The clinical implementation and application of a novel treatment planning system (TPS) for scanned ion beams is described, which is in clinical use for carbon ion treatments at the German heavy ion facility (GSI). All treatment plans are evaluated on the basis of biologically effective dose distributions. For therapy control, in-beam positron emission tomography (PET) and an online monitoring system for the beam intensity and position are used. The absence of a gantry restricts the treatment plans to horizontal beams. Most of the treatment plans consist of two nearly opposing lateral fields or sometimes orthogonal fields. In only a very few cases a single beam was used. For patients with very complex target volumes lateral and even distal field patching techniques were applied. Additional improvements can be achieved when the patient's head is fixed in a tilted position, in order to achieve sparing of the organs at risk. In order to test the stability of dose distributions in the case of patient misalignments we routinely simulate the effects of misalignments for patients with critical structures next to the target volume. The uncertainties in the range calculation are taken into account by a margin around the target volume of typically 2-3 mm, which can, however, be extended if the simulation demonstrates larger deviations. The novel TPS developed for scanned ion beams was introduced into clinical routine in December 1997 and was used for the treatment planning of 63 patients with head and neck tumours until July 2000. Planning strategies and methods were developed for this tumour location that facilitate the treatment of a larger number of patients with the scanned heavy ion beam in a clinical setting. Further developments aim towards a simultaneous optimization of the treatment field intensities and more effective procedures for the patient set-up. The results demonstrate that ion beams can be integrated into a clinical environment for treatment planning and delivery.

Hypoxia-induced radioresistance constitutes a major obstacle for a curative treatment of cancer. The aim of this study was to investigate effects of photon and carbon ion irradiation in combination with inhibitors of DNA-Damage Response (DDR) on tumor cell radiosensitivity under hypoxic conditions. Human non-small cell lung cancer (NSCLC) models, A549 and H1437, were irradiated with dose series of photon and carbon ions under hypoxia (1% O2) vs. normoxic conditions (21% O2). Clonogenic survival was studied after dual combinations of radiotherapy with inhibitors of DNA-dependent Protein Kinase (DNAPKi, M3814) and ATM serine/threonine kinase (ATMi). The OER at 30% survival for photon irradiation of A549 cells was 1.4. The maximal oxygen effect measured as survival ratio was 2.34 at 8 Gy photon irradiation of A549 cells. In contrast, no significant oxygen effect was found after carbon ion irradiation. Accordingly, the relative effect of 6 Gy carbon ions was determined as 3.8 under normoxia and. 4.11 under hypoxia. ATM and DNA-PK inhibitors dose dependently sensitized tumor cells for both radiation qualities. For 100 nM DNAPKi the survival ratio at 4 Gy more than doubled from 1.59 under normoxia to 3.3 under hypoxia revealing a strong radiosensitizing effect under hypoxic conditions. In contrast, this ratio only moderately increased after photon irradiation and ATMi under hypoxia. The most effective treatment was combined carbon ion irradiation and DNA damage repair inhibition. Carbon ions efficiently eradicate hypoxic tumor cells. Both, ATMi and DNAPKi elicit radiosensitizing effects. DNAPKi preferentially sensitizes hypoxic cells to radiotherapy.

The influence of artefacts due to metal implants on the range of ion beams is investigated, using a geometrically well-defined head and pelvic phantom together with inserts from steel, titanium and tungsten. The ranges along various beam paths including artefacts were calculated from the TPS and compared to known calculations for phantoms without any insert. In the head phantom, beams intersecting the streak artefacts lead to errors in the range of around or below 1%, which is mainly due to a cancellation of various effects. Beams through the metal or close to it show an underestimation of 3.5% of the range for tungsten. For the pelvic phantom, a large underestimation of the range is observed for a lateral path through the metal insert. In the case of tungsten and steel, range errors of -5% and -18% are observed, respectively. Such beam paths are typically used for pelvic tumours in radiotherapy with ion beams. For beams in the anterior-posterior direction through the inserts, an overestimation of ion ranges of up to 3% for titanium and 8% for steel is expected, respectively. Beam paths outside the metal insert show a large cancellation for the lateral beams (leading to errors of around 1% only) and somewhat higher errors for anterior-posterior beams (around 3% for titanium and 6% for steel). The analysis of CT data of patients with dental implants of gold as compared to patients with healthy teeth also showed a significant effect of the artefacts on the distribution of HU in the data, namely a redistribution of HU to higher and lower values as compared to patients with healthy teeth. The corresponding mean range variation was a 2.5% reduction in the data with artefacts as compared to the data without artefacts. It is concluded that beam paths through metal implants should generally be avoided in proton and ion therapy. In this case, the underestimation of ion range due to artefacts alone may amount to 3% for dental fillings and up to 5% and 18% for hip prosthesis made of titanium and steel, respectively. It is important to note that the size of the metal inserts cannot be determined correctly from the images, so that a correction of the ranges in metal also leads to large uncertainties. Finally, it should be stressed that the stated relative deviations are strictly valid only for the investigated phantoms and can only give a rough estimate on the size of range uncertainties that may appear in real patients.

Treatment standard for patients with primary glioblastoma (GBM) is combined radiochemotherapy with temozolomide (TMZ). Radiation is delivered up to a total dose of 60 Gy using photons. Using this treatment regimen, overall survival could be extended significantly however, median overall survival is still only about 15 months.

Treatment of patients with recurrent glioma includes neurosurgical resection, chemotherapy, or radiation therapy. In most cases, a full course of radiotherapy has been applied after primary diagnosis, therefore application of re-irradiation has to be applied cauteously. With modern precision photon techniques such as fractionated stereotactic radiotherapy (FSRT), a second course of radiotherapy is safe and effective and leads to survival times of 22, 16 and 8 months for recurrent WHO grade II, III and IV gliomas.