The 38,460 MENACE

In 2013, an estimated 45,220 new cases of pancreatic cancer will be diagnosed, affecting men and women nearly equally, and an estimated 38,460 deaths will occur, making pancreatic carcinoma the fourth-leading cause of U.S. cancer deaths, with incidence slowly but steadily increasing in the last decade. This especially deadly cancer has an overall survival rate of less than 4 percent and a five-year survival of 6 percent in both the United States and Europe. In about 90 percent of cases, pancreatic cancer has already metastasized by the time of diagnosis, which partly accounts for its high mortality rate. Of the 10 percent in which the tumor is still local, only half are surgery candidates.

Pancreatic cancer is frequently in the news for reasons in addition to its intractability. Recently, celebrities including Luciano Pavarotti, Patrick Swayze, Steve Jobs, and Bonnie Franklin have succumbed to it, and the resulting media coverage has raised public awareness. Although new treatments are vigorously sought, advances in the main approaches—chemotherapy/radiation and/or surgery—have proven difficult to come by. Improvements in survival are still measured only in months; for most patients, treatment is palliative at best. Disease profile (i.e., whether the mass is located in the pancreas head, body, tail, or uncinate process, as well as whether or not it has spread) guides treatment choice, but many consider staging unhelpful beyond the broad categories of resectable or not when resection is currently the only hope of cure. Most pancreatic cancers are adenocarcinomas (95%), by far the most difficult to treat.

With the large majority facing grim prognoses, patients are commonly encouraged to participate in clinical trials.

Surgery

Surgery is considered the primary treatment modality when possible because it offers the highest degree of palliation and, in some cases, increases short-term survival.

For less than 20 percent of patients, with small tumors localized to the pancreas head and/or neck, complete resection with pancreatoduodenectomy (Whipple procedure) improves five-year survival to 18 to 24 percent. However, the resulting reduction in islet cells impairs insulin production and often causes secondary diabetes, especially in those who were already experiencing blood sugar control difficulty (the jury is still out in these cases, whether the cancer caused the islet dysfunction or vice versa).

Still, for some patients, “the original problem is much worse than having diabetes so the treatment is worth the risk,” says Jay H. Shubrook Jr., DO, of the UMA Diabetes and Endocrine Clinical Care and Research Center in Athens, Ohio.

A study conducted at Johns Hopkins University in Baltimore found that having Whipple done by an experienced surgeon at a center where the procedure is commonly done improves outcome more than any other prognostic indicator.

In a trial at the University of Texas Cancer Center, researchers led by Mark J. Truty, MD, reevaluated a cohort of 88 high-risk patients with a previous failed surgery and deemed 81 eligible for another attempt at resection. After restaging the tumor, surgeons used chemoradiation before again attempting resection. Of the 81 patients, 66 underwent successful pancreatectomy and had an average survival of about 2.5 years. Multimodal treatment has demonstrated conflicting results, but this trial reversed the typical sequence of treatments by doing chemoradiation before surgery rather than postoperatively. Adjuvant therapy can be done at any treatment stage.

Patients with unresectable cancers may benefit from palliative surgery, and particular symptoms may depend on tumor location and extent. For patients with biliary obstruction, a stent placed during endoscopic retrograde cholangiopancreatography (ERCP) can relieve associated symptoms, such as jaundice, nausea, and vomiting. Celiac axis and intrapleural nerve block helps reduce tumorassociated pain. Psychologic treatment can also be implemented to address the disabling effects that receiving this grim diagnosis can produce.

Short of complete resection, although quality of life improves, overall survival does not. Researchers are now turning to genetics to try to better understand pancreatic cancer, with the recent discovery that pancreatic adenocarcinoma develops over many years through progressive pancreatic intraepithelial neoplasia, commonly diagnosed with ERCP. Thus, targeted therapies are another area showing promise. Erlotinib ablates epidermal growth factor receptor, for example, to stunt tumor growth.

Chemotherapy

Hands down the best news in pancreatic cancer research comes from the chemotherapy sector, with two new drug combinations making inroads as potential new first-line therapies. For many years, first-line chemotherapy has consisted of the single agent gemcitabine, increasing survival by five to seven months. Trials adding various cytotoxic agents to the gemcitabine regimen generally did not increase survival beyond what gemcitabine alone accomplished.

Until recently, that is. Phase 3 of the Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) study of 861 patients, which was presented at the January 2013 Gastrointestinal Cancers Symposium, “demonstrated a survival benefit of gemcitabine/nab-paclitaxel over gemcitabine,” says Andrew H. Ko, MD of the University of California in San Francisco. Although the survival benefit is modest at overall two months, researchers are encouraged with any survival increase with this notoriously tough cancer. Nab (nanoparticle albumin-bound)-paclitaxel is currently indicated for breast cancer.

Gemcitabine, alone or in combination, was considered the “reference regimen” for pancreatic cancer chemotherapy until FOLFIRINOX improved survival time better than any other agent(s) in a 2005–2009 French study led by Thierry Conroy, MD, at Université de Lorraine, Nancy, France. This regimen of fluorouracil, leucovorin, irinotecan, and oxaliplatin not only nearly doubled survival time to 11.1 v. 6.8 months compared to gemcitabine in phase 3 of the study, but it also increased time until quality-of-life deterioration, with 31 percent reporting significant decrease.

However, FOLFIRINOX users had higher incidences of adverse events including neutropenia, thrombocytopenia, diarrhea, sensory neuropathy, and alopecia. Researchers concluded that FOLFIRINOX is a first-line choice for advancedstage disease patients age younger than 76 years with healthy hearts and livers who are still either as active as or slightly less active than they were prior to diagnosis. A subsequent companion French study published in 2012 with quality of life as the primary endpoint demonstrated that FOLFIRINOX outperformed gemcitabine.

While hopeful, the FOLFIRINOX findings do not apply to most pancreatic adenocarcinoma patients, who would not meet the treatment criteria and for whom the drug combination would prove too toxic. For these less robust patients, nab-paclitaxel is perhaps soon to be an option, though a more expensive one.

For now, the best approach seems to be differentiated treatment, which takes into account individualized factors, including genetic markers, tumor staging, and overall patient health.

“With the greater array of options that physicians and patients will have to choose from in the future, the key will be to identify patient and tumor features that help guide this decision-making process,” says Ko.

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