[en] Purpose: To extend the application area of particle therapy with carbon ions the many already established treatment regimens for different tumor entities have to be taken into consideration. The present study investigates the effect of combined radiochemotherapy with temozolomide (TMZ) and high linear energy transfer (LET) irradiation with carbon ions versus photons. Materials and methods: Clonogenic survival was analyzed for human glioma cell lines with different O6-methylguanine-DNA methyltransferase (MGMT) status, LN18 (MGMT+) and LN-229 (MGMT-), after exposure to different doses of either carbon ion or photon irradiation at different time points relative to TMZ application. Cell cycle distribution was measured by flow cytometry. MGMT status of the cell lines was verified by Western blot. Results: LN-18 and LN-229 reacted in accordance to their MGMT status with different sensitivity to TMZ treatment. Combined treatment with irradiation showed additive cytotoxic effects for both cell lines with low radiation doses but no radiosensitization. With increasing photon doses the combination effect was reduced, and the efficacy of the combined treatment was not dependent on administration schedule. Carbon ion irradiation showed the well known increased relative biological efficiency (RBE), overcame the abovementioned antagonism and was also not schedule-dependent. Conclusions: The in vitro effectiveness of TMZ in combined radiochemotherapy is independent of administration time or MGMT-expression. Both cell lines are significantly more sensitive to combined treatment with carbon ion radiation than to photon radiation but do not show any super-additive effects. (authors)

[en] There are already numerous reports about high local control rates in patients with craniopharyngioma but there are only few studies with follow up times of more than 10 years. This study is an analysis of long term control, tumor response and side effects after fractionated stereotactic radiotherapy (FSRT) for patients with craniopharyngioma. 55 patients who were treated with FSRT for craniopharyngioma were analyzed. Median age was 37 years (range 6–70 years), among them eight children < 18 years. Radiotherapy (RT) was indicated for progressive disease after neurosurgical resection or postoperatively after repeated resection or partial resection. A median dose of 52.2 Gy (50 – 57.6 Gy) was applied with typical dose per fraction of 1.8 Gy five times per week. The regular follow up examinations comprised in addition to contrast enhanced MRI scans thorough physical examinations and clinical evaluation. During median follow up of 128 months (2 – 276 months) local control rate was 95.3% after 5 years, 92.1% after 10 years and 88.1% after 20 years. Overall survival after 10 years was 83.3% and after 20 years 67.8% whereby none of the deaths were directly attributed to craniopharyngioma. Overall treatment was tolerated well with almost no severe acute or chronic side effects. One patient developed complete anosmia, another one’s initially impaired vision deteriorated further. In 83.6% of the cases with radiological follow up a regression of irradiated tumor residues was monitored, in 7 cases complete response was achieved. 44 patients presented themselves initially with endocrinologic dysfunction none of them showed signs of further deterioration during follow up. No secondary malignancies were observed. Long term results for patients with craniopharyngioma after stereotactic radiotherapy are with respect to low treatment related side effects as well as to local control and overall survival excellent

[en] Purpose: We evaluated the influence of tumor location and tumor spread in primary glioblastoma (GBM), with respect to the subventricular zone (SVZ), on recurrence behavior, progression-free survival (PFS), and overall survival (OS). Methods and Materials: 607 patients (376 male and 231 female) with a median age of 61.3 years (range, 3.0-87.9 years) and primary GBM treated with radiation therapy (RT) from 2004 to 2012 at a single institution were included in this retrospective study. Preoperative images and follow-up examination results were assessed to evaluate tumor location. Tumors were classified according to the tumor location in relation to the SVZ. Results: The median PFS of the study population was 5.2 months (range, 1-91 months), and the median OS was 13.8 months (range, 1-102 months). Kaplan-Meier analysis showed that tumor location in close proximity to the SVZ was associated with a significant decline in PFS and OS (4.8 and 12.3 months, respectively; each P<.001). Furthermore, in cases where tumors were involved with the SVZ, distant cerebral progression (43.8%; P=.005) and multifocal progression (39.8%; P=.008) were more common. Interestingly, opening of the ventricle during the previous surgery showed no impact on PFS and OS. Conclusion: GBM in close proximity to the SVZ was associated with decreased survival and had a higher risk of multifocal or distant progression. Ventricle opening during surgery had no effect on survival rates

