The right dose for the right patient: reducing toxic effects from chemotherapy

Associate Professor of Medicine Daniel Catenacci, MD, in his laboratory

Associate Professor of Medicine Daniel Catenacci, MD, in his laboratory. Photo credit: Tiha M. Long, PhD.

Chemotherapy is a type of treatment that targets and kills rapidly dividing cells, such as cancer, and is a hallmark of cancer treatment. Unfortunately, this type of medicine also kills rapidly dividing cells that are not cancerous, such as blood and skin cells and the lining of the intestine. This toxicity causes serious side effects, leaving patients ill and bedridden. Many patients are reluctant to start potent chemotherapy regimens, no matter how effective, because they are concerned about the toll the side effects will take on daily living.

Chemotherapy is utilized to treat numerous types of cancer, including gastroesophageal cancers (cancers of the esophagus and stomach). These types of cancer are difficult to treat, and most patients do not make it beyond five years after the time of diagnosis. The chemotherapy combination, FOLFIRINOX, has shown great success in treating difficult cancers, but the side effects can be brutal, leading to difficult decisions for patients.

Physician-scientists at the UChicago Medicine Comprehensive Cancer Center have been working not only to improve the results of chemotherapy, but also to improve the quality of life during and after treatment. A recent clinical breakthrough from the Comprehensive Cancer Center has shown promise for dramatically reducing the suffering of patients with gastroesophageal cancer. This discovery was a journey from translational research to clinical results that can be traced back more than two decades.

A critical discovery from the laboratory of Mark Ratain, MD, dating back to 1998, revealed how a gene called UGT1A1 can cause people to have different responses to a chemotherapy agent, irinotecan (a component of FOLFIRINOX). The enzyme, UGT1A1, breaks down irinotecan within the body. Ratain, who is the Leon O. Jacobson Professor of Medicine and associate director for clinical sciences at the Comprehensive Cancer Center, discovered that this gene was widely variable in different people.

He investigated if differences in UGT1A1 could predict how a patient would react to treatment with irinotecan. He anticipated that patients with normal levels of the enzyme could break down the irinotecan efficiently but that patients with low levels of the enzyme would have higher concentrations of irinotecan in their body.

In 2002, he led a phase 1 clinical trial that elucidated how specific genetic variants regulated the activity of UGT1A1 and correlated this with the concentration of chemotherapy agents in the body. The study suggested that patients with genetic variants that produced low levels of the enzyme had severe toxicities due to higher levels of irinotecan in their bodies2. It became clear that patient genotype correlated with the level of toxicity.

This discovery set the stage to move chemotherapy into the realm of personalized medicine. Years later, Ratain would pass the baton to another physician-scientist at UChicago Medicine to continue this vital work.

Associate Professor of Medicine Daniel Catenacci, MD, director of the Gastrointestinal Oncology Program at UChicago Medicine and assistant director of translational research at the Comprehensive Cancer Center, is an expert in the area of gastroesophageal cancers. He is an active researcher who utilizes advances in translational research to improve options for patients. Catenacci has a personal tie to the gastroesophageal cancers he treats. He shared that his own grandfather died from the disease before he was born. Now, his goal is to help other patients survive longer in order to have more time with their families.

This personal connection steered him toward the field and now his patients are the motivating factor that pushes him to not only help them beat cancer, but to reduce unnecessary illness and suffering while they undergo treatment.

Catenacci told us, “We are not only concerned with finding new medications, but also with improving what we have. In this example, we have a chemotherapeutic drug that is effective but has a terrible reputation. Here, we have an opportunity to minimize the suffering that patients go through—personalizing therapy not only to improve the outcome, but to alleviate their pain and improve their quality of life.”

Catenacci knew that the chemotherapy regimen FOLFIRINOX was effective but that many patients were weary to move forward because of the severe toxicity. Ratain’s work suggested that these individuals may have mutant forms of UGT1A1, which causes the enzyme to be produced at a lower level, leading to higher levels of drug in the body and worse side effects. This knowledge motivated Catenacci to move forward with a clinical trial utilizing genotyping to personalize the dose of the irinotecan component.

There was a possibility that decreasing the dose would decrease the effectiveness of the drug, no matter what genotype a patient had. Catenacci needed to finally find the answer to that question– could patients with mutant UGT1A1 receive a lower dose of the drug and still achieve the same response?

To address this question and help numerous patients, Catenacci spearheaded a phase 2 clinical trial to test genotype-directed dosing of FOLFIRINOX, known as gFOLFIRINOX3. He wanted to detect the population with variant forms of UGT1A1, which is more than 45% of patients, and help to alleviate the worst of the chemotherapy-associated illness that often deterred patients from taking this potentially life-saving regimen.

For this study, patients that had normal UGT1A1 and produced high levels of the enzyme, received the usual high dose of irinotecan. Higher doses are required for these patients to maintain effective levels of irinotecan in the body. Individuals with one mutant and one normal copy of UGT1A1 made less enzyme and so they received a lower dose.

Lastly, a third group that had two mutant copies of UGT1A1 and produced very low levels of enzyme, received the lowest level of the chemotherapy agent. The results were positive: 92% of patients had successful surgeries in which all cancer cells were removed, and the edges of the resected area were cancer-free.

Overall, the responses were the same or better than other standard approaches, which indicated that the personalized dosing according to genotype was successful. Critically, the patients had dramatically reduced side effects, and were able to maintain a much higher quality of life during their treatment.

In regard to these results, Ratain commented, “I am very pleased to see the impact of our studies conducted more than two decades ago regarding the relationship of UGT1A1 genotype to the safety and tolerability of irinotecan.”

He continued, “The recent study by Catenacci and colleagues is important as it provides evidence that preemptive dose reductions of irinotecan on the basis of UGT1A1 genotype do not reduce the efficacy of this agent.”

“Moving forward,” Ratain asserted, “it will be important to expand genetic testing to other targets that impact tolerance to chemotherapies.”

Professor of Surgery Mitchell Posner, MD, chief of the section of general surgery and surgical oncology at UChicago Medicine and physician-in-chief of the Comprehensive Cancer Center, commented, “Dr. Catenacci’s research, this specific trial and other similar trials that are designed by faculty members of UChicago Medicine Comprehensive Cancer Center, are defining the future of individualized cancer care and will have a significant impact on improving the effectiveness of cancer treatment while simultaneously enhancing the quality of life of those patients receiving that therapy.”

Working together, these investigators have illuminated the path to clinical success. Guided by strong research results and motivated by their patients, Catenacci and Ratain achieved impactful clinical results that move the field of personalized medicine forward to make a real difference for patients with cancer.

References:

1 Iyer et al., J Clin Invest 101:847-54, 1998.

2 Innocenti et al., J Clin Oncol 22:1382-8, 2004.

3 Catenacci et al., JAMA Network Open 3:2, 2020.

Daniel Catenacci

Daniel Catenacci, MD

Daniel Catenacci, MD, is an adult gastrointestinal medical oncologist and director of the Gastrointestinal Oncology Program at the University of Chicago. He serves as the assistant director of translational research in the Comprehensive Cancer Center.

View Dr. Catenacci's physician profile
Mark Ratain, MD

Mark J. Ratain, MD

Medical oncologist Mark J. Ratain, MD, is an expert in the use of investigational drugs to treat advanced solid tumors. He has a special interest in pharmacogenetics — the study of how genetic variation affects the body's response to medications. He serves as director of the Center for Personalized Therapeutics.

View Dr. Ratain's physician profile