The tumor core boost study: A feasibility study of radical dose escalation to the central part of large tumors with an integrated boost in the palliative treatment setting.

PURPOSE: For patients with large tumors palliative radiotherapy often is the only local treatment option. To prevent toxicity the administered doses are low. Dose escalation to the tumor could be an option to better smyptom control and prolong local control rates. In this prospective study we used a very pragmatic approach with a simultaneously integrated boost (SIB) to an almost geometrically defined tumor core to achieve this. The primary endpoint was to demonstrate feasibility. METHOD: Patients with solid tumors > 4 cm in diameter of different histologies were eligible in this single arm, prospective, multi-institutional clinical feasibility trial with two treatment concepts: 5â€¯× 5 Gy with an integrated boost to the tumor core of 5â€¯× 10 Gy or 10â€¯× 3 Gy with a boost of 10â€¯× 6 Gy. The objective of dose escalation in this study was to deliver a minimum dose of 150% of the prescribed dose to the gross tumor volume (GTV) tumor core and to reach a maximum of at least 200% in the tumor core. RESULTS: In all, 21 patients at three study sites were recruited between January 2019 and November 2020 and were almost evenly spread (9 to 12) between the two concepts. The treated planning target volumes (PTV) averaged 389.42 cm3 (range 49.4-1179.6 cm3). The corresponding core volumes were 72.85 cm3 on average (range 4.21-338.3 cm3). Dose escalation to the tumor core with mean doses of 167.7-207.7% related to the nonboost prescribed isodose led to PTV mean doses of 120.5-163.3%. Treatment delivery and short-term follow-up was successful in all patients. CONCLUSIONS: Palliative radiotherapy with SIB to the tumor core seems to be a feasible and well-tolerated treatment concept for large tumors. The applied high doses of up to 50 Gy in 5 fractions (or 60 Gy in 10 fractions) did not cause unexpected side effects in the 42 day follow-up period. Further research is needed for more information on efficacy and long-term toxicity.

Correction to: MicroRNA expression profiling for the prediction of resistance to neoadjuvant radiochemotherapy in squamous cell carcinoma of the esophagus.

Following publication of the original article [1], the authors reported that for one of the authors, Stephanie E. Combs, the middle name was accidentally omitted. They also reported that for two of the authors, Daniel Habermehl and Stephanie E. Combs, two affiliations were accidentally omitted. In this Correction the incorrect and correct author name are shown and the two omitted affiliations are listed.

MicroRNA expression profiling for the prediction of resistance to neoadjuvant radiochemotherapy in squamous cell carcinoma of the esophagus.

BACKGROUND: MicroRNAs (miRNAs) play an important role in cancer biology. Neoadjuvant radiochemotherapy followed by surgery is a standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, a subset of patients do not respond. We evaluated whether miRNA profiles can predict resistance to radiochemotherapy. METHODS: Formalin-fixed, paraffin-embedded pretherapeutic biopsies of patients treated by radiochemotherapy followed by esophagectomy were analyzed. The response was determined by histopathological tumor regression grading. miRNA profiling was performed by microarray analysis (Agilent platform) in 16 non-responders and 15 responders. Differentially expressed miRNAs were confirmed by real-time quantitative PCR (qRT-PCR) in an expanded cohort of 53 cases. RESULTS: The miRNA profiles within and between non-responders and responders were highly similar (r = 0.96, 0.94 and 0.95). However, 12 miRNAs were differentially expressed (> twofold; p ≤ 0.025): non-responders showed upregulation of hsa-miR-1323, hsa-miR-3678-3p, hsv2-miR-H7-3p, hsa-miR-194*, hsa-miR-3152, kshv-miR-K12-4-3p, hsa-miR-665 and hsa-miR-3659 and downregulation of hsa-miR-126*, hsa-miR-484, hsa-miR-330-3p and hsa-miR-3653. qRT-PCR analysis confirmed the microarray findings for hsa-miR-194* and hsa-miR-665 (p < 0.001 each) with AUC values of 0.811 (95% CI 0.694-0.927) and 0.817 (95% CI 0.704-0.930), respectively, in ROC analysis. CONCLUSIONS: Our results indicate that miRNAs are involved in the therapeutic response in ESCC and suggest that miRNA profiles could facilitate pretherapeutic patient selection.

Perioperative chemotherapy vs. neoadjuvant chemoradiation in gastroesophageal junction adenocarcinoma : A population-based evaluation of the Munich Cancer Registry.

