Radiotherapy has been booming since 1990s with implementation of intensity modulated radiotherapy (IMRT), which could greatly reduce normal tissue complications (NTCs) than 3-dimensional conformal radiotherapy (3D-CRT) by increasing treatment time [1–4]. Literally, minimizing NTCs and meanwhile maximizing treatment outcomes had been the history of radiotherapy in the past [5–8]. Fortunately, recent progress of FLASH radiotherapy (FLASH-RT) might cause drastic alteration in this field [9–12]. The merits of FLASH-RT consist of 2 aspects: remarkably reducing NTCs and dramatically increasing the killing efficiency for cancer cells. That says, FLASH-RT could possibly comprise most of the efforts in the past by implementing one single technique: increase dose rate (DR) to > 40Gy/s.
In prevalent radiotherapy with a Varian TrueBeam™ linac, the highest DR for 6MeV X-rays of flattening filter free (6MVFFF) is ~ 1.2x103MUs/min. To achieve FLASH-RT, the DR for this X-rays should be increased to ~ 105MUs/min, about 2 orders higher, hence contemporary linacs need major renovations or probably redesigns. The DR for other treatment modalities are either comparable or lower than external beams. For instance, high dose rate (HDR) brachytherapy, the DR at full source strength, e.g., 10Ci Ir-192, is comparable to that of a linear accelerator (linac) at ~ 400MUs/min. For prevalent Gamma Knife, e.g., Elekta™ Leksell Perfexion or Icon, the DR at full source strength is ~ 3.5Gy/min, also comparable to external beams. Considering the challenges to generate ultra-high DR X-rays, increasing charged particles intensity, e.g., protons or carbon ions, at proton/carbon ion accelerators could be a more reasonable option because those particles have much higher kinetic energy [10]. As known, the mean energy for 6MeV X-rays is ~ 2MeV, generated by 6MeV electrons through Bremsstrahlung process. The kinetic energy of protons in radiotherapy, however, is ~ 250MeV, about 2 orders higher than 6-10MeV X-rays. That is, using protons or carbon ions is likely to meet the FLASH-RT DR, if the same number of those charged particles as X-ray photons are delivered at prevalent DR for linacs.
Since IMRT was originally invented to reduce NTCs [1–4], by implementing FLASH-RT, a good question might be: Is IMRT still necessary? Hitherto, a successful treatment modality in radiotherapy should either increase tumor control probability (TCP, e.g., stereotactic radiotherapy (SBRT)), or decrease NTC probability (NTCP, e.g., 3D-CRT, IMRT), or both (e.g., stereotactic radiosurgery (SRS)). For this reason, a TCP-based modality was always combined to a NCTP-based modality. For instance, the entire SBRT procedure is often called SBRT utilizing IMRT, or SBRT utilizing 3D-CRT (rarely though). Like SRS, FLASH-RT seems to be able to handle both TCP and NTCP. Nevertheless, the NTCs in FLASH-RT are not completely vanished, though significantly minimized. Considering this, FLASH-RT utilizing 3D-CRT could be more often for X-ray external beams in the future, whereas FLASH-RT utilizing IMRT might still exist but not popular due to beam modulation issues, which is discussed later.
Since IMRT was initiated in 1990s, beam modulations were always conducted at the treatment end, e.g., the gantry of the linacs, by implementing multi-leaf collimators (MLCs) to generate many instantaneous small fields, i.e., sliding windows or step-shots, for dose-volume tune-up [1–3]. Hence an IMRT treatment needs ~ 3 times MUs as much as a corresponding 3D-CRT treatment for the same prescribed doses [13–14]. That is, the resultant DR for IMRT is dropped to ~ 1/3 as the DR for a 3D-CRT treatment. Contemporary IMPT (the proton version of IMRT) treatment has comparable or even lower DRs as IMRT because pencil-beam modulations are being used, thus a typical IMPT treatment (~ 2Gy) takes quite a few minutes. Obviously, pencil-beam modulation for IMPT can never achieve the FLASH-RT DR, hence it should be completely renovated. Although the reason for contemporary low DR is the beam modulation, we still need to keep it because it was essential for dose conformity and normal tissue sparing. The only solution seems to be modulating the proton beam earlier, i.e., prior to reaching the treatment end.
In this study, we propose a novel design for clinical proton synchrotron accelerator, which could generate early modulated proton beams, namely, early modulated proton therapy (EMPT), hence possibly achieve the extremely high DR for FLASH-RT.