Looking back on four decades of pediatric clinical research with Victor Santana, MD

“To be a good pediatric oncologist, you first have to be a good pediatrician dedicated to the well-being of children,” says Victor Santana, MD, Department of Global Pediatric Medicine. Santana has spent over four decades at St. Jude devoted to the clinical care of children with cancer. His fascination with both children’s health and the intricate nature of cancer treatment drove his journey into pediatric oncology. This is the firm foundation on which he still approaches research and patient care today.

In addition to being a good children’s doctor, pediatric oncology lies at the intersection of the lab and the clinic. To move the needle toward novel therapeutic options for patients, it is necessary to understand the biology of pediatric cancer, which is unique compared to adult cancers, and conduct clinical trials. Since pediatric cancers are rare diseases, a concerted and collaborative effort is needed in clinical research.

Clinical trials are the understated foundation behind many medical breakthroughs – while pediatric clinical researchers are the architects. Throughout his career, Santana has led or enrolled patients in many different clinical trials. These diverse studies are built against a similar backdrop of challenges, traversing a long and fascinating history – punctuated by significant milestones marking progress against disease.

Evolution of clinical trials

Key milestones mark the history of clinical trials at St. Jude. One of the earliest focuses for the hospital was leukemia. Donald Pinkel, MD, and his pioneering Total Therapy approach to acute lymphoblastic leukemia (ALL) transformed the perception of ALL from a fatal condition to a curable disease. By 1967-68, the Total Therapy approach had achieved a 50% cure rate, marking the first substantial cure rate for generalized cancer and primarily drug treatment of cancer. Improved technology, updated training, better infection control, safer blood transfusions and newer drugs have since increased reported cure rates up to 94% for children with ALL.

By the early 2000s, the hospital was up to its 15th study in the series, TOTXV, which aimed to optimize chemotherapy for ALL based on minimal residual disease, the small number of leukemia cells left in the body after treatment. The study also pioneered the use of intrathecal therapy, the direct administration of chemotherapy drugs into the fluid-filled space between the brain and spinal cord, to replace brain radiation. “When I look at the history of ALL treatment, through a series of protocols, St. Jude basically eliminated the use of cranial spinal radiotherapy for these children,” Santana explains. “That is a real milestone.”

The Total Therapy trials stand as a hallmark of the St. Jude approach to clinical research – optimizing combination treatment regimens, basing clinical direction on biological understanding, and tailoring therapy so patients receive only the care necessary to limit late effects. As survival rates have improved, the questions clinical trials seek to answer have become more nuanced. “Clinical trials in pediatric cancer are now more complex because we have made much progress,” Santana explains. This is true in Santana’s work, which focuses on childhood solid tumors. He has worked to bring the advances first observed in leukemia to other pediatric malignancies, focusing on improving outcomes for high-risk and difficult to treat forms of the disease.

From leukemia to solid tumor research

Santana’s work spans the development and implementation of new chemotherapy drugs and immunotherapy approaches, which have substantially improved outcomes for children with high-risk solid tumors such as neuroblastoma, Ewing sarcoma and rhabdomyosarcoma. In the 1990s, his research focused on drugs used to treat cancer called camptothecins, specifically topotecan and irinotecan. “The research we did in the 1990s with the anti-cancer drugs demonstrated that these are very active drugs in pediatric solid tumors and are now considered key components of various chemotherapy regimens for several solid tumors," Santana explains. This work laid a foundation upon which researchers are continuing to innovate.

More recently, Santana has focused on integrating immunotherapy, treatments that harness the power of the immune system to kill cancer cells, into therapies for high-risk neuroblastoma. "In the past decade, we have demonstrated that a chemo-immunotherapy approach is critical for improving the anti-tumor efficacy and survival of children with high-risk neuroblastoma," he notes. Clinical trials led by Santana and his colleagues have shown that combining chemotherapy with immunotherapy agents significantly boosts the immune system's ability to target and destroy cancer cells.