BACKGROUND: To date, it remains unclear whether locally advanced adenocarcinoma of the gastroesophageal junction (AEG) should be treated with neoadjuvant chemoradiation (nCRT), analogous to esophageal cancer, or with perioperative chemotherapy (pCT), analogous to gastric cancer. The purpose of this study was to analyze the data of the Munich Cancer Registry (MCR) and to compare pCT and nCRT in AEG patients. PATIENTS AND METHODS: A total of 2,992 AEG patients, treated between 1998 and 2014, were included in the study. Baseline and tumor parameters as well as overall survival (OS) and tumor recurrence were compared between 56 patients undergoing nCRT and 64 patients undergoing pCT with UICC stage II/III cancer. In addition, uni- and multivariate analyses using Cox regression models were performed to evaluate the effect of tumor characteristics and treatment regimens on OS. RESULTS: In patients with UICC stage II/III AEG treated with either nCRT or pCT, no significant differences were seen for baseline and tumor characteristics. While there was a significantly higher cumulative incidence of locoregional treatment failure after pCT (32.8%; 95% CI: 18.0-48.4%) compared with nCRT (7.4%; 95% CI: 2.3-16.5%; p = 0.007), there was no significant difference for distant treatment failure (52.9%; 95% CI: 35.4-67.7% and 38.4%; 95% CI: 23.7-52.9%; p = 0.347). When analyzing the whole cohort, patients who received pCT were younger (58.3 years vs. 63.0 years; p = 0.016), had a higher chance of complete tumor resection (81% vs. 67%; p = 0.033), more resected lymph nodes (p = 0.036), and fewer lymph node metastases (p = 0.038) compared with patients who received nCRT. Nevertheless, there was still a strong trend toward a higher incidence of local treatment failure after pCT (25.8%; 95% CI: 14.7-38.3% vs. 12.6%; 95% CI: 5.5-22.8%; p = 0.053). Comparable to the results for patients with UICC stage II/III, no difference was seen for the incidence of distant treatment failure. When excluding patients with UICC stage IV cancer, no significant difference was found for OS. CONCLUSION: For UICC stage II/III carcinoma, nCRT was associated with an improved locoregional tumor control compared with pCT, while no further significant differences were seen between nCRT and pCT for UICC stage II/III AEG. Moreover, there was a strong trend toward improved locoregional tumor control after nCRT when analyzing all patients treated with nCRT or pCT, despite these patients having higher risk factors.

Dosimetric quantification of the incidental irradiation of the 'true' (deep) ano-inguinal lymphatic drainage of anal cancer patients not described in conventional contouring guidelines.

INTRODUCTION: The ano-inguinal lymphatic drainage (AILD) is located in the subcutaneous adipose tissue of the proximal medial thigh. Findings from fluorescence methods give us new information about anatomical conditions of the AILD. Current contouring guidelines do not advise the inclusion of the 'true' AILD into the clinical target volume (CTV). Aim of this work was the retrospective analysis of the incidental dose to the AILD in an anal cancer (AC) patient cohort who underwent definitive chemoradiation (CRT) therapy with Volumetric Arc Therapy - Intensity Modulated Radiation Therapy (VMAT-IMRT). METHODS: VMAT-IMRT plans of 15 AC patients were analyzed. Based on findings from new fluorescence methods we created a new volume, the expected AILD. The examined dosimetric parameters were the minimal, maximal and mean dose and V10-V50 that were delivered to the AILD, respectively. RESULTS: The median volume of AILD was 1047 cm³. Mean Dmin, Dmax and Dmean were 7.5 Gy, 58.9 Gy and 40.8 Gy for AILD. The clinical relevant dose of 30.0 Gray covered in mean 76% of the volume of the AILD, respectively. CONCLUSIONS: Only 76% of the AILD-volume received at least an expected required treatment dose of 30 Gy incidentally. Concerning the low number of loco-regional relapses in AC patients after definitive CRT one has to balance increased side effects against a rigid oncological-anatomical interpretation of the local lymphatic drainage by including the AILD into the standard CTV.

Volumetric response of intracranial meningioma after photon or particle irradiation.

BACKGROUND: Meningiomas are usually slow growing, well circumscribed intracranial tumors. In symptom-free cases observation with close follow-up imaging could be performed. Symptomatic meningiomas could be surgically removed and/or treated with radiotherapy. The study aimed to evaluate the volumetric response of intracranial meningiomas at different time points after photon, proton, and a mixed photon and carbon ion boost irradiation. PATIENTS AND METHODS: In Group A 38 patients received proton therapy (median dose: 56 GyE in 1.8-2 GyE daily fractions) or a mixed photon/carbon ion therapy (50 Gy in 2 Gy daily fractions with intensity modulated radiotherapy (IMRT) and 18 GyE in 3 GyE daily dose carbon ion boost). Thirty-nine patients (Group B) were treated by photon therapy with IMRT or fractionated stereotactic radiotherapy technique (median dose: 56 Gy in 1.8-2 Gy daily fractions). The delineation of the tumor volume was based on the initial, one- and two-year follow-up magnetic resonance imaging and these volumes were compared to evaluate the volumetric tumor response. RESULTS: Significant tumor volume shrinkage was detected at one- and at two-year follow-up both after irradiation by particles and by photons. No significant difference in tumor volume change was observed between photon, proton or combined photon plus carbon ion boost treated patients. WHO grade and gender appear to be determining factors for tumor volume shrinkage. CONCLUSION: Significant volumetric shrinkage of meningiomas could be observed independently of the applied radiation modality. Long-term follow-up is recommended to evaluate further dynamic of size reduction and its correlation with outcome data.

