New protocol improves odds for previously unresectable pancreatic cancers

Pancreatic ductal adenocarcinoma is a highly aggressive malignancy with a dismally poor prognosis. For all stages of pancreatic cancer, the one- and five-year survival rates are 20 percent and 5 percent, respectively. The main cause is late detection and tumor spread, which affects 50 percent of patients at diagnosis. For this group, palliative chemotherapy is most often the only treatment option.

Only 15 to 20 percent of patients are considered surgically resectable. Although surgery offers the only chance of a potential cure, the majority of patients develop metastatic disease after seemingly curative operations — the result of undetectable cancer spread at the time of the operation.

Because surgery alone is of no benefit, the standard of care for the last two decades has been surgery followed by chemotherapy. Although technical refinements and modern advances in postoperative care have reduced severity of surgical complications and operative mortality, they have had no real impact on long-term cancer survival. Patients with resectable cancers have an average survival of 18 to 20 months, and overall five-year survival rates are 20 to 25 percent.

Mark J. Truty, M.D., M.S., a surgical oncologist at Mayo Clinic's campus in Rochester, Minnesota, explains:

"Resectability is more than just removability. It is dependent on a variety of factors that determine whether or not an operation will improve a patient's long-term outcome over nonoperative treatment with chemotherapy and radiation.

"An operation for pancreatic cancer is only successful if three requisites are met. First, the cancer must be capable of being removed with a negative margin. This depends on the extent of the local involvement of the tumor and nearby critical vascular structures, complexity of the operation, and experience of the surgeon. Second, patients must not have any evidence or suspicion of metastases. Finally, patients must be able to tolerate an extensive operation with limited and reversible complications that allow them to receive chemotherapy after surgery. The terrible and stagnant outcomes that we have seen with the current standard of care in pancreatic cancer primarily occur because these three requisites are not being met."

Mayo Clinic is now utilizing a unique multimodality neoadjuvant approach in which chemotherapy followed by radiation is administered before surgery in an effort to address all three requisites. This approach can shrink the tumor and improve the probability of a margin negative operation. It also identifies patients who have occult metastases at diagnosis, thereby sparing them unnecessary high-risk surgery; if chemotherapy cannot control the cancer preoperatively, there is no reason to think it will postoperatively. Finally, it gives patients time to physically improve and nutritionally prepare for a complex and aggressive operation in an effort to limit postoperative complications.

"One of the challenges of pancreatic cancer is that patients are malnourished and debilitated, so it's not unexpected that they would have poor outcomes," Dr. Truty says. "In our protocol, patients are working with physicians, therapists and dietitians while receiving chemotherapy for several months, followed by radiation treatment. At the end of neoadjuvant treatment — and prior to surgery — they are in much better shape, physically and mentally."

The initial chemotherapeutic agents depend primarily on a patient's physical status. FOLFIRINOX (folinic acid, fluorouracil, irinotecan and oxaliplatin) and gemcitabine plus paclitaxel have proven efficacy over previous therapies, but FOLFIRINOX, because of its toxicities, is better suited to younger, stronger patients.

In all cases, careful patient selection is critical for good outcomes.

"We are looking for no metastases, regression or nonprogression of the primary tumor, a biomarker response, and improvement in clinical symptoms at diagnosis. Patients who fulfill these criteria and go to surgery do markedly better than average," Dr. Truty explains. "Margin rates are improved, lymph node involvement is less, and in many cases, there is very little tumor left. Before it was a game of chance. Now we are trying to strategize and perform the right operation on the right patients."

Long-term data for the multimodality approach is promising — a doubling of median survival to 30 or 40 months and a five-year survival rate of 30 to 40 percent. Dr. Truty expects the numbers will continue to improve and says similar strategies utilized elsewhere may not have achieved the same results due to a lack of standardization.

"We offer a protocol-based approach," he says. "Although each patient and cancer is different, we limit variability to maximize outcome. This helps us push the envelope surgically, to take patients who were previously unresectable and get them through aggressive, complex procedures with multiple vessel resections and reconstructions. These are high-stakes operations, but we feel they are worth it because outcomes are significantly improved with the multimodality approach.

"We see many patients who are being denied a potential cure because the outcomes for this disease are historically poor and physicians may not be aware of the therapeutic revolution that has occurred in the last few years. Obviously, there is still room for improvement, but our message to patients and providers is not to accept the initial opinion that their pancreatic cancers are inoperable."