Research Spotlight:
How Studies with ‘Negative Results’ Still Make a Positive Impact
Meg Macy, MD
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Clinical research is based on specific questions that scientists strive to answer. And all Children’s Oncology Group (COG) researchers share a collective hope that the answers to those questions pave the way to better treatments and outcomes for children with cancer. Sometimes results meet or exceed study goals. Sometimes they miss the target, but it doesn’t mean the study has ‘failed.’ Several years ago, COG researchers made a thrilling discovery for children with high-risk neuroblastoma, a rare and often-deadly cancer that forms in the immature nerve cells of young children. Some neuroblastoma patients relapse after their first treatment or never respond to treatment at all.
The research team found that adding an immunotherapy drug to an existing regimen of chemotherapy drugs shrank the tumors of more than half of patients, in a treatment combination they called DIT, short for dinutuximab (the immunotherapy drug) and irinotecan-temozolomide (the chemotherapy drugs). |
Leaders of that trial then challenged Meg Macy, MD, Professor of Pediatrics Section of Hematology, Oncology & Bone Marrow Transplantation at University of Colorado Cancer Center, to find a drug that would make DIT work for the 50% of children who did not respond to it.
Dr. Macy and her study Co-Chair Kelly Goldsmith, MD, turned their attention to difluoromethylornithine, or DFMO, the focus of other trials and reports, investigating in a randomized way, different ways it could potentially boost the effectiveness of chemotherapy for neuroblastoma patients.
DFMO was also an FDA-approved treatment for a different disease that affects the nervous system, called African sleeping sickness. The parasites that cause African sleeping sickness and neuroblastoma tumors both rely on a chemical in the body called polyamines to grow. DFMO decreases polyamines, so Dr. Macy, Dr. Goldsmith, and their team wanted to find out if it might help patients who didn’t respond to DIT.
Dr. Macy’s study set a primary goal: a response rate of at least 20% for children treated with both DFMO and DIT. But when results came in, children who received both treatments fared no better than those on DIT alone. In research terminology, it was a “negative result,” but Dr. Macy was far from disappointed.
“In some ways I wasn’t surprised, because DIT already had a high response rate,” she said. “But from day one, I knew that even if this study didn’t show a difference with the addition of DFMO, we would still learn about the biology of neuroblastoma and these two treatments in general.”
The positives of ‘negative results’
Although Dr. Macy’s trial did not meet the intended goal, it shed important new light on other aspects of neuroblastoma. For example, they captured more detailed nuances of different ways patients responded to DIT with and without DFMO. Researchers call those nuances “minor responses.”
“Some patients have big soft-tissue tumors. Those don’t tend to shrink, but their bony lesions, which are often very painful, can go away,” Dr. Macy explained. “That could be clinically very beneficial for some patients,"
They also discovered that fewer patients on DFMO and DIT experienced significant pain than those taking DIT alone.
The study also shed light on a known risk of DFMO. Researchers knew that of DFMO caused temporary hearing loss in patients treated with high doses. Dr. Macy’s study closely monitored the results of hearing exams and immediately paused the trial as soon as a handful of children showed hearing loss.
After a break from DFMO treatment, their hearing bounced back, so the trial was amended to give patients a weeklong break every 28 days to help preserve their hearing.
These and other findings related to how DIT alters or activates the immune system reveal important clues that help researchers shape future studies. The same is true for the “negative results.”
“Negative results are just as important to publish, so we don’t repeat those same studies and expose patients to ineffective or toxic therapies,” she said. “Sometimes we think in our heads it’s going to be X, and it turns out to be Y. Either way, we learn and contribute to science and improving the care of our patients.”
Contributions like this move research closer to curing more kids with high-risk neuroblastoma and other cancers that are especially hard to treat. Conducting well-designed and well-controlled clinical trials is central to COG’s mission.
“Even ‘negative’ studies answer questions and help us design the next study on the basis of data,” said Children’s Oncology Group Chair Douglas S. Hawkins, MD. “We need to know what does and does not work objectively to improve outcomes for children with hard-to-treat cancer.”
Dr. Macy and her study Co-Chair Kelly Goldsmith, MD, turned their attention to difluoromethylornithine, or DFMO, the focus of other trials and reports, investigating in a randomized way, different ways it could potentially boost the effectiveness of chemotherapy for neuroblastoma patients.
DFMO was also an FDA-approved treatment for a different disease that affects the nervous system, called African sleeping sickness. The parasites that cause African sleeping sickness and neuroblastoma tumors both rely on a chemical in the body called polyamines to grow. DFMO decreases polyamines, so Dr. Macy, Dr. Goldsmith, and their team wanted to find out if it might help patients who didn’t respond to DIT.
Dr. Macy’s study set a primary goal: a response rate of at least 20% for children treated with both DFMO and DIT. But when results came in, children who received both treatments fared no better than those on DIT alone. In research terminology, it was a “negative result,” but Dr. Macy was far from disappointed.
“In some ways I wasn’t surprised, because DIT already had a high response rate,” she said. “But from day one, I knew that even if this study didn’t show a difference with the addition of DFMO, we would still learn about the biology of neuroblastoma and these two treatments in general.”
The positives of ‘negative results’
Although Dr. Macy’s trial did not meet the intended goal, it shed important new light on other aspects of neuroblastoma. For example, they captured more detailed nuances of different ways patients responded to DIT with and without DFMO. Researchers call those nuances “minor responses.”
“Some patients have big soft-tissue tumors. Those don’t tend to shrink, but their bony lesions, which are often very painful, can go away,” Dr. Macy explained. “That could be clinically very beneficial for some patients,"
They also discovered that fewer patients on DFMO and DIT experienced significant pain than those taking DIT alone.
The study also shed light on a known risk of DFMO. Researchers knew that of DFMO caused temporary hearing loss in patients treated with high doses. Dr. Macy’s study closely monitored the results of hearing exams and immediately paused the trial as soon as a handful of children showed hearing loss.
After a break from DFMO treatment, their hearing bounced back, so the trial was amended to give patients a weeklong break every 28 days to help preserve their hearing.
These and other findings related to how DIT alters or activates the immune system reveal important clues that help researchers shape future studies. The same is true for the “negative results.”
“Negative results are just as important to publish, so we don’t repeat those same studies and expose patients to ineffective or toxic therapies,” she said. “Sometimes we think in our heads it’s going to be X, and it turns out to be Y. Either way, we learn and contribute to science and improving the care of our patients.”
Contributions like this move research closer to curing more kids with high-risk neuroblastoma and other cancers that are especially hard to treat. Conducting well-designed and well-controlled clinical trials is central to COG’s mission.
“Even ‘negative’ studies answer questions and help us design the next study on the basis of data,” said Children’s Oncology Group Chair Douglas S. Hawkins, MD. “We need to know what does and does not work objectively to improve outcomes for children with hard-to-treat cancer.”