Current Treatment for Pancreatic Cancer: For Patients

Pancreatic ductal adenocarcinoma (PDAC) is by far the most common type of pancreatic cancer, accounting for more than 90% of cases. The overall 5-year survival rate of PDAC is a dismal 10%. With surgery, the best treatment option for pancreatic cancer, the 5-year survival rate increases to 25%. Surgical removal of the tumor is not an option for most pancreatic cancer cases because symptoms and diagnosis occur too late after the cancer has advanced or metastasized. This article outlines the current landscape of treatment options for pancreatic cancer including large and small surgical procedures, chemotherapy, other therapeutics, and radiation therapy, and how these treatments may be combined to optimize patient outcomes.

Chemotherapy for operable and inoperable pancreatic cancer

Chemotherapy provides a survival benefit for both operable and inoperable pancreatic cancer. However, the benefits of chemotherapy are limited by the development of drug resistance and the severe or disabling adverse effects. Other cancer treatments such as small molecule and immune checkpoint inhibitors have been found to benefit other cancers but lack evidence for PDAC at this time. As a result, most patients with PDAC are managed through chemotherapy alone. The chemotherapies used in pancreatic cancer are not new drugs but new pancreatic cancer treatment regimes are being tested that combine these older chemotherapy drugs together or with other treatments.

There are several chemotherapy regimens approved for metastatic PDAC. Which chemotherapy drug or combination of drugs a patient is recommended depends on their performance status, symptom burden, and comorbidity profile. Performance status is an assessment of the patient’s well-being and ability to perform self-care and daily activities. Symptom burden is a measure of how often or how severe the PDAC symptoms are. Comorbidity refers to other diseases or conditions that the patient is living with in addition to PDAC. A patient who is physically active and able to perform work activities would be offered a more aggressive chemotherapy regimen than someone capable of limited self-care who spends most waking hours in a bed.

In addition to being offered as first-line therapy, chemotherapy may be offered as a second-line therapy in pancreatic cancer depending on the preference of the patient and overall wellness. Certain chemotherapies have higher toxicities and have increased rates of certain side effects. Some types of chemotherapy are more likely to decrease the number of white blood cells, which leaves the patient at risk for infection. Another side effect more common in some types of chemotherapy is neuropathy, which is nerve damage that can cause pain or weakness.

How does chemotherapy work and why does resistance occur?

Chemotherapies are synthetically produced or naturally derived compounds that are toxic to cells and prevent cell growth and replication. Cells replicate by cell division. When cells divide and go from one to two cells, they need to duplicate their DNA so that they can pass it on to each of the two cells. Some chemotherapy agents incorporate into the DNA and prevent the DNA from being copied. Others disrupt the separation of copied chromosomes in each cell. Some cancer cells develop resistance to chemotherapy by gaining molecular changes that prevent the drug from entering the cell or inhibit its activity.

The study of molecular changes, also called biomarkers, that give cancer cells resistance to chemotherapy is an active area of research. Certain tumor biomarkers can predict which therapies are more likely to be effective for a particular cancer type. Biomarkers associated with chemotherapy resistance can also be targeted by drugs that when administered in combination with the chemotherapy make chemotherapy more effective. There are clinical trials testing various approaches to tackling chemotherapy resistance. Using two chemotherapy agents has shown promise for some types of pancreatic cancer.

The tumor microenvironment also negatively influences the response of PDAC to chemotherapy drugs. The environment around the tumor impedes the drug from reaching the tumor and is rich in factors that promote tumor growth. It is thought that the co-administration of drugs that target the tumor microenvironment could help chemotherapies be made more effective.

Radiation therapy

Radiation therapy is the use of high-energy radiation from X-rays, photons, electrons, and other sources to kill cancer cells. Radiation therapy is used alone or together with other treatments including surgery. Radiation may be given before, during, or after surgery to slow the growth of cancer cells. External beam radiation (EBRT) is delivered by a machine outside the body and aims radiation at the tumor or area of the body where the tumor is located. Stereotactic body radiation therapy (SBRT) is a type of EBRT used for locally advanced pancreatic cancer and for cancer that has returned after surgery. SBRT may be used to shrink tumors, prevent recurrence, and relieve pain. For patients who cannot have surgery due to other health conditions, SBRT may be the primary treatment.

