaling (Yu 2011).

Anticoagulants in the Management of Pancreatic Cancer

Increased coagulation (blood clot formation or thrombosis) is common in pancreatic cancer patients and presents a life-threatening complication (Shah 2010). Moreover, advanced pancreatic cancer is associated with a high risk of patients developing venous thromboembolism (VTE); incidence range from 17% to 57% and is associated with a poor prognosis (Yates 2011; Pruemer 2005). Emerging clinical data strongly suggests that anticoagulant treatment may improve pancreatic cancer patient survival by decreasing thromboembolic complications as well as by separate anticancer activity (Mandalà 2011; Nakchbandi 2008).

Pancreatic cancer is usually associated with obstruction of the bile duct, which can elevate the level of fibrinogen. Elevated fibrinogen increases the risk of thrombosis and is also associated with increased invasiveness, metastasis, and poor clinical outcome. Increased fibrinogen levels result in increased platelet aggregation and therefore increased risk of blood clotting (Wang 2009).

Aspirin inhibits platelet aggregation (i.e. has antithrombotic effects) primarily by irreversibly inhibiting cyclooxygenase-1 (COX-1). Moreover, daily aspirin use (75 mg and up) for at least 5 years reduces deaths due to pancreatic cancers. The benefit increases with duration of use (Rothwell 2011).

Furthermore, recent data suggests that aspirin use greater than or equal to 1 day/month is associated with significantly decreased risk of developing pancreatic cancer. This association was also found for those who took low-dose aspirin for heart disease prevention (Tan 2011).

Preclinical studies confirm that aspirin significantly suppresses pancreatic cancer development by inhibiting the proliferation of pancreatic cancer cells, in vitro, through cell cycle arrest. In vivo studies show that aspirin delays the progression, and partially represses the invasion, of pancreatic cancer formation through inhibition of NF-kappaB activation (Fendrich 2010; Sclabas 2005).

Aspirin augments the anti-cancer effects of gemcitabine as well as its pro-apoptotic effect in pancreatic cancer cells. It also inhibits proliferation of gemcitabine-resistant human pancreatic cancer cells (Ou 2010).

Data indicate that the anticoagulants low molecular weight heparin (LMW heparin) and warfarin have a beneficial effect on the treatment of patients with pancreatic carcinoma (Conroy 2011; Sohail 2009). LMW heparin (added to gemcitabine plus cisplatinum) resulted in a significant improvement in survival over the use of chemotherapeutic agents alone (13.0 versus 5.5 months) (Icli 2007). However, another recent study did not show a survival benefit of LMW heparin (nadroparin) in patients with advanced pancreatic cancer (van Doormaal 2011). The addition of warfarin to chemotherapy increased mean survival from 2.3 to 5.0 months (Nakchbandi 2006).

Many dietary and botanical supplements have anticoagulant, antiplatelet and/or anti-thrombotic effects. These include omega 3-fatty acids from fish oil, vitamin E, ginger, and gingko (antiplatelet properties); dong quai and anise (anticoagulant effects); fucus (bladder wrack) (heparin-like activity); and high doses of vitamin E. However, caution should be exerted as the aforementioned can interact with standard anticoagulants and antiplatelet drugs such as aspirin, warfarin, and LMW heparin (Mousa 2010).

Determining thrombotic risk with biomarker tests (via blood tests) is crucial to identify those pancreatic cancer patients at highest risk of VTE in order to improve prognosis (Menapace 2010). Biomarkers associated with increased VTE risk in cancer include platelet and leukocyte counts, C-reactive protein, D-dimer, and PT time (Sohail 2009).

Biologically Targeted Therapies

It is well-known that specific gene mutations (e.g., K-ras, p53) are involved in pancreatic cancer development and progression, which is why drugs have been developed to specifically target these genes. However, even patients that have a known gene mutation (e.g., K-ras) respond differently to targeted treatments because the gene mutation itself can vary between patients (e.g., K-ras often mutates at codons 12, 13, or 64). Therefore, when the targeted treatment is tested in genetically dissimilar patients, it often fails (Fisher 2011). Clinical trials investigating therapies targeting K-ras, EGFR, vascular endothelial growth factor (VEGF), immunotherapy using tumor-associated antigens, and biologic therapy such as TNFerade (GenVec, Inc., Gaithersburg, MD) have all failed to substantially improve survival (Fisher 2011).

Example: K-ras. In pancreatic cancer, constitutively active K-ras is found in over 95% of tumors, making it a molecular fingerprint of this cancer (Kranenburg 2005). K-ras initiates pancreatic cancer development and is also involved in its progression. As K-ras plays such a critical role in pancreatic cancer, there has been extensive research to discover compounds that inhibit it and the pathways it affects. Researchers have tried using farnesyltransferase inhibitor (FTI) drugs to suppress the K-ras gene, but with no success: A phase III clinical trial with Tipifarnib (Zamestra™), which targets Ras farnesylation, plus gemcitabine, did not improve survival (Fisher 2011).

For targeted therapy to work, the target must be present in the tumor cells, even if the percentage of tumor cells harboring that mutation is small. Therefore, tumor cell gene mutation analyses would need to be performed for each patient prior to any proposed targeted treatment strategy. These molecular analyses (which are not FDA-approved or widely available to pancreatic cancer patients) for the expression of drug targets (e.g., K-ras, p53, etc.) and chemoresistance markers, in tumor cells can be performed by independent laboratories, such as Genzyme Genetics.

The Pharmacogenomics Approach

In the personalized genomic approach a patient’s tumor(s) would be biopsied and undergo rapid sequencing analysis or biotyping and then compared to the patient’s genetic mutations, so that a personalized treatment strategy could be developed. This method would quickly decipher all targets and differences among patients and their tumors thus identifying which patients should respond to particular combinations of targeted therapies. Instead of taking a one-size-fits-all approach to pancreatic cancer, shared mutations would be matched to a particular drug. For example, Her2 amplification, which occurs in 2% – 3% of pancreatic cancers, might allow some pancreatic cancer patients to be candidates for anti-Her2 drugs, such as trastuzumab or lapatinib.

With a personalized genomic approach, a combination of multiple targeted therapies is most likely to be effective for patients whose tumors have been analyzed and shown to have specific markers (e.g., Kras, p53, Her2 etc.) that can actually be targeted. Repeat sequencing analysis could be performed at frequent intervals during treatment, or if new metastases or recurrent disease occurred, and treatment could be changed accordingly to take into consideration any genetic differences between the original tumor and metastatic cancer cells.

Certain genetic tests are already commercially available by direct consumer marketing to patients, even though their efficacy has not been proven in large scale clinical trials. For example, European laboratories perform molecular analyses of tumor cells for the expression of drug targets and chemoresistance markers, from a blood sample, tumor tissues, ascites or bone marrow. In the future, the genome of individual patients and their tumors will be available at an affordable cost.

To learn more about advanced molecular testing, refer to the Life Extension Magazine article "Designing an Individually Tailored Cancer Treatment Utilizing Advanced CTC Molecular Analysis".