[en] Densely ionizing charged particle irradiation offers physical as well as biological advantages compared with photon irradiation. Radiobiological data for the combination of such particle irradiation (i.e. therapeutic carbon ions) with commonly used chemotherapeutics are still limited. Recent in vitro results indicate a general prevalence of additive cytotoxic effects in combined treatments, but an extension of established multimodal treatment regimens with photons to the inclusion of particle therapy needs to evaluate possible peculiarities of using high linear energy transfer (LET) radiation. The present study investigates the effect of combined radiochemotherapy using gemcitabine and high-LET irradiation with therapeutic carbon ions. In particular, the earlier observation of S-phase specific radiosensitization with photon irradiation should be evaluated with carbon ions. In the absence of the drug gemcitabine, carbon ion irradiation produced the typical survival behavior seen with X-rays—increased relative biological efficiency, and depletion of the survival curve's shoulder. By means of serum deprivation and subsequent replenishment, ∼70% S-phase content of the cell population was achieved, and such preparations showed radioresistance in both treatment arms—,photon and carbon ion irradiation. Combined modality treatment with gemcitabine caused significant reduction of clonogenic survival especially for the S-phase cells. WIDR cells exhibited S-phase–specific radioresistance with high-LET irradiation, although this was less pronounced than for X-ray exposure. The combined treatment with therapeutic carbon ions and gemcitabine caused the resistance phenomenon to disappear phenotypically

[en] The benefits of new innovations in glioblastoma therapies should not be curtailed as a result of delays in commencement of radiation therapy, caused by clinical circumstances as well as diagnostic procedures. This study evaluates whether delays in chemo-radiotherapy after surgery, while determining O6-methylguanine-DNA-methyltransferase (MGMT) promoter status, affect the survival rates of patients with glioblastoma (GBM). Our sample comprised 50 GBM patients in a retrospective analysis of three prospective studies that focused on combined radiotherapy and required MGMT promoter-status testing as inclusion criteria. Results were compared with a reference group of 127 favourable GBM cases (Karnofsky performance-status scale ≥ 70), in which the patients underwent standard postoperative chemo-radiotherapy with temozolomide. Survival time was calculated using the Kaplan-Meier method, and a multivariate analysis of the delays between surgical and radiotherapy procedures was performed using the Cox regression model. The study group’s median overall survival time was 16.2 months (with a range of 2 to 56 months), versus the reference group’s survival time of 18.2 months (with a range of 1 to 92 months) (p = 0.64). The delay between surgery and radiotherapy was increased by 8 days in the study patients (p < 0.001), with a median delay of 35 days (range: 18–49 days) corresponding to the typical 27-day delay (range: 5–98 days) for those in the reference group. Univariate and multivariate analyses did not show any negative association between survival time and delaying radiation therapy to determine MGMT-promoter status; commencement of radiation therapy sooner than 24 days after surgery was the threshold for significantly decreased overall survival (p = 0.01) and progression-free (p = 0.03) survival. Delaying postoperative chemoradiation for GBM patients—carried out in order to determine MGMT-promoter status—did not have a negative impact on survival time. Indeed, the data of the present study shows that initiating radiation therapy sooner than 24 days after surgery has a negative impact on progression and survival

No abstract available

[en] To retrospectively assess the feasibility and safety of a sequential proton boost following conventional chemoradiation in high-grade glioma (HGG).

