‘Pancreatic cancer progresses quickly, so never delay treatment by seeking multiple opinions’

Pancreatic cancer has a notoriously poor prognosis, with a cure rate (five-year relative survival rate) of only around 15 percent among the top 10 multiple cancers in Korea.

However, there is hope for pancreatic cancer. While pancreatic cancer's cure rate is currently low, it is definitely on the rise. According to the National Cancer Registry, the five-year survival rate for pancreatic cancer was 8.4 percent from 2001 to 2005 and 8.6 percent from 2006 to 2010, never exceeding 10 percent. However, it has increased to 11.0 percent from 2011 to 2015, 15.1 percent from 2016 to 2020, and 16.5 percent from 2018 to 2022.

The improvement in pancreatic cancer outcomes has been attributed mainly to the introduction of the chemotherapy treatment -- the FOLFIRINOX regimen.

However, a trend is also expected to drive pancreatic cancer treatment performance in the future. This introduction of “precision medicine” focuses on various pancreatic cancer treatment targets, such as KRAS G12C-G12D-G12V, BRCA1-2, and Claudin 18.2.

Korea Biomedical Review talked to Professor Park Joon-seong of the Department of Hepatopancreatic Surgery at Seoul National University Hospital about the current state of diagnosis and treatment of pancreatic cancer in Korea, who believes that pancreatic cancer treatment based on scientific evidence can lead to an upward trend in the future.

Question: Pancreatic cancer is one of the top 10 cancers in Korea, ranking eighth among multiple cancers, and has been increasing in recent years along with the aging population. According to the National Cancer Registry, newly diagnosed pancreatic cancer patients increased from 9,190 in 2021 to 9,790 in 2022. Other than the population aging, are there any other reasons why the incidence of pancreatic cancer is increasing in Korea, and how do you think the trend of pancreatic cancer patients in Korea will change in the future?

Answer: First of all, the number of pancreatic cancer patients in Korea is increasing, which is related to the aging of the population, but I think that the change in Korean dietary habits, which include eating fatty foods, may also have had an impact. Another reason is that early detection has increased. Pancreatic masses (pancreatic cysts), which are pre-cancerous lesions that were difficult to detect in the past, have been diagnosed recently. Lesions removed from pancreatic masses that were thought to have a high chance of progressing to cancer are often confirmed to be early-stage pancreatic cancer.

The number of pancreatic cancer patients in Korea is expected to increase in the future. Based on the data inferred by AI based on Korea's National Cancer Registry statistics and the reality of Korea following Japanese data with a gap of 10 to 15 years, the number of pancreatic cancer patients in Korea will increase. In the AI prediction based on domestic data, pancreatic cancer was the fourth most common cancer in 2030-2035, along with thyroid, lung, and breast cancer. Currently, there are about 9,000 new pancreatic cancer patients a year, and it is predicted that by then, there will be about 40,000 new pancreatic cancer patients a year.

Q: The cause of pancreatic cancer is unclear, but we know that risk factors include smoking, alcohol, obesity, poorly controlled blood sugar, chronic pancreatitis, pancreatic masses, and genetic predisposition, such as BRCA1-2 gene mutations. Do you see a higher incidence of pancreatic cancer in patients with these risk factors in the clinic?

A: The most obvious predisposing factor for pancreatic cancer is smoking. And “poorly controlled blood sugar” doesn't mean that if you have diabetes and your blood sugar is uncontrolled, you're at a higher risk of pancreatic cancer, but instead that if your blood sugar has been well controlled and then suddenly becomes uncontrolled without anything happening, you're slightly more likely to develop pancreatic cancer. Chronic pancreatitis is a bit of an ambiguous risk factor for pancreatic cancer, with different healthcare professionals saying different things. However, it is thought that having chronic pancreatitis may slightly increase your risk of developing pancreatic cancer because the inflammation is constantly irritating the pancreas.

There are many types of pancreatic masses, most benign, and two of which are considered the worst: mucinous cysts and intraductal papillary mucinous neoplasms (IPMNs). In addition, while having a BRCA1-2 gene mutation naturally increases the risk of developing pancreatic cancer, BRCA1-2 gene mutations do not increase the risk of pancreatic cancer as much as they do for breast and ovarian cancers, and a family history of two or more pancreatic cancer cases in the first three generations of a family member under the age of 60 significantly increases the risk of pancreatic cancer by two to three times.

