• Cancer

    A revolution in pancreatic cancer treatment

Mark Truty, M.D., during his first year of college, with his father, Kazimierz, shortly before he was diagnosed with pancreatic cancer.

Mark Truty, M.D., has dedicated his career to giving patients with pancreatic cancer more quality time with their loved ones. Much more time. The mission is personal for him. His own father, Kazimierz Truty, a Polish immigrant and mechanic at a meatpacking plant near Chicago, died 20 years ago from pancreatic cancer at age 58.

“My dad had typical symptoms of back pain, weight loss and diarrhea,” says Dr. Truty, a surgeon in Mayo Clinic's Division of Hepatobiliary & Pancreatic Surgery. “His symptoms continued, and he developed jaundice and was admitted to a community hospital. A general surgeon who wasn’t experienced with pancreatic cancer operated on the tumor, which was wrapped around blood vessels, and cut through the tumor in trying to remove it. My dad was in the hospital for 89 days, had two more emergency operations and eventually went home, too ill for chemotherapy. He died in my arms after weeks of suffering.

“I was 19 years old, so it was a while ago, but scenarios exactly like this still happen across the country every day,” he says. “When I got into medicine, I knew we had to advance the science and treatment for this disease. Pancreatic cancer treatment hadn’t evolved in three decades. Doctors did the same thing — performed inadequate operations on those whom surgery was unlikely to benefit and avoided surgery in many patients who would potentially benefit from an operation — and expected different results. This approach has been a miserable failure. I applied the surgical skills I learned from my mentors at Mayo Clinic during my training and collaborated with colleagues in other disciplines to break away from that traditional dogma.

“Patients want to know there’s hope. They want another holiday with their loved ones. After they’re diagnosed, they ask me if they’ll live to see another Christmas. Now I get to tell many of them yes.”

Upending traditional treatment

How are Dr. Truty and his Mayo Clinic surgical colleagues so confident in their ability to help patients see another holiday? They’ve upended traditional treatment for pancreatic cancer by introducing a sequenced treatment strategy that’s being mimicked at other leading medical centers around the world.

The multidisciplinary approach includes boosting patients’ health to endure treatment, providing neoadjuvant chemotherapy and radiation, and performing aggressive operations.

The numbers don’t lie. Patients with stage III pancreatic cancer (traditionally inoperable) have had eye-popping improvement in their outcomes. And they show no signs of cancer recurrence in follow up.

Realizing surgery alone isn’t enough

The three-decades-old practice Dr. Truty describes involved a standard approach to surgery — operating on only very localized tumors that account for 15 percent of patients, followed by chemotherapy (proven to improve survival) if the patient could tolerate it. There was a glitch, however: many patients didn’t receive the recommended chemotherapy due  to challenges recovering from surgery or a belief that they didn’t need it.

Despite significant technical improvements in the operation and advances in perioperative patient care, long-term outcomes and average length of survival didn’t budge, averaging only 20 to 24 months. One reason for that may be that tumors thought to be localized had actually spread, reinforcing the concept that although surgery is necessary for long-term survival, it is not sufficient and alone is of minimal benefit. Dr. Truty says all patients with pancreatic cancer need chemotherapy to treat micrometastases.

“It was great that we learned how to safely perform these complex surgeries and decrease complications, but that alone wasn’t going to affect longevity,” says Dr. Truty. “Technical advances cannot defeat biological limitations.”

Wish list

Dr. Truty describes what’s still needed to more effectively identify and treat pancreatic cancer.

Diagnosis prior to development of metastatic disease:

Researchers at Mayo Clinic are working on a more effective, noninvasive screening tool, but it is probably five to 10 years away, he says.

Type 2 diabetes is now considered a risk factor for pancreatic cancer, along with smoking and family history of the disease. Scientists aren’t sure if pancreatic cancer causes diabetes or if diabetes increases the risk of pancreatic cancer.

But most people diagnosed with pancreatic cancer have had a new diagnosis of diabetes within two years or had longstanding diabetes that worsened.

Better chemotherapy drugs:

Dr. Truty’s lab removes pancreatic tumors from patients and grows them in special mice. The tumors are genetically sequenced by investigators in the Mayo Clinic Center for Individualized Medicine to find possible drug targets in the mice. “We have hundreds of identical mice with a single patient’s tumor in them, which enables us to screen a large number of available and new drugs with no risk to the patient,” he says. “If we find a drug
that works in a mouse, it’s predictive of it working in the patient. We look for a biomarker that predicts the drug’s response so we can use the same drug in other patients with that biomarker in a clinical trial.

