Co-authors Radhe Mohan, PhD, of MD Anderson Cancer Center; Indras Das, PhD, of New York University, and I were motivated to understand why the clinical benefit of PT has not been definitively demonstrated, despite the clinical potential of protons attributable to their physical characteristics.
As we articulate in our paper, this may be, in part, due to PT technology which is still evolving and improving, insufficient appreciation of the fundamental differences between protons and photon therapies, and the limited understanding of the consequences of these differences. One key difference is the greater sensitivity of proton dose distributions to inter- and intra-fractional anatomic variations. Another one is the potential of increased radiobiological effectiveness (RBE) of protons which may be exploited to enhance the clinical efficacy of PT.
From a technological perspective, IMPT is potentially the most powerful tool for cancer radiation therapy, but as Tony Lomax pointed out in 2015, “pencil beam scanning proton therapy and treatment planning is very much in its infancy.” The present status of proton therapy may be likened to that of photon therapy before the development, introduction, and evolution of IMRT and IGRT during the past three decades. Thus, the aim of their critical review paper was to identify the current limitations of and uncertainties in IMPT and to describe ongoing and future developments that will minimize them and mitigate their effects. As the number of centers using IMPT increases, research and development effort will concomitantly increase, resulting in improvements in the technologic, biological and physical aspect of IMPT to provide an unsurpassed treatment method leading to improved treatment outcomes.
The major challenge in writing the paper was that each of the many steps in the process of IMPT is complex, and, at the same time, there was a need to balance being comprehensive and focused in writing a succinct and comprehensible overview. After deliberation, we decided to address three major areas of IMPT in our paper: treatment planning, treatment delivery and motion management. Treatment planning subtopics included uncertainties in proton range and dose computations, robust planning and robust optimization, adaptive treatment planning and delivery, and RBE considerations for protons. Treatment-delivery subtopics included improvement in proton beam characteristics, in-room image-guidance, contour-based pencil beam scanning and proton range determination during treatment delivery. We also discussed various issues related to the impact of inter-fractional (e.g., tumor shrinkage, weight loss) and intra-fractional (e.g., respiration-induced motion) anatomy variations and strategies to mitigate their impact.
The importance of this effort is in the assembly, in a single overview paper, of most of the critical issues that need to be addressed in moving IMPT forward. Low hanging fruits were identified, which can be achieved in the near term, which are more critical to proton therapy (IMPT in particular) than photon therapy. One example is the use of dual-energy CT for the reduction in range uncertainties and image artefacts, and for improved accuracy of dose calculations. Another example is the use of in-room image guidance to facilitate adaptive planning. Concurrently, many methods are being developed for in-room proton range measurement during treatment which could also contribute to range-uncertainty reduction. Several methods for robust planning and robust optimization are now available for minimizing the sensitivity of proton dose distributions to treatment uncertainties. On the technology for proton treatment delivery, efforts to reduce spot size and energy-switching time are on-going as well as consideration of contour-based scanning to improve dose conformality. Longer-term research should be directed to improving our understanding of the biological properties of protons and their effect on clinical outcomes, and the development of methods to circumvent the detrimental effort of tumor/organ motion.
Whereas in the past two and a half decades photon radiotherapy has been significantly improved with IMRT and IGRT, we surmise similar improvements can and will be realized for proton therapy in the coming decades by empowering IMPT through physics, biology and technology. On-going and future efforts to address the limitations of current proton therapy methods as identified in this paper should greatly improve IMPT and make it considerably more effective such that its advantage over photon therapy can be clearly demonstrated.
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