A collaborative, multidisciplinary approach has driven advancements in pediatric solid tumor treatments at St. Jude. "Pediatric cancer requires a multidisciplinary approach with collaborators including surgeons, radiation therapists, oncologists, immunologists and stem cell transplantation experts," Santana emphasizes. This collaboration ensures that each patient's treatment plan is comprehensive and incorporates the latest scientific and clinical insights. Collaboration with basic scientists at St. Jude has also been crucial in translating preclinical findings into clinical trials.

Advocacy in clinical trials

In addition to the development of more precise therapy, Santana notes another advance when he reflects on the history of clinical trials: the growing influence of advocacy groups and more education for patient families. "Parents have become more educated," Santana notes, attributing this partly to web-based resource platforms, such as the national clinical trials database, that provide easy access to trial information. This increased knowledge has made parents active participants in the discussion and decision-making process.

Advocacy groups have also played a decisive role by questioning exclusion criteria and advocating for more inclusive trials. "Sometimes you talk to advocates, and they say, 'Why do you have that inclusion criteria? It makes no sense for us,'" Santana explains. The feedback has been vital in shaping more effective and inclusive clinical trials. In addition, patients and parents want to know the results of the clinical trials they participated in, so active communication is critical to maintaining trust in research.

Government policy and regulations are also increasingly involved in supporting pediatric clinical trials. Initiatives such as the 21st Century Cures Act and Pediatric Research Equity Act have paved the way for greater governmental support. "A lot of the fruits of those things are still yet to be seen, but they show that there is a partnership with the government and regulators to advance clinical research in children," Santana notes.

Global initiatives and collaborations in clinical trials

In his four decades at St. Jude, Santana has seen the institution’s profound impact on advancing pediatric cancer treatment, not just in Memphis and its affiliate institutions, but worldwide. Today, he works to leverage clinical and cultural insights to address barriers to global patient care and access to clinical trials. He particularly notes the St. Jude Global program’s partnership with the World Health Organization (WHO). St. Jude is the first and only WHO Collaborating Centre for Childhood Cancer, combining efforts to ensure more children worldwide receive life-saving care. “St. Jude has recognized that in order to do global work, you have to partner with organizations that are policymakers,” said Santana.

Santana’s current research explores factors that affect a person’s decision to participate in clinical trials. For example, Santana and his colleagues Dylan Graetz, MD, and Carolyn Russo, MD, designed a study in which patients’ parents shared their reasoning as to why they may or may not choose to participate in clinical research. This work was inspired by a previous study examining such barriers to participation from physicians’ perspectives. Such studies can help remove barriers and increase access to clinical trials, which will, in turn, help patients and improve the understanding of cancer and other catastrophic diseases. Santana and his colleagues are also researching clinical trial disparities to better address the needs of adolescents and young adults, and studying stigma as a factor in healthcare gaps.

Whether through multi-site clinical trials or by sharing knowledge and resources globally, collaboration has been a critical factor in advancing pediatric cancer care – and will continue to be an area of focus for Santana.

Milestones and a personal touch

Reflecting on his career, Santana notes that pediatric cancer treatment is a team effort with many contributors. “I cannot recount a personal legacy because pediatric cancer is a team effort, and many have contributed to the work I have been engaged in regarding clinical trials,” explains Santana. His personal goal is to offer innovative, compassionate care to his patients.

For Santana, the most rewarding aspect of his work is seeing former patients return as healthy adults. “Whenever I get a call from our clinic’s desk clerk and they say, 'Dr. Santana, this off-treatment patient is here, and they want to say hello to you,’ I stop what I'm doing, and I go visit with them,” Santana shares. These moments, coupled with the challenges posed by patient losses, drive his commitment to improving outcomes and continuing his vital work.

Santana is optimistic about the future of cancer care, particularly the potential of immunotherapy and precision medicine. He is excited about their potential to improve outcomes for all patients, though he acknowledges the significant challenges in making these advanced treatments accessible to all, especially in global contexts. The tasks at hand are bold, but the history of pediatric cancer care and clinical trials has shown dedication, focus and collaboration can overcome these challenges.