# Transformative Technology for FLASH Radiation Therapy
## 2 Beam Conditions for the FLASH Effect
### FLASH with Proton and Ion Beams  
Although pulsed FLASH has been proposed using large synchrotrons and fast extraction, the dose volume remains small and scanning problematic as the beam would likely be re-positioned between spills which makes the treatment time likely incompatible with FLASH conditions. The FLASH output from the 230-250 MeV proton therapy iso-cyclotrons was initially tested with shoot-through (non-degraded) beams achieving FLASH intensities [23,24] but, in recent years, several publications of FLASH studies with spread-out proton Bragg peaks have appeared [16,25,26,27]. Most of these studies have demonstrated FLASH effects in small animals but also highlighted the technical challenges that Bragg-peak FLASH proton therapy will face. For a review of the current status and future directions of preclinical proton FLASH research, see [PERSON] et al. [25]. FLASH research with helium and carbon ions have been confined to in vitro cell survival studies. These studies demonstrated a protection by FLASH irradiation only at very low oxygen concentrations of 1% or less [26,27]. Several clinical studies with protons are underway and the feasibility study \"FLASH Radiotherapy for the Treatment of Symptomatic Bone Metastases (FAST-01)\" has been completed and reported [8]. Individual RF (MHz) proton bunch structures may be important for proton FLASH (see discussion below); proton RF \"bunches\" are fractions of a microsecond, and electron RF bunches are fractions of a nanosecond. Further, CW proton beams are \"quasi-continuous\", whereas 100-300 Hz electron linacs produce a -microsecond \"macropulse\" containing many RF bunches and the \"instantaneous\" dose rate is averaged over the macro-pulse. For proton FLASH, the evidence from the preclinical studies mentioned above shows that a FLASH effect can be achieved despite an orders-of-magnitude-lower dose rate in the proton bunches delivered by iso-cyclotrons as long as the mean dose rate is compatible to those delivered by electron FLASH studies. For pulsed electron beams, the IDR is integrated over the microsecond individual macro-pulse, which repeats at the 100-300 Hz rate of the pulsed linac., as shown in Figure 2. The usually quoted 100 ms treatment time as optimal for electron FLASH may also apply to quasi-continuous proton beams and other quasi-CW FLASH RT sources such as SRF electron linacs. FLASH beam intensities have been demonstrated using proton-therapy iso-cyclotrons (cyclotrons that produce continuous rather than pulsed beams) and more recently synchro-cyclotrons (cyclotrons that produce pulsed beams of microsecond-length pulses with gaps of milliseconds) [28,29,30]. With regard to ion therapy, currently, only synchrotrons are available and synchrotrons, even the rapid-cycling 15 Hz ion synchrotron, are not capable of producing the intense ion beams required for FLASH radiotherapy for a clinical application. In addition to providing intense ion beams, FLASH radiotherapy studies need to be extended to incorporate the Bragg peak, range dependencies, and dosimetry into a broader research initiative. Since there are innovative accelerator technologies under development that may provide FLASHintensities for protons and ions, beam conditions can be proposed for the FLASH effect based on the relative biological effects (RBE) and linear energy transfers (LET) between the different particle beams. These extrapolations are presented in Table 2 and compared with a more conventional dose rate and dose fraction. Most preclinical studies published to date have not been systematically co-ordinated around beam parameters, including the mean and IDR, total dose, pulse structure, fractionation, and radiation type. Although there is a wide range of dose rates, some observations can be made nonetheless, although these may apply only to electron FLASH [12; 14; 21]. The following itemized list characterizes FLASH from the qualitative and quantitative points of view and raises some questions:  
* FLASH effects--general a.