“This is true individualized oncology, and it’s happening at Mayo Clinic. This work is especially important for rare tumors for which there is no data.”

Dr. Truty says not many medical centers are very successful in growing pancreatic cancer in xenografts. Mayo Clinic succeeds in this effort because of the collaboration between surgeons and pathologists. They can transfer tumor tissue to mice within 30 minutes — “from warm patient to warm mouse.”

“Testing drugs in mice helps us shorten the time normally required to develop clinical trials,” says Dr. Truty. “Most pancreatic cancer patients don’t have the luxury of time to wait five to 10 years for a traditional trial.”

The lab also is transplanting tissue into mice from patients who have had chemotherapy, radiation and surgery to determine if the cancer is completely killed or likely to return. If the cancer cells grow in the mice, it gives Dr. Truty a heads-up to intervene with the patient while the tumor is still small.

Introducing new, ordered components

Not content with the status quo, Dr. Truty and his colleagues explored ways to further improve outcomes. In examining national data of pancreatic cancer patients, they found that surgical patients with elevated levels of the tumor marker CA 19-9 fared significantly worse than those without CA 19-9 elevations, even if their surgery was followed by chemotherapy. The only treatment sequence that provided good long-term outcomes was chemotherapy before surgery. (Read related story).

As a result of that finding, all Mayo Clinic pancreatic cancer patients now have a CA 19-9 blood test at diagnosis to guide treatment. CA 19-9 elevation indicates patients may have metastatic disease, and such patients may benefit from chemotherapy before surgery even if their tumor is otherwise surgically resectable. Pancreatic cancer can spread without it being detectable on scans — the aforementioned micrometastasis — according to Dr. Truty.

“We believe obtaining CA 19-9 levels at diagnosis provides an opportunity to clinically assess tumor aggressiveness,” says Dr. Truty. “The test is widely available, inexpensive and a good predictor of how the patient will fare.”

Armed with this revelation, pancreatic cancer specialists at Mayo Clinic have flipped the script and introduced neoadjuvant chemotherapy for many patients to improve survival and ensure that an operation will be of significant benefit.

There is, however, a larger fraction (35 percent) of patients whose tumors were traditionally considered too high risk for surgery due to growth outside of the pancreas and involvement of critical veins and arteries. Today more than 50 percent of these patients are having operations preceded by chemotherapy, using more effective drug combinations. Neoadjuvant radiation also has been added to the mix. Dr. Truty and other surgeons in his division were instrumental in turning those formerly “unresectable” cases into successful curative cancer surgeries.

Dr. Truty says having these three tools — chemotherapy, radiation and surgery — in the toolbox isn’t the key. Rather, how they’re used and in what sequence is key.

“I compare it to making my wife’s chocolate chip cookies,” he says. “I used the same ingredients, but my cookies didn’t turn out as well. Why? She knows how use all the ingredients in the right amounts and in the right order to get the optimal final product.

“What is the optimal final product for patients with pancreatic cancer? It is not the operation. Our goal is to extend quantity and maintain or improve quality of life. Surgery may be a critical component, or it can worsen both of these goals. We don’t have any secret ingredient. We tailor treatment to each patient and use the available tools in the right order and right amounts to accomplish our goals.”

Although other centers have now adopted this approach, Dr. Truty and his Mayo Clinic colleagues are leading the way in defining how to use this strategy most effectively.

Using more sensitive scanning

The treatment sequencing developed at Mayo Clinic includes looking at the entire patient and addressing their weight loss, malnourishment, jaundice, depression and other medical problems at diagnosis. Mayo Clinic’s multidisciplinary approach involves helping patients get in the best mental and physical shape to battle cancer treatment. After patients are stabilized, they receive modern combinatorial chemotherapy administered by Mayo Clinic medical oncologists specializing in pancreatic cancer.

“Traditionally, we looked at CT scans to see if chemotherapy had successfully reduced tumors,” says Dr. Truty. “But our experience reveals that only 25 percent of tumors show shrinkage on CT scans. That doesn’t mean the therapy wasn’t effective. A  PET MRI scanner is much more sensitive and a better indicator of whether chemotherapy is killing cancer elsewhere in the body. If there is evidence of response with PET MRI, we’re confident the therapy also is treating the cancer ‘seeds.’ Most patients don’t die from their primary tumors; they die from metastases.”

