Laboratory research of cancer diseases, rack with RNA samples

Located just behind the stomach, measuring about 6 inches long and less than 2 inches wide, is an organ called the pancreas. Shaped like a fish with a wide head, a tapering body and a small, pointed tail, the pancreas contains 2 different types of glands – exocrine and endocrine – which are a vital part of the digestive system and a critical controller of blood sugar levels.

Tumors of the pancreas are malignant neoplasms arising in the pancreas. Because of its ‘hidden’ location, these tumors are rarely palpable. As a result, most symptoms of pancreatic cancer do not appear until the tumor has grown large enough to interfere with the function of the pancreas or other nearby organs including the stomach, duodenum, liver, or gallbladder.

Finding symptoms late in the development of pancreatic cancer makes this cancer difficult to treat. And, as a result, it may surpass the incidence of breast, prostate, and colorectal cancers. Experts believe that prostate cancer may become the second leading cause of cancer deaths in the coming decade. However, there is good news in the progress made in the development of novel treatments.


…[albumin-bound nab-paclitaxel] is the only chemotherapy approved in combination with gemcitabine based on an improvement in overall survival for first line metastatic pancreatic cancer patients and is fast becoming the standard of care in this extremely difficult to treat disease…


Incidence
Statistically, pancreatic cancer strikes approximately 9 out of every 100,000 people every year in the United States. Being one of the deadliest forms of cancer, the disease accounts for about 3% of all cancers in the United States and 7% of all cancer deaths. In real numbers, the American Cancer Society estimated that 45,000 Americans will be diagnosed with cancer of the pancreas. Furthermore, almost equal number of patients will die from pancreatic cancer during the first years after diagnosis. The average lifetime risk of developing pancreatic cancer is about 1 in 67 (1.5%). However, this risk may be altered by certain risk factors.

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Risk factors
According to the American Cancer Society, smokingis one of the most important risk factors for the development of pancreatic cancer. Statistical evidence suggest that this risk is about twice as high among smokers compared to those who have never smoked. Cancer-causing chemicals in cigarette smoke that enter the blood and damage the pancreas are considered one of the causes. Scientists believe that 20% to 30% of exocrine pancreatic cancer cases are caused by cigarette smoke. However, Cigar, pipe and the use of smokeless tobacco increases the risk of getting the disease.

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Other risk factors includebringing overweight. In very overweight or obese people 20% are more likely to develop pancreatic cancer. Age, gener, race, family history as well as exposure to workplace chemicals, including certain pesticides, dyes, and chemicals used in metal refining, may increase the risk of developing pancreatic cancer.

Pancreatic cancer is also more common in people who have type 2 diabetes (T2DM). Doctors believe that this type of diabetes, which often starts in adulthood, is often related to being overweight or obese – and may result in the development of pancreatic cancer. However, evidence shows that in some people pancreatic cancer may cause diabetes (and, interestingly, not the other way around). This can happen when cancer spreads through the pancreas and damages enough of the insulin-making cells to cause diabetes. Finally, pancreatic cancer may be cause by pre-existing conditions such as chronic pancreatitis, a long-term inflammation of the pancreas, and infection of the stomach with the ulcer-causing bacteria Helicobacter pylori(H. pylori) and excess stomach acid.

Not a single disease
One of the factors making treatment of cancer of the pancreas complex, is that it is not one disease. In fact,experts have identified as many as twenty different tumors that have been lumped under the term “cancer of the pancreas.” However, each of these tumors has a different appearance when examined. While some of these cancers require different treatments, each of them carry there own unique prognosis.

A new foundation for research
At this year?s ASCO Gastrointestinal Cancers Symposium (ASCO GI; being held in San Francisco,January 21-23, 2016), 10 studies, including phase I and Phase II studies, highlighted combinations that use albumin-bound nab-paclitaxel, a drug manufactured using patented nab? technology (Abraxane?; Celgene) and gemcitabine (Gemzar?; Eli Lilly and Company) establishing this therapy as the foundation for research in first-line metastatic pancreatic cancer.

In September 2013, the U.S.Food and Drug Administration (FDA) approved albumin-bound nab-paclitaxel as first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. Only a few months later, in December 2013, the drug,in combination with gemcitabine, was approved for first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas in Europe.