Tumor-type specific pancreatic cancer treatments

Patients that carry certain gene mutations have tumors that are more susceptible to certain chemotherapy approaches such as combining two types of chemotherapy or combining chemotherapy with another cancer drug. Immunotherapy, therapeutics that boost the ability of the patient’s immune system to fight cancer, is not widely used in PDAC. The exception is a subset of patients with PDAC that have a deficiency in their ability to repair DNA, called dMMR/MSI-H PDAC. Immunotherapy has shown improved survival in these patients, which make up only 1% of PDAC patients. Other targeted therapies, which target tumors with specific types of mutations are beginning to show promise.

Surgical removal of the tumor

Surgical removal of the pancreatic tumor is referred to as resection and offers a significant increase in survival for patients who are eligible. Patients with resectable or operable pancreatic cancer may be eligible for surgery to remove the tumor, depending on their health and performance status. Patients that are eligible have no evidence of metastasis and the pancreatic tumor does not contact major arteries and veins.

The overall 5-year survival rate for patients undergoing resection for stage I PDAC is 38.2% compared to 2.9% for patients who did not have surgery. To achieve long-term survival the only treatment option for patients with PDAC is surgery with perioperative chemotherapy. Unfortunately, only 15-20% of patients are candidates for surgical resection and recurrence rates are 76.7% after two years. There is no strict age limit for surgical resection but frailty and life expectancy are considerations when determining if surgery is appropriate for a particular patient. While patients over 80 years old have an increased risk of mortality after surgery, a survival benefit in those who have surgery is still seen in this population. Patients should receive counselling to understand the potential risks, benefits, and limitations of surgery.

Chemotherapy before or after surgery

The standard of care for patients with resectable pancreatic cancer has been to have surgery first followed by adjuvant chemotherapy. Adjuvant means in addition to the primary treatment, which in this case is surgery. Chemotherapy as an adjuvant therapy after pancreatic cancer surgery provides improved survival. Some patients delay postoperative chemotherapy while recovering from pancreatic resections and the time of initiation of adjuvant therapy does not seem to affect survival.

More recently, patients with resectable pancreatic cancer are recommended to have neoadjuvant therapy, meaning chemotherapy before the main treatment of surgery. It is hoped that neoadjuvant therapy will shrink the tumor before surgery and make it more likely to be completely removed. How the patient’s cancer responds to neoadjuvant therapy may provide information about the tumor’s behavior and prognosis. Clinical trials are evaluating if neoadjuvant therapy is the best course of action for resectable pancreatic cancer. Neoadjuvant therapy may be considered for certain patients whose surgery may be at higher risk.

Neoadjuvant therapy is recommended for patients with borderline resectable pancreatic cancer because it may make the tumor safer to remove. In these patients, the tumor is only in the pancreas but contacts blood vessels or nearby structures. In patients with borderline resectable pancreatic cancer, treatment with neoadjuvant therapy results in about 60-70% going on to have a resection. Patients who received neoadjuvant therapy had surgery that was more successful at completely removing the tumor and had improved overall survival. If the patient does not respond to neoadjuvant therapy and shows progression, their pancreatic cancer may be managed without surgery.

Patients who have locally advanced pancreatic cancer and receive neoadjuvant therapy have about a 28% rate of going on to have surgical resection. Locally advanced pancreatic cancer has spread outside the pancreas and involves nearby blood vessels, lymph nodes, and other tissues. For patients with high-performance status, the National Comprehensive Cancer Network (NCCN) recommends enrolling in a clinical trial of neoadjuvant chemoradiation which combines chemotherapy and radiation therapy. After receiving neoadjuvant chemoradiation, patients with locally advanced pancreatic cancer may be re-evaluated for surgery. If there is more than a 50% decrease in the pancreatic cancer blood test, CA 19-9, along with other improvements, patients may be considered for surgery.