There are fewer than 50 PET MRI scanners in the world. Mayo Clinic has two of them — in Minnesota and Arizona — and the Florida campus is getting one soon. Dr. Truty says the scanner has revolutionized Mayo Clinic’s practice and is an example of how a significant advance in one field — radiology — has allowed evolution in another — oncology.

“PET MRI helps us determine if the chemotherapy is working,” he says. “If it is, we continue chemo- therapy until there is no more viable cancer or until the patient can no longer tolerate the side effects. If scans indicate chemotherapy isn’t working, we switch to another drug combination.”

Preparing for surgery

After chemotherapy, Dr. Truty relies on his colleagues in radiation oncology to initiate therapy, including proton beam, instead of going straight to surgery. “Surgery is only beneficial if we can remove tumors with negative margins,” he says. “Our ability to achieve negative-margin operations is markedly improved when patients have had radiation directed toward the intended surgical site.

“If there’s no evidence of metastases after radiation therapy and the patient is in good enough physical condition, we operate. We do operations most surgeons wouldn’t attempt, often with the assistance of our vascular surgery colleagues. We  are aggressive in removing all the surrounding structure where the tumor may have been in contact with vessels, doing a complex vascular resection and reconstruction. We do more of these arterial custom ‘bespoke’ vascular resections than any other center

— some of the operations lasting 14 hours.”

During the operation the surgeons send tumor samples to a pathologist, who quick-freezes the tissue and examines it for cancer — a technique developed at Mayo Clinic — and then reports back about margins and whether any cancer is still present.

After surgery, some patients receive additional chemotherapy.

The preliminary outcomes with this approach, referred to as total neoadjuvant therapy, will be published soon. The survival benefit is significant.

Collaborating is key

Axel Grothey, M.D. (left), and Mark Truty, M.D., each lost a parent to pancreatic cancer, which makes their mission to revolutionize treatment much more personal. Dr. Grothey says this collaboration is one of the most rewarding he’s had at Mayo Clinic.

Axel Grothey, M.D., a Mayo Clinic oncologist, works closely with Dr. Truty and other cancer surgeons. Like Dr. Truty, Dr. Grothey has personal experience with pancreatic cancer.

In 2003 his mother, Inge, was diagnosed with locally advanced pancreatic cancer in Germany. She had surgery, complicated by blood vessel involvement, and died within a week.

“Improving the outcomes and life expectancy for patients with this disease is very dear to me,” he says.

Dr. Grothey reiterates that aggressive surgery makes sense only if the cancer elsewhere in a patient’s body can be controlled. That’s where new chemotherapy agents come in.

“A  cure is only achievable if control of the tumor spread occurs and the primary tumor can be removed,” he says. “It’s not just about surgical skill but, rather, our overall management of each patient with an integrated team approach. Mayo Clinic does teamwork like nowhere else.”

Dr. Grothey cautions that every patient isn’t a candidate for this pancreatic cancer protocol. “Sometimes patients want to be unrealistically aggressive and use every available tool even though that approach may negatively affect their quality of  life without adding to their longevity. We try to rein them in. In the right patients, we’re more than happy to be aggressive, and there’s no better place to be than Mayo Clinic.

“Working with Dr. Truty and our other colleagues to revolutionize pancreatic cancer treatment has been one of the most rewarding collaborations I’ve had in 14 years at Mayo Clinic.”

Shushing the naysayers

Dr. Truty says that while this approach isn’t a cure for every patient, it’s getting close. The protocol has resulted in significant improvement in survival, even for patients whose tumors previously would have been considered inoperable. Data on more than 160 patients with stage III cancer show remarkable success. With conventional treatment, their expected median survival would be less than a year. Their actual median survival is more than 50 months and counting. The majority of these patients show no signs of cancer.

“When I first started, we didn’t use neoadjuvant therapy, and there were a lot of naysayers ... until we had data to demonstrate our success,” says Dr. Truty. “Now other medical centers are using this approach, with Mayo Clinic leading the way.

“Pancreatic cancer is stigmatic for its traditionally deadly diagnosis. Patients begin ‘making arrangements’ and talking about hospice. That’s changing. We’re able to help people who have been told their disease is not treatable. I encourage Mayo Clinic alumni to tell their patients to get another opinion. Many community providers aren’t aware of the revolution underway in the treatment of pancreatic cancer. I’ll be happy when pancreatic patients around the world have the hope our patients feel.”


This article was originally published in Mayo Clinic Alumni magazine, Issue 1, 2018.

Editor's note: Since the time of publication, Dr. Grothey has moved on in his career and now holds a leadership position at Sarah Cannon.

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