Q: Pancreatic cancer is a poorly detected cancer, with only about 20 percent of early-stage pancreatic cancers being operable. According to the National Cancer Registry, 13.8 percent of pancreatic cancers are localized, 31.3 percent are regional, 43.8 percent are distantly metastatic, and 11.1 percent are undetermined. What screening strategies do you recommend for people with risk factors to increase early detection of pancreatic cancer?

A: Some foreign countries recommend screening for pancreatic cancer at the age of 40 or older if there is a family history of pancreatic cancer. Still, there are no such guidelines in Korea. People with a family history of pancreatic cancer and those with hereditary pancreatitis are at higher risk for pancreatic cancer. About 20 percent of patients with chronic pancreatitis have hereditary pancreatitis. People with BRCA, a gene mutation associated with pancreatic cancer, diabetes for more than 10 years, and a smoking history of more than 10 pack-years (10 years of smoking one pack of cigarettes daily or five years of smoking two packs of cigarettes daily) are also at high risk.

People may also be at risk for pancreatic cancer if a pancreatic nodule is detected by chance during a medical examination. However, if the nodule does not grow when checked regularly, it is considered a simple nodule, and if it grows, it is considered to be at high risk for pancreatic cancer. If a pancreatic nodule hasn't grown in five years, it's not considered a significant risk. Still, checking it regularly for up to 10 years is recommended. Outside of pancreatic nodules, there is no recommended screening strategy. If you are over 40, I can only recommend periodic abdominal ultrasound examinations.

In addition, as pancreatic cancer has increased so much in Korea in recent years, there are many lectures on high-risk groups for pancreatic cancer in training lectures at internal medicine clinics, so we can quickly identify high-risk or early pancreatic cancer patients who were previously missed. Patients are being diagnosed with pancreatic cancer sooner than in the past because primary care physicians are referring patients to university hospitals when they see dilated pancreatic ducts, atrophy of the pancreas, or watery shadows on abdominal ultrasounds.

Q: What are the typical symptoms of pancreatic cancer? Does pancreatic head cancer, which is cancer of the head of the pancreas, present with jaundice at a relatively early stage, or do symptoms vary depending on where the cancer is located?

A: Symptoms that may indicate pancreatic cancer include pain in the gullet, side, back, or lower back or difficulty digesting food. In particular, if your back hurts when you sleep upright but is fine when you sleep curled up, you may have pancreatic cancer. The pancreas is located right behind the spine, so if you have pancreatic cancer, it will press on the nerves in your spine when you lie upright, causing pain. The symptoms of pancreatic cancer are similar regardless of where it occurs, except that cancer in the head of the pancreas can block the biliary tract, which can cause jaundice in the early stages of pancreatic cancer.

Q: How is pancreatic cancer diagnosed, and what additional tests are needed after a pancreatic cancer diagnosis?

A: In the past, pancreatic cancer was suspected and confirmed by surgery and biopsy, but nowadays, abdominal CT, MRI, and endoscopic ultrasound are used to confirm the diagnosis, and treatment is started when the cancer is confirmed. Once pancreatic cancer is diagnosed, whether it is an early or late stage, CT, MRI, and PET-CT (positron tomography, a three-dimensional image of the body's physiochemical and functional properties using a radioactive medicine that emits positrons) are routinely performed to understand the patient's condition.

Q: We know that pancreatic cancer treatment is divided into “resectable pancreatic cancer” based on whether surgery is possible, “borderline resectable pancreatic cancer,” which is challenging to resect immediately but can be resected later depending on prior treatment, and “unresectable pancreatic cancer” which is inoperable. What are the treatments for each?

A: Early-stage resectable pancreatic cancer is treated with chemotherapy, and recently, upfront chemotherapy has also been used. In resectable pancreatic cancer, it's now 50/50 between patients who have surgery after upfront chemo and patients who have chemo after surgery. Still, we don't know which treatment is superior. We are currently studying this through a collaborative multicenter study under the Cancer Conquest Project, an international consortium study involving Australia and Taiwan, and the results will probably not be available for five years.

In addition, borderline resectable pancreatic cancer is treated with chemotherapy first to make it operable, and about 20-30 percent of patients go on to surgery. If it is determined that surgery is not possible, chemotherapy and radiation therapy are continued. Unresectable pancreatic cancer is treated with chemotherapy and radiation, usually with chemotherapy first and radiation as an additional treatment option.

