Future of Precision Medicine in Radiation Oncology – Role of Molecular Imaging Srinivasan Vijayakumar1,2,5, M.D., Shankar Giri1,2,5, M.D., Eldrin Bhanat1,2,M.D., Vani Vijayakumar3, M.D., Christian R. Gomez1,2,4,5,Ph.D. 1Cancer Institute; 2Department of Radiation Oncology; 3Department of Radiology. Division of Nuclear Medicine; 4Department of Pathology, University of Mississippi Medical Center, Jackson, MS. 5G.V. (Sonny) Montgomery Veteran Administration Medical Center, Jackson, MS. Abstract Results Radiation Oncology’s Progress Recent advances in genomic medicine and biology, electronic medical records and 'Big Data' provide great opportunities for improved patient focused cancer care in radiation oncology. Whereas there is a great excitement in the possibilities of targeted agents development in cancer care using the principles of precision medicine, the potential scope of advances that are feasible in developing new paradigms in radiation oncology-precision medicine is being overlooked. Radiation Therapy [RT] is used in approximately 60% of patients with cancer at some point during the course of their cancer illness. About 50% of the use of RT is for curative purposes. Radiotherapy plays a crucial role in the management of many malignancies (Reproduced from Vijayakumar et al, The Lancet, 349: S1-S3, 1997). The past 25 years have seen tremendous technological advances in the use of RT. This has enabled the radiation oncology teams to deliver RT doses with more accuracy and precision. This has led to dose escalation and improved local control of tumors. The toxicity profile with the use of RT has decreased. The quality of life of patients receiving RT has increased. With the enhanced use of combined Chemo-radiotherapy approaches survival rates have improved (Reproduced from Begg et al, Nature Reviews Cancer, 11:4, 239-253, 2011). Whereas technological advances have been successfully implement in RT, there is a neglect in the use of recent biological advances and implementation of precision medicine concepts in RT (Reproduced from Vijayakumar et al, 2016 Precision Medicine in Radiation Oncology: Personalizing Radiation Treatment. National Institutes of Health. Bethesda, 2016), there is an urgent need to invest in basic science, translational and clinical trial investigations in the use of Precision Medicine in Radiation Oncology. Such investigations will lead to: Individualized target dose prescriptions. Customized toxicity profile predictions. Improved iatrogenic second malignancy risk assessment. New indications developments in the use of RT in benign diseases. Dose de-escalations in specific sub-populations, especially in children. Use of Biological agents to enhance therapeutic response to RT. NCI and the Federal Government should invest in these investigations to develop new hypotheses; this will not only lead to improved cancer care, but also make USA lead the world in Radiation Oncology-Precision Medicine with beneficial economic impacts for the United States. Molecular Imaging will be an important component each one of the above six advances. Improved local control and survival rates: Cervix, head and neck, non-small cell lung and esophageal cancer. Improved Quality of Life (decreased toxicity): Prostate, head and neck, childhood cancer and lymphoma. Multivariable analysis (Weighted multiple linear regression and random effects metaregression): Personalized approach, compared with a non-personalized approach resulted in consistent and independent correlation with: - Higher median RR 31% v 10.5%, respectively; (P < 0.001) . - Prolonged median PFS 5.9 v 2.7 months, respectively; (P < 0.001) . - OS 13.7 v 8.9 months, respectively; (P < 0.001). Personalized arms using a genomic biomarker when compared to Personalized arms using a genomic biomarker: - Higher median RR. - Prolonged median PFS and OS (P < 0.05). A personalized strategy was associated with a lower treatment-related death rate than a non-personalized strategy: - Median,1.5% v 2.3%, respectively (P < 0.05). Goals to be achieved Improvement in local control and survival: (Esophageal, advanced head and neck, non small cell, small cell lung cancer and glioblastoma multiforme). Doses need to be individual specific rather than group specific. Be able to predict the recipient of therapy toxicity. Need proving data to combine biological – target agents with radiotherapy. Future looks promising with biologically targeted agents using the principles of Precision Medicine. Benefit of Personalized Therapy