During ASCO GI Celgene announced results from multiple analyses evaluating the feasibility the outcomes of second-line treatments following the combination treatment with albumin-bound nab-paclitaxel and gemcitabine in first-line metastatic pancreatic cancer patients. These studies highlight the research into emerging treatment plans following treatment with albumin-bound nab-paclitaxeland gemcitabinein first-line metastatic pancreatic cancer.

?Abraxane is the only chemotherapy approved in combination with gemcitabine based on an improvement in overall survival forfirst linemetastatic pancreatic cancer patients and is fast becoming the standard of care in this extremely difficult to treat disease,? noted Jacqualyn A. Fouse, Ph.D., President, Hematology/Oncology at Celgene. ?We are excited that Abraxaneplus gemcitabine is serving as the foundation for a new wave of potential treatments that may further improve the treatment paradigm in this disease and are fully committed to continuing to serve these patients.?

Albumin-bound nab-paclitaxel + gemcitabine followed by 5-FU-based therapies
Results from multiple analyses presented during the 2016 ASCO Gastrointestinal Cancers Symposium (ASCO GI) also evaluated the outcomes of second-line treatments following albumin-bound nab-paclitaxel and gemcitabine in first-line metastatic pancreatic cancer patients.

In particular, a post-hoc analysis of MPACT (MetastaticPancreaticAdenocarcinomaClinicalTrial), the pivotal phase III study of albumin-bound nab-paclitaxel and gemcitabine compared with gemcitabine alone in first-line metastatic pancreatic cancer evaluated the outcomes of patients who received a second-line treatment during an observational extension of the study.[1][2][3]

In this study, a total of 347 (40%) patients received second-line therapy in the extension, and of those patients, the majority (77%, including 132 who had received albumin-bound nab-paclitaxeland gemcitabinein the first line and 135 who had received gemcitabine alone) received 5-FU-based therapies or capecitabine combinations.

A post hoc analysis of overall survival (OS) was conducted and demonstrated that patients (n=170) who received albumin-bound nab-paclitaxel and gemcitabine, followed by second-line therapy had a median OS of 12.8 months, compared with 9.9 months for patients (n= 177) who received gemcitabine alone, followed by second-line therapy. Of patients receiving second-line therapies, the majority (n=132) received 5FU or capecitabine-containing regimens and had a median OS of 13.5 months. Patients receiving FOLFIRINOX* following albumin-bound nab-paclitaxel and gemcitabine (n=18)had the longest median overall survival at 15.7 months. OS was calculated using the Kaplan-Meier method.

The analysis provided data demonstrating the feasibility of second-line treatment in patients with MPC after first-line albumin-bound nab-paclitaxeland gemcitabine.

?As the body of research and approved options increase in pancreatic cancer, there is now evidence that second-line treatment is feasible and beneficial for certain patients with metastatic disease,? said David Goldstein, MD, medical oncologist at Prince of Wales Hospital in Sydney,Australia and the lead investigator of the analysis. ?We are seeing an exciting evolution in the treatment of this disease and for patients and physicians, it is now time to consider a total treatment plan when choosing an initial therapy.?

Navigating Cancer
A retrospective cohort study performed using data U.S. community data from Navigating Cancer, an electronic medical record platform, sought to compare the time to treatment discontinuation and database persistence, used as a proxy for OS, between albumin-bound nab-paclitaxeland gemcitabineand FOLFIRINOX in the first-line setting.

The analysis showed that time to treatment discontinuation and database persistence for patients with first-line metastatic pancreatic cancer (n=202) were numerically similar (8.6 in each arm) between albumin-bound nab-paclitaxeland gemcitabine(n=122) and FOLFIRINOX(n=80). With the exception of the age of patients, which favored FOLFIRINOX(median age 67 for albumin-bound nab-paclitaxeland gemcitabineyears vs. 61.4 years for FOLFIRINOX), baseline characteristics were generally similar between the groups.

