Genetics, Signaling Paths Next Frontiers in Pancreatic Cancer Treatment
Article date: October 28, 2010
By Melissa Weber
Pancreatic cancer’s reputation hasn’t been a pretty one. It usually lurks inside the body undetected until it's reached an advanced stage, and when finally caught, rejects just about any treatment. Only about 5% of patients live five years past diagnosis, which is among the lowest survival rates for any cancer.
But 2 new treatment theories could offer new hope against this difficult to treat disease. One is rooted in genetics, hitting the disease by exploiting a gene that is mutated in some patients. The other aims to crack the cancer’s life-sustaining armor. Along with targeted approaches like these, researchers are also actively pursuing new ways of using existing drugs.
“The hope is that… there will be clear new directions in terms of the next decade of treatments,” says pancreatic cancer specialist Eileen O’Reilly, MD, of Memorial Sloan-Kettering Cancer Center in New York.
Where We Are Now
Roughly 43,000 people are diagnosed with pancreatic cancer in the US each year, and fewer than 1 in 5 of these cancers are caught early enough to be surgically removed.
Yet even after the tumor is removed, the cancer reappears about 80% of the time. Post-surgery treatment to try to reduce the risk of recurrence is critical, but the options have been historically limited.
One of the most common treatments is the chemotherapy drug gemcitabine (Gemzar). Another is a chemo combo that pairs 5-FU with leucovorin. Doctors have used both treatments in pancreatic cancer patients for years, but a recent study published in the Journal of the American Medical Association sought to determine which of the two was more effective.
There was no clear winner: researchers found that patients in both groups lived about 23 months. Gemcitabine did get the edge when it came to serious side effects, causing fewer cases of severe diarrhea and mouth sores than patients taking the 5-FU/leucovorin combo.
New Ways to Use Old Treatments
Although the survival rates in both groups were almost identical, the study’s lead author said the results will nonetheless affect the current approach to treatment after surgery.
“It gives the option to use either 5-FU or gemcitabine, use the other when one fails, use them in combination, or use combinations based either on 5-FU or gemcitabine,” says John Neoptolemos, MD, director of the University of Liverpool’s cancer research center in the United Kingdom. “From this trial, we now have greatly increased options for future directions.”
One of those possible directions is an ongoing trial to determine whether adding capecitabine (Xeloda), an oral form of 5-FU, to gemcitabine can help prevent the return of pancreatic cancer after surgery. Results of this study, also led by Neoptolemos, won’t be available for at least 5 years.
For patients diagnosed too late for surgery, O’Reilly says an emerging treatment option to combat metastatic disease is a multi-drug combination dubbed FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin). Patients receiving FOLFIRINOX lived more than four months longer than patients receiving gemcitabine alone (11.1 months versus 6.8 months), according to early results from a study presented in June at the annual meeting of the American Society of Clinical Oncology.
The catch? Patients enrolled in the trial were limited to those in otherwise good health. O’Reilly says taking FOLFIRINOX means being able to withstand the sometimes severe side effects, such as low blood counts, numbness or pain in the hands and feet, vomiting, fatigue, and diarrhea.
“A fit individual with a high level of functioning stands to benefit from a combination approach,” she says. “People who are frail, whether because of the disease and its complications or because of other medical illnesses, definitely don’t do well with intensive combinations and are often better served by a single-agent approach along with supportive care.”
Where We’re Headed
Recently, a better understanding of what’s going on inside a pancreatic tumor—and what caused it to develop in the first place—has provided some possible new paths for fighting this complex cancer.
O’Reilly and Neoptolemos agree that one of the most promising new areas of research involves targeting what’s called the stroma—the matrix that surrounds cancer cells, fueling their survival and growth. This dense layer of tissue is especially tough in pancreatic tumors, which may help prevent chemotherapy drugs or other treatments from getting to the cells. This may help explain why these treatments haven't been very effective. A signaling pathway known as “hedgehog” plays a key role in this process, and a number of drugs that inhibit hedgehog signaling are now in development. With the tumor’s protective environment in disarray, O’Reilly says chemotherapy drugs may better penetrate the tumor's tough veneer. Researchers funded by the American Cancer Society are among the scientists studying this issue.
New treatments may also come from peering inside a person’s genes. O’Reilly says 5% to 7% of patients with pancreatic cancer may harbor mutations in the BRCA1 or BRCA2 genes, which are best known for increasing the risk of breast and ovarian cancers.
Grabbing her attention is a new class of drugs called PARP inhibitors, which have shown promising early results in breast and ovarian cancer patients with BRCA mutations. When DNA is in need of repair, BRCA proteins normally help mend the damage. Cancer cells with BRCA mutations can't rely on these proteins, but another repair protein in the cells called PARP serves as backup. Knock out PARP and the cancer cell can’t repair itself. PARP inhibitors may prove especially useful when used along with chemotherapy.
American Cancer Society-funded researchers have identified other genes, such as KRAS and p53, that play a role in pancreatic cancer, widening the field of potential targets for new therapies. The Society currently funds 31 research projects looking at pancreatic cancer treatments, diagnosis, prevention, and causes.
Reviewed by members of the ACS Medical Content Staff
Citations: “Adjuvant Chemotherapy With Fluorouracil Plus Folinic Acid vs Gemcitabine Following Pancreatic Cancer Resection.” Published in the Sept. 8 issue of the Journal of the American Medical Association. First author, John Neoptolemos, University of Liverpool.
“Randomized phase III trial comparing FOLFIRINOX versus gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma: final analysis results of the PRODIGE 4/ACCORD 11 trial.” Presented at the 2010 American Society of Clinical Oncology annual meeting (Abstract No. 4010). Presenter, Thierry Conroy, Centre Alexis Vautrin.
“Importance of Age of Onset in Pancreatic Cancer Kindreds.” Published in the Jan. 20 issue of the Journal of the National Cancer Institute. First author, Kieran Brune, Johns Hopkins School of Medicine.
ACS News Center stories are provided as a source of cancer-related news and are not intended to be used as press releases.
Thank you for your feedback.