Discussion Personalized Medicine: “In its broadest sense, ‘personalized medicine’ is the tailoring of medical treatment to the characteristics of an individual patient and moves beyond the current approach of stratifying patients into treatment groups based on phenotypic biomarkers. Nowhere in medicine has the impact of personalized medicine been greater than in oncology. For scientists and oncologists, the term “personalized medicine” is often used interchangeably with terms such as “genomic medicine”, “precision medicine” and “precision oncology”. These terms are used to describe the use of an individual patient's molecular information (including genomics and proteomics) to inform diagnosis, prognosis, treatment and prevention of cancer for that patient. As the transition from stratified cancer medicine to truly personalized cancer medicine intensifies, it is this definition that the ESMO Personalized Medicine Task Force prefers to use when describing personalized cancer medicine. But irrespective of the term used, the direction of travel is clear—precision diagnosis and treatment of cancer at the molecular level—and this change in paradigm has profound implications, from preclinical definition of mechanism of action to the development of molecular taxonomies of cancer, and from genome diagnostics to trial design.” (Ciardiello et al, ESMO, 25:9, 1673-1678, 2014) (Reproduced from Schwaederle et al, JCO, 33: 32, 2015) Comprehensive analysis of phase II, single-agent arms revealed that, across malignancies, a personalized strategy was an independent predictor of better outcomes and fewer toxic deaths. Non-personalized targeted therapies were associated with significantly poorer outcomes than cytotoxic agents, which in turn were worse than personalized targeted therapy. (Reproduced from Schwaederle et al, JCO, 33: 32, 2015) THIS DEMONSTRATES THE IMPORTANCE OF PRECISION MEDICINE IN THE FUTURE Precision Medicine Principles in Research Imaging-Scientists and Radiation Oncologists [Jerai et al, JNM, 56, 1752-1765, 2015] Background Use of Molecular Imaging in Radiation Oncology NCCN Recommendations on use of 18 F-FDG PET/CT for Target Definition and Treatment Response Evaluation in Radiotherapy Individualized target dose prescriptions. Customized toxicity profile predictions. Improved iatrogenic second malignancy risk assessment. New indications developments in the use of RT in benign diseases. Dose de-escalations in specific sub-populations, especially in children. Use of Biological agents to enhance therapeutic response to RT. Further define and enhance the role of molecular imaging applications in radiotherapy. In the past three decades Radiation Oncology has advanced in the fields of: Technological: (3DCRT, IMRT, IGRT, Molecular imaging in treatment planning). Combined chemo radiotherapy treatments: (Head and neck, lung, esophageal, anal cancers and GBM). Biological Agents in Combination with RT: (Limited Applications, Head and neck cancer). Steps to be taken Close and collaborative work between radiologists, nuclear medicine clinicians, scientists, medical physicists and radiation oncologists. NCI / NIH investments this particular area of research. Education of residents and fellows on the importance of emerging role of precision medicine in radiology and radiation oncology. Encouragement of physician scientists in radiology, nuclear medicine and radiation oncology to focus on these areas of translational science. Follows all steps of treatment process but with some specific challenges, particularly for defining treatment targets (e.g., requiring accurate spatial localization) and in treatment response assessment (e.g., requiring special attention to radiation-induced inflammation). Vertical bars during radiotherapy indicate individual treatment fractions. Methods Methods to Incorporate Molecular Images into Radiation Therapy Planning and their Respective Degrees of Complexity Schwaederle et al reviewed phase II single-agent studies (570 studies; 32,149 patients) published between January 1, 2010, and December 31, 2012 (PubMed search). Response rate (RR), progression-free survival (PFS), and overall survival (OS) were compared for arms that used a personalized strategy versus those that did not. Support Funding sources (to CRG): New Investigator Award, CDMRP-PCRP. Collaborative Undergraduate HBCU Student Summer Training Program Award, CDMRP-PCRP. Treatment Sciences Creativity Award. Prostate Cancer Foundation. (Reproduced from Jeraj et al, JNM, 56, 1752-1765, 2015)