Treatment of primary or recurrent non-resectable pancreatic cancer with proton beam irradiation combined with gemcitabine-based chemotherapy.

BACKGROUND: Pancreatic cancer accounts for around 4.6% of cancers deaths worldwide per year. Despite many advances in treatment regimes, the prognosis is still poor. Only 20% of tumors are primarily resectable. Recurrences-both with distant metastasis as well as locoregional-are frequent. For patients with primary nonresectable localized disease or localized recurrences, we offered chemoradiation to achieve local control over a long period of time. We here report our results on combined chemoradiation of pancreatic tumors and local recurrences using proton beam therapy. MATERIALS AND METHODS: We report on 25 patients with localized nonresectable pancreatic cancer (15 patients) or local recurrent disease (10 patients). All patients were treated with combined proton radiochemotherapy. Overall survival, progression-free survival, local control, and treatment-related toxicity were analyzed using statistically methods. RESULTS: Median RT dose was 54.0 Gy (RBE) for proton irradiation. The toxicity of treatment was acceptable. Four CTCAE grade III and IV adverse events (bone marrow disfunction, gastrointestinal [GI] disorders, stent dislocation, myocardial infarction) were recorded during or directly after the end of radiotherapy; two of them were related to combined chemoradiation (bone marrow disfunction, GI disorders). Six weeks after radiotherapy, one additional grade IV toxicity was reported (ileus, caused by peritoneal carcinomatosis, not treatment related). The median progression-free survival was 5.9 months and median overall survival was 11.0 months. The pretherapy CA19­9 level was a statistically significant prognostic factor for enhanced overall survival. Local control at 6 months and 12 months were determined to be 86% and 80%, respectively. CONCLUSION: Combined proton chemoradiation leads to high local control rates. Unfortunately, PFS and OS are driven by distant metastasis and were not improved compared to historical data and reports. With this in mind, enhanced chemotherapeutical regimes, in combination with local irradiation, should be evaluated.

Comparison of carbon ion and photon reirradiation for recurrent glioblastoma.

PURPOSE: Purpose of this study was to investigate overall survival in recurrent glioblastoma treated with either carbon ion reirradiation or photon reirradiation. MATERIALS AND METHODS: In this retrospective study we evaluated 78 consecutive patients with recurrent IDH (Isocitrate dehydrogenase)-wildtype glioblastoma (38 patients carbon ion re-radiotherapy, 40 patients photon re-radiotherapy) treated with either carbon ion reirradiation or stereotactic photon reirradiation. 45 Gy (RBE; 15 fractions) carbon ion reirradiation (CIRT) or 39 Gy (13 fractions) photon reirradiation (FSRT) was administered, respectively. Overall survival was investigated with respect to histological, clinical, and epidemiological features. Kaplan-Meier and multivariate Cox statistics were calculated. A propensity score-matched analysis of the FSRT and CIRT groups using variables from a validated prognosis score was carried out. RESULTS: The type of reirradiation (CIRT vs. FSRT) significantly influenced overall survival-8.0 months vs. 6.5 months (univariate: p = 0.046)-and remained an independent prognostic factor in multivariate analysis (p = 0.017). Propensity score-adjusted analysis with CIRT versus FSRT as the dependent variable yielded a significant overall survival advantage for the CIRT group (median OS 8.9 versus 7.2 months, p = 0.041, 1­year survival 29 versus 10%). Adverse events (AE) were evaluated for both subgroups. For the FSRT group no toxicity ≥ grade 4 occurred. For the CIRT subgroup no grade 5 AE occurred, but 1 patient developed a grade 4 radionecrosis. We encountered 4 grade 3 toxicities. One patient developed a zoster at the trunk, 2 progressed in their paresis, and 1 featured progressive dysesthesia. CONCLUSION: In conclusion, carbon ion treatment is a safe and feasible treatment option for recurrent glioblastoma. Due to the retrospective nature of the study and two different dose levels for CIRT or FSRT, the improved outcome in CIRT reirradiation might be an effect of higher biological impact from carbon ions or a simple dose-escalation effect. This hypothesis needs prospective testing in larger patient cohorts. A prospective phase III randomized trial is in preparation at our center.

