Organs at risk
Surely, treatment concepts are highly influencing the clinical outcome, but target volumes, field setups and the consecutive dose distributions can directly be translated into different risk profiles. Posterior fields deposit high doses to the spinal cord and the kidneys, right lateral fields result in dose exposure to the liver. Higher doses in intestinal structures are generated by left lateral and anterior fields.
A possible single posterior field setup is of major concern, because of its steep RBE-increase at the distal end of the SOBP, leading to unexpected high doses to the small intestine. Based on SBRT trials, less than 4%/ 5 ccm of the stomach should receive more than 22.5 Gy [
49]. With ion beam therapy being accompanied by RBE-increase at the distal end, this constraint might be exceeded. There is a retrospective analysis of a small cohort with promising results after high dose proton radiotherapy with little adverse side effects [
50]. Unfortunately, M.D. Anderson Cancer Center and Takatori et al. reported several events of intestinal ulcerations after high dose proton radiotherapy of pancreatic cancer [
24,
51‐
54]. So, the stomach/small bowel is one of the main OARs in ion beam therapy of pancreatic cancer – there are up to 50% radiation-induced ulcers after high dose proton radiotherapy with concurrent gemcitabine application [
24]. Similarly, Terashima et al. reported high intestinal toxicity after aggressive simultaneous radiochemotherapy [
55]. Shinoto et al. could show, that a possible constraint for ulcerations of the upper gastrointestinal tract might be D2ccm < 46 Gy(RBE) [
23].
High dose deposition in the colon might also result in clinically relevant complications, which is why Terashima et al. divided their patient collective into those with contact to the intestines and those without, thus applying 50 Gy(RBE) or 70.2 Gy(RBE) to the target volume [
55]. Another possibility might be simultaneous integrated protection in the target volume, which has also been used by Terashima et al. [
55]. With regard to gastrointestinal complications, at HIT there is experience on comparable dose protocols with intestinal structures adjacent to the target volume, such as carbon ion therapy of sacral chordoma and locally recurrent rectal cancer, where no higher gastrointestinal toxicities were recorded [
56,
57].
Intra- and interfractional variability and dosimetric changes
As described before, ion beam radiotherapy is on the one hand characterized by very sharp dose gradients, but on the other hand these sharp dose gradients lead to great challenges in case of dosimetric uncertainties. Robustness in ion beam therapy of pancreatic cancer is dependent on patient immobilization, target volume, beam optimization, beam setups, interfractional and intrafractional changes:
Due to tumor and OAR movements during radiotherapy a robust patient immobilization setup has to be established, especially in highly precise hypofractionated particle therapy [
58,
59]. To date, no general recommendation on the most reliable setup in pancreatic cancer patients can be given, but the different setups lead to significant movement reductions of the tumor, the pancreas in total and the OARs compared to without any immobilization [
60‐
62]. Further studies on the exact tumor movement by the use of 4D–MRI (magnetic resonance imaging) and 4D–CT scans have to be conducted, in order to improve treatment planning and enable dose escalation in particle therapy.
In case of photon radiotherapy these challenges resulted in the PTV concept and obviously, this has to be taken over in ion beam therapy, despite of limiting the advantages of the sharp dose gradients with regard to dose exposure to the OARs [
37]. Nevertheless, the exact margins of the different treatment volumes have to be re-evaluated for ion beam radiotherapy.
Based on the central position in the abdomen, pancreatic cancer is totally surrounded by OARs, and that’s the reason why ion beam therapy of abdominal organs, and especially pancreatic cancer is very complex. Inter- and intraindividual (inter- and intrafractional) changes in organ motion and intestinal fillings anterior and left laterally of the target volume are a great challenge for robust ion beam therapy. Kumagai et al. reported an analysis of passive scattered carbon ion beams, showing that anterior-posterior and left-right field setups cause the highest dose affections [
63]. Therefore, the established 4- and 3-fields setups have to be critically analyzed. Steitz et al. at HIT could also show that SBO plan optimization is able to compensate interfractional bowel movement in case of dose deposition in the target volume [
64].
Intrafractional movements due to breathing lead to a decrease in robustness, possibly resulting in overdosage in OARs and underdosage in the target volume [
65‐
67]. As breathing itself obviously influences all organs and tissues, gating might be a solution. Taniguchi et al. analyzed doses in duodenum and stomach in patients with LAPC treated with a five-fraction protocol: results show a decreasing dose exposure of the OARs during expiration compared to inspiration [
67]. Furthermore, Fontana et al. could show, that the expiration phase also has the highest stability of pancreatic cancer motion in 4D–MRI [
60]. So, including breathing phases in treatment planning and gating in general is highly promising in pancreatic cancer patients [
68].
With regard to the above-mentioned robustness challenge, one could assume that ion beam therapy of pancreatic cancer should be conducted by the use of a single posterior field. A single posterior beam might be robust, but small rotations of the processi transversi can lead to different dose depositions in the pancreatic cancer. Nevertheless, Batista et al. have presented data about pancreatic cancer, that supported this hypothesis. A single posterior field and two oblique posterior fields are superior in case of robustness [
40]. But, dose deposition by a single field leads to high integral dose in its trajectory, resulting in high dose deposition in the spinal cord itself, probably violating general QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) constraints [
69].
However, intra- and interfractional changes are not totally understood. We need re-planning scenarios, as slight changes result in significant dose variations especially in case of scanned particle therapy, which is used at HIT [
63,
67,
70,
71]. Of course, there are advantages of scanning, e.g. in case of conformal and highly precise dose deposition in the target volume [
30]. But active scanning is at the same time highly vulnerable due to robustness problems, such as interplay effects. At least, Richter et al. at HIT were able to show, that fractionation is a potential tool to reduce dose inhomogeneity by interplay effects [
66,
72]. This in return promotes normofractionated radiotherapy, instead of the established hypofractionated dose regimes. Additionally other methods of compensation, such as tracking, are currently under critical investigation and might provide additional benefit for moving targets.