Looking Beyond Translation
May 16, 2012 2 Comments
An article in the May 3, 2012, New England Journal of Medicine, (NEJM) from the Mount Sinai School of Medicine and Mayo Clinic, examined the concept of translational research and its largely unfulfilled mission. (Gelijns AC, Gabriel SC. Looking Beyond Translation – Integrating Clinical Research with Medical Practice. NEJM 2012; 366:1659–1661). These investigators reviewed many of the precepts of clinical research and described mechanisms by which outcomes could be improved. Among the points they raised is the need to integrate clinical research with clinical practice to create “patient-centered, science-driven healthcare.”
Despite their academic credentials, Drs. Gelijns and Gabriel recognized that academic medical settings are not always conducive to conducting clinical research. They also describe the lack of incentives for clinical physicians to undertake research studies. They go on to examine the need to refocus medical education onto a science of healthcare delivery. Finally, they decry the performance metrics by which clinical physicians are gauged (tests performed and numbers of patients seen) and contrast that with the equally unsatisfactory metrics for academicians (grants received and papers published). We couldn’t agree more.
While many of the points raised are worthwhile, these authors fail to grasp the fundamental problem at hand. Falling back on the age-old adage that pediatric malignancies have been cured through the clinical trial process, they criticize the adult oncology physicians for their lack of accrual. Their focus on participation in clinical trials as the highest accomplishment to which a medical oncologist might aspire is misguided and misleading. Grinding patients through ill-conceived clinical trials is no way to cure cancer. What are needed are intelligent solutions to complex problems. Complexity by its nature precludes the use of linear reasoning in the solution of problems. So complex is the cancer problem that investigators long since abdicated insights for statistical significance hoping that by throwing enough patients onto protocols, discernible patterns will emerge.
Childhood cancers have not been cured by protocols. They have been cured because they are curable. The average pediatric malignancy manifests a small number of mutational changes. Founder clones identified within these tumors can be eradicated even with the blunt instrument of contemporary chemotherapy. It is not an accident that childhood leukemia is curable, but instead a manifestation of the cells of origin. Childhood ALL, the most common pediatric malignancy is a prime example. Hematopoietic elements by nature are good at dying. Chemotherapy just helps them along.
As we move from pediatric oncology to adult oncology however, we encounter a horse of a different color. There are the common adult tumors like colon and lung that have accumulated a myriad of perturbations over a lifetime of exposures and genetic errors. The pathway back to normality is fraught with hazards and the founder clones are often numerous and diverse.
To meaningfully advance cancer therapeutics we need wholly new conceptual frameworks that connect complex systems to available solutions. Analytic platforms that can reproduce human tumor biology in the laboratory will provide clinicians the targets for treatment, the results they seek and the incentive to participate in clinical trials.
Pediatric oncology served as the model for cancer researchers who believed enrolling more patients in clinical trials would speed up the process of learning which therapeutic interventions worked best for which patients. The NCI-funded Pediatric Oncology Group, over the past five decades enrolled about 90 percent of all children with cancer in clinical trials. This enabled pediatric oncologists to steadily refine the treatment regimens to the point where survival rates today are over 80 percent, up from 20 percent in the 1960s.
According to Sharon Murphy, a visiting fellow at the Institute of Medicine and former head of the Pediatric Oncology Group, the trials built over time on previous learning by incorporating better scientific understanding of the science of the disease into treatment. It led to risk stratification, she explains, which is the holy grail of personalized medicine that researchers often talk about in adult oncology but has proven elusive, except in a few situations.
As you mention about the fundamental problem at hand, falling back on the age-old adage that pediatric malignancies have been cured through the clinical trial process, yet not all pediatric oncologists believe repeating that approach in adult oncology will lead to similar progress. Adult tumors can take decades to develop and are resistant to treatment. Pediatric cancers, in contrast, usually arise from embryonic development and develop into cancers that are much more susceptible to chemotherapy and radiation, according to Joseph V. Simone, director of the University of Florida’s Shands Cancer Center.
In any case, getting more adult patients enrolled in clinical trials wouldn’t be easy anyway. Many cancer patients confronting their life-threatening illness are understandably reluctant to take a 50-50 chance of getting put in the arm of a clinical trial that doesn’t receive the experimental therapy. And that’s only half the problem. Most patients are treated by community oncologists in private offices, not at academic medical centers that get NCI financial support to enroll patients in trials.
I believe the more sophisticated researchers in the field are beginning to appreciate that the complexity of human biology demands more global (functional) analytic platforms that encompass all of the mechanisms of response, the targets for treatment they seek.
Good post Dr. Nagourney!
Thanks. We are on the same page.