Background: The fast development of energy- and intensity-modulated radiation therapy during the last two decades using photon and electron beams has when implemented resulted in a considerable improvement of radiation therapy, particularly if combined with radiobiologically based treatment optimization techniques. This has made intensity-modulated electron and photon beams as powerful as today's uniform dose proton therapy. To be able to cure also the most advanced hypoxic and radiation-resistant tumors of complex local spread, intensity-modulated light ion beams are really the ultimate tool and in clinical practice 2 to 3 times less expensive per patient treated than proton therapy. This development and the recent development of advanced tumor diagnostics based on PET-CT imaging of the tumor cell density open the field for new powerful radiobiologically based treatment optimization methods. The ultimate step is to use the unique radiobiologic and dose distributional advantages of light ion beams for truly optimized bioeffect planning where the integral three-dimensional dose delivery and tumor cell survival can be monitored by PET-CT imaging and corrected by biologically based adaptive therapy optimization methods.
Purpose: The main purpose of the present paper is to discuss the principal areas of development of therapy optimization, by considering the therapy chain from tumor diagnostics and the use of three-dimensional predictive assay to biologically based treatment optimization with special focus on the rapid clinical development of advanced light ion therapy.
Methods: Besides the "classical" approaches using low ionization density hydrogen ions (protons, but also possibly deuterons and tritium nuclei) and high ionization density carbon ions, two new approaches will be discussed. In the first one, lithium or beryllium or boron ions, which induce the least detrimental biologic effect to normal tissues for a given biologic effect in a small volume of the tumor, will be key particles. In the second approach, referred patients will be given a high-dose, high-precision "boost" treatment with carbon or oxygen ions during 1 week preceding the final treatment with conventional radiation in the referring hospital. The rationale behind these approaches is to minimize the high ionization density dose to the normal-tissue stroma outside but sometimes also inside the tumor bed and to ensure a more uniform and optimal biologic effectiveness in the tumor, also on the microscopic scale. The present discussion indicates that BIologically Optimized predictive Assay based light ion Radiation Therapy (Bio-Art) is really the ultimate way to perform high-precision radiation therapy using checkpoints of the integral dose delivery and the tumor response and, based on this information, perform compensating corrections of the dose delivery. By using biologically optimized scanned high-energy photon or ion beams, it is possible to measure in vivo the three-dimensional dose delivery using the same PET-CT camera that was used for diagnosing the tumor spread. This method thus opens up the door for truly three-dimensional biologically optimized adaptive radiation therapy, where the measured dose delivery to the true target tissues can be used to fine-adjust the incoming beams, so that possible errors in the integral therapy process are eliminated toward the end of the treatment. Interestingly enough, practically all major error sources--such as organ motion, treatment planning errors, patient setup errors, and dose delivery problems due to gantry, multileaf, or scanning beam errors--can be corrected for in this way.
Results and conclusions: Radiobiologically optimized dose delivery using intensity and radiation quality modulation based on high-resolution PET-CT or Magnetic Resonance Spectroscopic Imaging (MRSI)-based tumor and normal-tissue imaging is probably the ultimate development of radiation therapy, taking the unique physical and biologic advantages of light ions fully into account in truly patient-individualized curative treatment schedules. Using recently available biologically based treatment ilable biologically based treatment optimization algorithms, it is possible to improve the treatment outcome for advanced tumors by as much as 10-40%. The adaptive radiotherapy process based both on three-dimensional tumor cell survival and dose delivery monitoring has the potential of percent accuracy in tumor response and dose delivery monitoring, using two-dimensional, narrow high-energy photon beam scanning and three-dimensional (11)C Bragg peak scanning for radiation quality and intensity-modulated dose delivery. There is no doubt that the future of radiation therapy is very promising, and gradually more and more patients may not even need advanced surgery. Instead, they could be cured by biologically optimized electron, photon, or light ion therapy, where the densely ionizing Bragg peak is placed solely in the gross tumor, and a lower ionization density is used in microscopically invasive tumor volumes.