Q: Treatment outcomes for pancreatic cancer have been steadily improving. In the early 2010s, the five-year relative survival rate was less than 15 percent, but it has recently increased to 16.5 percent. What factors are driving the improvement in pancreatic cancer outcomes?

A: The improvement in pancreatic cancer outcomes is due mainly to advances in chemotherapy. With the introduction of the FOLFIRINOX regimen (a combination of oxyplatin, leucovorin, irinotecan, and 5-fluorouracil), the five-year relative survival rate for pancreatic cancer has increased from less than 15 percent a few years ago to over 15 percent today. However, the effectiveness of the FOLFIRINOX regimen has peaked at 16.5 percent. It will take another anticancer drug to continue the upward trend.

Q: What are the advances in surgical treatment, one of the main treatments for pancreatic cancer?

A: Key advances include the introduction of laparoscopic surgery and robotic surgery. Laparoscopic surgery is minimally invasive and allows pancreatic cancer patients to recover faster than open surgery. In addition, data from Seoul National University Hospital showed that the survival rate of pancreatic cancer patients was slightly better for robotic surgery than open surgery. This may be because patients who underwent robotic surgery recovered faster than those who underwent open surgery and, as a result, were able to receive chemotherapy in a much better nutritional state.

I also think that pancreatic cancer patients who have good economic conditions to receive robotic surgery, which is not covered by health insurance, will be more supportive of their family members and others and will be able to continue treatment well enough without giving up treatment due to economic conditions. Surgeons' surgical treatment techniques have already been standardized through research, and they perform the same surgery everywhere in the world. We've almost reached the end of the road regarding advances in surgical techniques.

Q: How is pancreatic cancer surgery performed? Since pancreatic cancer is a recurrent cancer, is there a strategy for removing more of the pancreas than is necessary? Also, pancreatic cancer surgery is known to be a difficult surgery with many complications. Why is this so?

A: In the 1970s and 1980s, it was thought that removing the entire pancreas when someone had pancreatic cancer would improve outcomes, but this has not been proven to be the case. Today, the standard of care is pancreatectomy if the cancer is located in the anterior pancreas (tail). If the cancer is located in the posterior pancreas (head), we perform pancreaticoduodenectomy. Of course, if the cancer is in both the pancreas tail and the pancreatic head, the entire pancreas is removed.

Also, if the cancer is only in the pancreatic tail or head, the entire pancreas is already atrophied, and it is unlikely that the pancreas can function even if it is connected. Therefore, the entire pancreas is removed. This procedure has become more preferred because it can reduce complications. In addition, resecting the lower part of the pancreas has few complications. Still, if the head of the pancreas is removed, it has a high surgical risk because it must be connected to the small intestine (duodenum).

No matter how well the surgery is performed, the pancreas and small intestine can leak some pancreatic juice. The primary role of pancreatic juice is to dissolve proteins. Our body is almost entirely protein, so when pancreatic juice leaks, it can cause the surrounding blood vessels to burst. This is a hazardous complication. This is why pancreaticoduodenectomy is considered a higher-risk surgery than pancreatectomy, and the actual complications of pancreaticoduodenectomy are higher than those of pancreatectomy.

Q: Compared to other cancers, pancreatic cancer has a more complicated and thicker tumor microenvironment, which makes it difficult for anticancer drugs to penetrate. As a result, it is often poorly treated, leading to further progression of the cancer and high mortality. Pancreatic cancer is a highly metastasizing cancer and often recurs after surgery, so what is being done to prevent this, and what kind of treatment is followed by recurrence?

A: About 50-60 percent of pancreatic cancer recurs within two years after surgery. Therefore, in operable pancreatic cancer, we give additional chemotherapy for six months and periodically check for recurrence. If the cancer recurs, chemotherapy is continued. Also, suppose the size of the cancer has shrunk a lot through chemotherapy, but there is one spot that does not disappear. In that case, we may try surgical treatment again.

Q: Recently, precision medicine targeting pancreatic cancer-related gene mutations has been tried for pancreatic cancer. What is the current status, and how will pancreatic cancer treatment change?

A: Although many genetic mutations associated with pancreatic cancer have been identified, there are no drugs currently available that target many of the genetic mutations in pancreatic cancer. If there are a lot of genetic mutations in pancreatic cancer, new drugs will need to be developed and put into clinical trials for approval. We do a lot of cancer treatment research through basket trials (testing drugs against the same gene mutation in different cancers) and umbrella trials (testing multiple drugs against a single cancer caused by different gene mutations).