[en] Several studies have demonstrated the negative impact of radiotherapy protocol deviations on tumor control in medulloblastoma. In the SIOP PNET5 MB trial, a pretreatment radiotherapy quality control (RT-QC) program was introduced. A first analysis for patients enrolled in Germany, Switzerland and Austria with focus on types of deviations in the initial plan proposals and review criteria for modern radiation technologies was performed. Sixty-nine craniospinal irradiation (CSI) plans were available for detailed analyses. RT-QC was performed according to protocol definitions on dose uniformity. Because of the lack of definitions for high-precision 3D conformal radiotherapy within the protocol, additional criteria for RT-QC on delineation and coverage of clinical target volume (CTV) and planning target volume (PTV) were defined and evaluated. Target volume (CTV/PTV) deviations occurred in 49.3% of initial CSI plan proposals (33.3% minor, 15.9% major). Dose uniformity deviations were less frequent (43.5%). Modification of the RT plan was recommended in 43.5% of CSI plans. Unacceptable RT plans were predominantly related to incorrect target delineation rather than dose uniformity. Unacceptable plans were negatively correlated to the number of enrolled patients per institution with a cutoff of 5 patients (p = 0.001). This prospective pretreatment individual case review study revealed a high rate of deviations and emphasizes the strong need of pretreatment RT-QC in clinical trials for medulloblastoma. Furthermore, the experiences point out the necessity of new RT-QC criteria for high-precision CSI techniques.

[en] This study aimed to compare the results of irradiation with protons versus irradiation with carbon ions in a raster scan technique in patients with skull base chordomas and to identify risk factors that may compromise treatment results. A total of 147 patients (85 men, 62 women) were irradiated with carbon ions (111 patients) or protons (36 patients) with a median dose of 66 Gy (RBE (Relative biological effectiveness); carbon ions) in 4 weeks or 74 Gy (RBE; protons) in 7 weeks at the Heidelberg Ion Beam Therapy Center (HIT) in Heidelberg, Germany. The median follow-up time was 49.3 months. All patients had gross residual disease at the beginning of RT. Compression of the brainstem was present in 38%, contact without compression in 18%, and no contact but less than 3 mm distance in 16%. Local control and overall survival were evaluated using the Kaplan-Meier Method based on scheduled treatment (protons vs. carbon ions) and compared via the log rank test. Subgroup analyses were performed to identify possible prognostic factors. During the follow-up, 41 patients (27.9%) developed a local recurrence. The median follow-up time was 49.3 months (95% CI: 40.8-53.8; reverse Kaplan-Meier median follow-up time 56.3 months, 95% CI: 51.9-60.7). No significant differences between protons and carbon ions were observed regarding LC, OS, or overall toxicity. The 1-year, 3-year, and 5-year LC rates were 97%, 80%, and 61% (protons) and 96%, 80%, and 65% (carbon ions), respectively. The corresponding OS rates were 100%, 92%, and 92% (protons) and 99%, 91%, and 83% (carbon ions). No significant prognostic factors for LC or OS could be determined regarding the whole cohort; however, a significantly improved LC could be observed if the tumor was > 3 mm distant from the brainstem in patients presenting in a primary situation. Outcomes of proton and carbon ion treatment of skull base chordomas seem similar regarding tumor control, survival, and toxicity. Close proximity to the brainstem might be a negative prognostic factor, at least in patients presenting in a primary situation.

[en] In Germany, Austria, and Switzerland, pretreatment radiotherapy quality control (RT-QC) for tumor bed boost (TB) in non-metastatic medulloblastoma (MB) was not mandatory but was recommended for patients enrolled in the SIOP PNET5 MB trial between 2014 and 2018. This individual case review (ICR) analysis aimed to evaluate types of deviations in the initial plan proposals and develop uniform review criteria for TB boost. A total of 78 patients were registered in this trial, of whom a subgroup of 65 patients were available for evaluation of the TB treatment plans. Dose uniformity was evaluated according to the definitions of the protocol. Additional RT-QC criteria for standardized review of target contours were elaborated and data evaluated accordingly. Of 65 initial TB plan proposals, 27 (41.5%) revealed deviations of target volume delineation. Deviations according to the dose uniformity criteria were present in 14 (21.5%) TB plans. In 25 (38.5%) cases a modification of the RT plan was recommended. Rejection of the TB plans was rather related to unacceptable target volume delineation than to insufficient dose uniformity. In this analysis of pretreatment RT-QC, protocol deviations were present in a high proportion of initial TB plan proposals. These findings emphasize the importance of pretreatment RT-QC in clinical trials for MB. Based on these data, a proposal for RT-QC criteria for tumor bed boost in non-metastatic MB was developed.