Carbon ion and proton beam irradiation of a normal human TK6 lymphoblastoid cell line within a magnetic field of 1.0 tesla.

BACKGROUND: Considering the increasing simultaneous application of magnetic resonance imaging (MRI) for more precise photon radiotherapy, it will be likely for particle radiotherapy to adopt MRI for future image guiding. It will then be imperative to evaluate the potential biological effects of a magnetic field (MF) on particle irradiation. This study explores such effects on the highly radiosensitive TK6 lymphoblastoid human cell line. METHODS: The following three parameters were measured after irradiation with either carbon ion or proton beams using spread out Bragg peaks and applying different doses within a perpendicular 1.0 T MF: (1) cell survival fraction (14 days postirradiation), (2) treatment-specific apoptosis, which was determined through the measurement of population in the sub-G1 phase, and (3) cell cycle progression by means of flow cytometry. These were compared to the same parameters measured without an MF. RESULTS: The clonogenic assay in both treatment groups showed almost identical survival curves with overlapping error bars. The calculated α values with and without an MF were 2.18 (σ=0.245) and 2.17 (σ=0.234) for carbon ions and 1.08 (σ=0.138) and 1.13 (σ=0.0679) for protons, respectively. Similarly, the treatment-specific apoptosis and cell cycle progression showed almost identical curves with overlapping error bars. A two-sample, unpooled t-test analysis was implemented for comparison of all mean values and showed p-values >0.05. CONCLUSION: No statistically significant difference in biological response of the TK6 cells was observed when they were irradiated using spreadout Bragg peaks within a perpendicular 1.0 T MF as compared to those, which received the same dose without the MF. This should serve as another supporting piece of evidence toward the implementation of MRI in particle radiotherapy, though further research is necessary.

Advantage of proton-radiotherapy for pediatric patients and adolescents with Hodgkin's disease.

Radiotherapy is frequently used in the therapy of lymphoma. Since lymphoma, for example Hodgkin's disease, frequently affect rather young patients, the induction of secondary cancer or other long-term adverse effects after irradiation are important issues to deal with. Especially for mediastinal manifestations numerous organs and substructures at risk play a role. The heart, its coronary vessels and cardiac valves, the lungs, the thyroid and, for female patients, the breast tissue are only the most important organs at risk. In this study we investigated if proton-radiotherapy might reduce the dose delivered to the organs at risk and thus minimize the therapy-associated toxicity. METHODS: In this work we compared the dose delivered to the heart, its coronary vessels and valves, the lungs, the thyroid gland and the breast tissue by different volumetric photon plans and a proton plan, all calculated for a dose of 28.8 Gy (EURO-NET-PHL-C2). Target Volumes have been defined by F18-FDG PET-positive areas, following a modified involved node approach. Data from ten young female patients with mediastinal lymphoma have been evaluated. Three different modern volumetric IMRT (VMAT) photon plans have been benchmarked against each other and against proton-irradiation concepts. For plan-evaluation conformity- and homogeneity-indices have been calculated as suggested in ICRU 83. The target volume coverage as well as the dose to important organs at risk as the heart with its substructures, the lungs, the breast tissue, the thyroid and the spinal cord were calculated and compared. For statistical evaluation mean doses to organs at risk were evaluated by non- parametric Kruskal-Wallis calculations with pairwise comparisons. RESULTS: Proton-plans and three different volumetric photon-plans have been calculated. Proton irradiation results in significant lower doses delivered to organ at risk. The median doses and the mean doses could be decreased while PTV coverage is comparable. As well conformity as homogeneity are slightly better for proton plans. For several organs a risk reduction for secondary malignancies has been calculated using literature data as reference. According to the used data derived from literature especially the secondary breast cancer risk, the secondary lung cancer risk and the risk for ischemic cardiac insults can be reduced significantly by using protons for radiotherapy of mediastinal lymphomas. CONCLUSION: Irradiation with protons for mediastinal Hodgkin-lymphoma results in significant lower doses for almost all organs at risk and is suitable to reduce long term side effects for pediatric and adolescent patients.

In vitro sensitivity of malignant melanoma cells lines to photon and heavy ion radiation.