Pancreatic cancer is also included in these trials. Still, there are very few pancreatic cancer patients in Korea with a gene mutation (KRAS G12C) that can be included in such trials, so it is not possible. G12D and G12V are the most common KRAS mutations in pancreatic cancer; no drug targets them. Pancreatic cancer is too small to fit into the current basket of clinical trials, so it is difficult for patients to benefit. However, this will change when a drug targeting many genetic mutations in pancreatic cancer becomes available.

In fact, in biliary tract cancer, when I wrote a paper 10-15 years ago saying that we can try to personalize treatment based on gene mutations and other characteristics, people thought it was very strange. In biliary tract cancer, if you're PD-L1 positive, you almost always get Keytruda. If you're HER2 positive, you get Herceptin, which is a drug that targets that. In the future, as more drugs become available for pancreatic cancer, I think we will have a situation where we can use them as we do for biliary tract cancer.

Q: What are some of the challenges that pancreatic cancer surgery patients may face at home?

A: Delayed gastric emptying. The stomach is not touched during pancreatic cancer surgery. Still, it is not uncommon for the stomach to not move food down into the small intestine for up to four to six weeks after pancreatic cancer surgery. It is not yet understood why this happens. Patients with delayed gastric emptying often have a lot of trouble eating because they vomit or can’t digest. However, it’s not a big deal because it usually improves in four to six weeks after surgery.

Q: Some patients suffer from oily stools or strong fart odor after pancreatic cancer surgery. What should they do?

A: This problem occurs not only after pancreatic cancer surgery but also when the pancreas loses its function, which can be solved by taking pancreatic enzymes. If you're already taking medication, you can increase the dose. The problem is that these medications are not covered by health insurance. It usually costs about 1 million won ($720) for three months, and many patients ask for a one-month supply because it's so expensive.

Pancreatic cancer patients keep asking for these drugs to be covered by insurance. Still, the pharmaceutical companies refuse to do so. These drugs are unavailable to pancreatic cancer surgery patients because if they are covered by health insurance, they are classified as digestive drugs, significantly reducing the price. In Korea, all salaried digestive drugs cost 70 won per pill. No pharmaceutical company would apply for benefits at 70 won, and no matter how much the patients complain, the pharmaceutical companies won't budge.

Q: Since pancreatic cancer surgery can change the ability to secrete digestive juices and control blood sugar, how should patients manage their health after surgery?

A: Theoretically, even if the pancreas is only 10 percent functional, there is no problem with digestion and no diabetes, but there are people who develop diabetes even if half of the pancreas is cut out in pancreatic cancer surgery. If you have a pancreatic subtotal resection, 60-70 percent of patients develop diabetes within two years, and if you have a pancreatic head resection, 30-40 percent of patients develop diabetes within two years. Therefore, pancreatic cancer surgery patients regularly check their blood sugar in the hospital. If they develop diabetes, they work with endocrinologists to actively control their sugar.

After pancreatic cancer surgery, it's best to eat well, in small portions, and often, without alcohol or tobacco. Fatty foods can be eaten as long as the patient can digest them without diarrhea. Protein is vital. In addition, too much fat is not good. Suppose you don't eat well because you are worried about diabetes. In that case, you will become nutritionally deficient, which is much worse for pancreatic cancer treatment. You shouldn't overeat, eat small, frequent meals and eat well. It’s also essential to maintain muscle strength through regular exercise.

Q: What would you like to say to pancreatic cancer patients and their families?

A: Patients and families are very disappointed when they are diagnosed with pancreatic cancer. They are disappointed because the treatment outcomes are so poor, and they are looking for breakthroughs on YouTube, but pancreatic cancer is already curable. Even though the outcome of pancreatic cancer is not good right now, the recent improvement is due to the use of scientifically proven treatments. The most important thing is to realize that the treatment is proven.

I also hope that people don't delay treatment for pancreatic cancer by shopping around. Pancreatic cancer progresses very quickly, so the first month or two is crucial. I wish I had been diagnosed at a local university hospital and treated right away. Still, I often see patients who wait two or three months for treatment at Seoul National University Hospital and get worse. Pancreatic cancer is treated the same way at all hospitals, so there is no need to delay treatment. If you are diagnosed with pancreatic cancer, you should start treatment quickly with standardized treatment.