The analysis also showed that tthere was a higher incidence of adverse events (all grades) with FOLFIRINOXcompared with albumin-bound nab-paclitaxeland gemcitabine(95% vs. 84%). Most common adverse events?s that led to discontinuation were anemia (8% for FOLFIRINOXand 2% for albumin-bound nab-paclitaxeland gemcitabine), neutropenia (6% for each), and dehydration (5% and 3%, respectively).

The analysis further evaluated various treatment plans including first-line albumin-bound nab-paclitaxeland gemcitabine, followed by second-line 5-FU-based therapies and first-line FOLFIRINOX, followed by second-line gemcitabine-based therapies. The duration of treatment for the albumin-bound nab-paclitaxeland gemcitabinearm was a median 8.7 months, compared with 8.4 months for the FOLFIRINOXarm (p=0.52). Further, the database persistence (proxy for OS) for patients receiving albumin-bound nab-paclitaxeland gemcitabine followed by 5-FU-based therapies (n=25) was a median 12.7 months, compared with 9.3 months for patients receiving FOLFIRINOXfollowed by gemcitabine-based therapies (n=41)(p=0.48).

Other clinical trials
During ASCO GI a number of other trials involving albumin-bound nab-paclitaxeland gemcitabinewere presented. Among these trials were a phase I study with demcizumab, is a humanized IgG2anti-DLL4 antibody that inhibits tumor growth and decreases cancer stem cell frequency in human tumor xenograft models in combination withgemcitabine +/- albumin-bound nab-paclitaxelin patients with pancreatic cancer. The trial results confirmed clinical encouraging activity in which this novel therapy was generally well tolerated with fatigue, nausea and vomiting being the most common related adverse events. The researchers involved in this trial showed that truncated demcizumab dosing (i.e., limited to 70 days) avoided clinically significant cardiopulmonary toxicity.

Another trial phase II/IIItrial (NCT02436668)has been initiated to evaluate the efficacy of ibrutinib (Imbruvica?; Pharmacyclics/Janssen Biotech) in combination with nab-paclitaxel and gemcitabine for the first line treatment of patients with metastatic pancreatic adenocarcinoma. [4 – 8]

Researchers also considered the treatment of patientswith stromal hyaluronan (HA)-high tumors receiving PEGPH20 + nab-paclitaxel + gemcitabinevs. albumin-bound nab-paclitaxeland gemcitabine alone. To compare the treatment effect of PEGPH20 combined with nab-paclitaxel and gemcitabine to nab-paclitaxel and gemcitabine in patients with Stage IV pancreatic cancer, they developed a new phase II trial designed tostudy safety and treatment effect in 237 subjects (2:1 randomization, PEGPH20 + albumin-boundnab-paclitaxel + gemcitabine : albumin-bound nab-paclitaxeland gemcitabinealone), preceded by two run-in phases (the first to assess safety and tolerability and a second to assess a new formulation of PEGHP20), 16 subjects total (randomized 3:1). [4 – 8]

An interim analysis of this ongoing phase II trials of this study showed significant improvements in PFS and ORR and a trend toward improved OS. Overal, PEGPH20 + nab-paclitaxel + gemcitabine was well tolerated, with thromboembolic events reduced with enoxaparin (LMWH) prophylaxis. A global phase III trial of PEGPH20 + albumin-boundnab-paclitaxel + gemcitabine will initiate later in the first quarter of 2016. [4 – 8]


* FOLFIRINOX, a chemotherapy regimen for treatment of advanced pancreatic cancer,emerged in 2010 as a new treatment for patients with metastatic pancreatic cancer. The treatment is made up of four drugs including

  • Folinic acid(leucovorinm or ‘FOL’), a vitamin B derivative that modulates/potentiates/reduces the side effects of fluorouracil
  • Fluorouracil(5-FU or ‘F’), a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops DNA synthesis,
  • Irinotecan (Camptosar or ‘IRIN’), a topoisomerase inhibitor, which prevents DNA from uncoiling and duplicating, and,
  • Oxaliplatin (Eloxatin or ‘OX’), a platinum-based antineoplastic agent, which inhibits DNA repair and/or DNA synthesis.

Last editorial review: February 2, 2016.

Featured Image: Laboratory research of cancer diseases. Courtesy: (c) 2016 Fotolia. Used with permission.

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