BACKGROUND: The role of radiotherapy in malignant melanoma is still in discussion due to its relative resistance to radiation. In various literature, heavy ions show a higher relative biological effectiveness than photons. The aim of this work is to evaluate the radiotherapeutical effect from photons as well as heavy ions on malignant melanoma cells and to indicate the possible radiosensitivity based on its proliferation-inhibitory effect. METHODS: Two different cell lines of malignant melanoma, WM115 (primary tumor) and WM266-4 (metastatic site, skin) were used in this in vitro study. The cells were treated with photons or heavy ions (C12 and O16 ions). Cell-proliferation assay using hemocytometer was used for the quantitative and qualitative evaluation of cell growth. Furthermore, flow cytometry was also used to analyze the cell cycle distribution. RESULTS: Heavy ions compared to photons and between the two heavy ion modalities, O16 ions showed an improved suppression of cell growth in both cell lines. Furthermore, a G2/M arrest was detected in both cell lines after all radiotherapy modalities - with the arrest increasing with the dose applied. CONCLUSION: Heavy ions showed a greater inhibitory effect on cell proliferation compared to photons and an increased G2/M arrest. Therefore, C12 and O16 heavy ions might overcome the relative radioresistance of malignant melanoma to photons. Further research is warranted.

Phase II study of induction chemotherapy with docetaxel, cisplatin, 5-fluorouracil followed by radioimmunotherapy with cetuximab and intensity-modulated radiotherapy in combination with a carbon ion boost for locally advanced tumors of the oro-, hypopharynx and larynx.

PURPOSE: This phase II trial was designed to evaluate efficacy and safety of a highly intensified therapy in locally advanced squamous cell carcinoma of the oro-, hypopharynx and larynx. METHODS: In this prospective, mono-centric, open-label, non-randomized phase II trial the single treatment arm consisted of a combined induction chemotherapy with docetaxel, cisplatin, 5-fluorouracil, followed by bioradiation with the monoclonal antibody cetuximab, carbon ion boost (24Gy(RBE) in 8 fractions) and IMRT (50 Gy in 25 fractions). The trial was closed early due to slow accrual. RESULTS: Eight patients (median age 52.5 years) were enrolled into the trial. The median follow-up was 13 months and the 12-months locoregional tumor control, progression-free survival and overall survival rates were 100.0% each. Complete remission was achieved in 7 patients. The most commonly late radiation adverse event was xerostomia (85.7% at 12 months). Five serious adverse events with recovery were documented in 4 patients: mucositis grade 3 (n = 2), decreased lymphocyte count grade 4, febrile neutropenia grade 4 and hypersensitivity grade 3 to cetuximab (n = 1 each). Most symptom scales had their worst value at the last treatment day and recovered until the 4th follow-up visit. CONCLUSION: The study treatment was tolerable and promising. Reduced quality of life recovered for most aspects until the last follow-up visit.

Tomotherapy radiosurgery for arteriovenous malformations--current possibilities and future options with helical tomotherapy dynamic jaws?

This planning study was performed to compare stereotactic linac based radiosurgery of Arteriovenous Malformations (AVM) with current Helical Tomotherapy (HT) and future HT techniques. For 10 patients with AVM, dose distributions and treatment times of "regular" HT delivery (Reg 2.5/1/0.6 cm field width), Running-Start-Stop Treatment (RSS 5/2.5 cm), Axial Mode (Axial 5 cm) and Dynamic Jaw/Dynamic Couch delivery with a maximum field width of 5 cm (DJDC 5) were analysed and compared to linac-based stereotactic radiosurgery. Axial produced the fastest treatment (Axial 4:47 min vs. Linac 32:42 min) at the cost of large brain exposure (V10% 289 ml). Except for Reg 0.6, all other HT techniques achieved significantly shorter treatment times than linac-based treatment (e.g. Reg 1, 19:42 min, DJDC 6:30 min). However, high-dose brain exposure (V60%) was higher in all HT plans (e.g. Reg 0.6, 10 ml, Linac 9 ml), and only Reg 0.6 showed better low-dose exposure (V10% of 167 ml vs. 199 ml, not significant). Neither current nor future HT modes in their current version outperformed linac-based stereotactic radiosurgery. However, AVM with special geometry might still benefit from HT.