Preoperative biliary drainage

The biliary drainage procedure is the insertion of a small tube with small holes along the sides to help bile flow more easily. The purpose is to relieve symptoms like jaundice which occur when the bile duct is blocked, causing bile to back up into the liver. Some studies have found that patients who had biliary drainage before surgery had increased complications compared with patients who did not have the procedure before surgery. Some patients with resectable PDAC who are having neoadjuvant treatment before surgery may require biliary drainage to relieve symptoms during this treatment period.

Detecting occult metastatic disease with staging laparoscopy

Staging laparoscopy, a keyhole procedure used to view and stage pancreatic cancer, is used on a case-by-case basis. Staging laparoscopy is minimally invasive, involving three small cuts in the abdomen and the insertion of a special camera called a laparoscope. Patients at the highest risk of having unresectable pancreatic cancer are most likely to benefit from this procedure, which identifies small or hidden metastasis called occult metastasis. Occult metastasis is too small to be detected in imaging tests like CT or MRI scans. Staging laparoscopy can save a person from having to undergo the more invasive surgical procedure of exploratory laparotomy.

Staging laparoscopy is indicated in patients that have abdominal pain, a tumor larger than 30 mm, abnormal areas on the liver, and high levels of CA 19-9. Recently, more patients with borderline resectable and locally advanced diseases are becoming eligible for surgery after neoadjuvant therapy to shrink their tumors. Due to the higher risk for occult metastatic disease in these patients, staging laparoscopy may be recommended before neoadjuvant therapy to find occult metastatic disease as early as possible. Research is ongoing to determine if other techniques such as laparoscopic ultrasound and imaging with near-infrared fluorescence imaging would add prognostic information related to occult metastatic disease in PDAC.

Palliative surgery

Palliative surgery, performed to reduce pain in the patient, is the type of surgery a patient may receive if they have unresectable pancreatic cancer. Hepaticojejunostomy and gastrojejunostomy are procedures that prevent biliary and gastric outlet obstruction. Hepaticojejunostomy connects the bile-carrying duct from the liver to the middle part of the small intestine. Gastrojejunostomy connects part of the stomach to the middle part of the small intestine.

The need for these surgical bypass procedures is being replaced by self-expandable metal stents (SEMS) inserted using an endoscope, which is a tube that enters the digestive system through the mouth. Compared with surgical bypass SEMS has a higher rate of recurrent obstruction and needs to repeat the procedure. Surgical bypass procedures are recommended for patients with obstructive jaundice who are found to be inoperable at the time of surgery. In some cases, a surgical bypass may be performed to prevent the obstruction from occurring. Decision-making about bypass procedures and SEMS involves patient factors and counseling.

Vascular resection and reconstruction

Vascular resection and reconstruction procedures can now allow some patients with locally advanced pancreatic cancer to have pancreatic tumor resection when this patient population was previously considered unresectable. Neoadjuvant therapy would be recommended for these patients before surgical resection.

Total pancreatectomy

Total pancreatectomy is the removal of the entire pancreas, occasionally performed for advanced cancers or large central tumors. Loss of the pancreas causes diabetes and an insufficiency of digestive enzymes. Patients will experience diabetes-associated symptoms and diarrhea. Total pancreatectomy is only warranted when absolutely necessary to remove all of the tumors with clear margins.

Summary of the treatments for pancreatic cancer

Pancreatic surgery is usually the main treatment recommended for patients with resectable pancreatic cancer, with the additional treatment of chemotherapy given before or after surgery. In some cases, preoperative chemotherapy may allow patients previously ineligible for surgery to receive surgery as a treatment. Chemotherapy is the recommended treatment for unresectable pancreatic cancer as long as the patient is well enough to handle the negative side effects. Two difficulties in treating pancreatic cancer are recurrence after surgery and resistance to chemotherapy. The treatment landscape for pancreatic cancer includes other cancer medications, radiation therapy, and surgical procedures that aim to improve survival and/or decrease pain and symptoms.

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