Comparison of dosimetric parameters and toxicity in esophageal cancer patients undergoing 3D conformal radiotherapy or VMAT.

PURPOSE: Volumetric-modulated arc therapy (VMAT) achieves high conformity to the planned target volume (PTV) and good sparing of organs at risk (OAR). This study compares dosimetric parameters and toxicity in esophageal cancer (EC) patients treated with VMAT and 3D conformal radiotherapy (3D-CRT). MATERIALS AND METHODS: Between 2007 and 2014, 17 SC patients received neoadjuvant chemoradiation (CRT) with VMAT. Dose-volume histograms and toxicity were compared between these patients and 20 treated with 3D-CRT. All patients were irradiated with a total dose of 45 Gy. All VMAT patients received simultaneous chemotherapy with cisplatin and 5­fluorouracil (5-FU) in treatment weeks 1 and 5. Of 20 patients treated with 3D-CRT, 13 (65 %) also received CRT with cisplatin and 5­FU, whereas 6 patients (30 %) received CRT with weekly oxaliplatin and cetuximab, and a continuous infusion of 5­FU (OE-7). RESULTS: There were no differences in baseline characteristics between the treatment groups. For the lungs, VMAT was associated with a higher V5 (median 90.1 % vs. 79.7 %; p = 0.013) and V10 (68.2 % vs. 56.6 %; p = 0.014), but with a lower V30 (median 6.6 % vs. 11.0 %; p = 0.030). Regarding heart parameters, VMAT was associated with a higher V5 (median 100.0 % vs. 91.0 %; p = 0.043), V10 (92.0 % vs. 79.2 %; p = 0.047), and Dmax (47.5 Gy vs. 46.3 Gy; p = 0.003), but with a lower median dose (18.7 Gy vs. 30.0 Gy; p = 0.026) and V30 (17.7 % vs. 50.4 %; p = 0.015). Complete resection was achieved in 16 VMAT and 19 3D-CRT patients. Due to systemic progression, 2 patients did not undergo surgery. The most frequent postoperative complication was anastomosis insufficiency, occurring in 1 VMAT (6.7 %) and 5 3D-CRT patients (27.8 %; p = 0.180). Postoperative pneumonia was seen in 2 patients of each group (p = 1.000). There was no significant difference in 3­year overall (65 % VMAT vs. 45 % 3D-CRT; p = 0.493) or 3­year progression-free survival (53 % VMAT vs. 35 % 3D-CRT; p = 0.453). CONCLUSION: Although dosimetric differences in lung and heart exposure were observed, no clinically relevant impact was detected in either patient group. In a real-life patient cohort, VMAT enables reduction of lung and heart V30 compared to 3D-CRT, which may contribute to reduced toxicity.

Metabolic liver function after stereotactic body radiation therapy for hepatocellular carcinoma.

Purpose The time course of changes of the liver function after stereotactic body radiotherapy (SBRT) was analyzed in patients treated for non-resectable hepatocellular carcinoma (HCC). Patients and methods Twenty-six patients with non-resectable HCC treated with SBRT were included in this study. Clinical, biochemical and treatment-related parameters were retrospectively collected. S-albumin, s-bilirubin, s-alkaline phosphatase (AP) and s-alanine transaminase (ALAT) at 0, 3, 6, and 12 months after radiotherapy were analyzed. Results Seventeen and nine patients were Child-Pugh class A and B, respectively. The liver was exposed to relatively high radiation doses with mean doses of 1.9-26 Gy. None of the patients developed classic radiotherapy-induced liver disease (RILD), but two patients developed non-classic RILD. Two patients developed grade 3 ascites and no grade 4-5 toxicities were observed. Six patients declined in Child-Pugh class. The s-albumin decreased significantly from a pretreatment median of 37.4-34.36 g/l at three months after SBRT and stabilized thereafter. S-bilirubin, s-AP and s-ALAT did not change significantly over the study period. Conclusion Despite the fact that patients received high radiation dose to the liver, there was only moderate morbidity related to the treatment. The s-albumin decreases over three months after SBRT reflecting minor to moderate hepatic toxicity. S-albumin should be observed in the follow-up of HCC patients treated with SBRT.

Reirradiation Using Carbon Ions in Patients with Locally Recurrent Rectal Cancer at HIT: First Results.

BACKGROUND: Locally recurrent rectal cancer remains a dreaded event because curative resection is unlikely to be performed in a large number of cases. Carbon ion radiotherapy offers physical and biologic advantages. A high precise local dose deposition and sparing of normal tissue is possible. This work summarizes our experience on feasibility and early toxicity of carbon ion radiotherapy in previously irradiated and operated patients. METHODS: Between 2010 and 2013, a total of 19 patients with a median age of 62 years (range 14-76 years) received carbon ion irradiation to treat locally recurrent rectal cancer at the Heidelberg Ion Beam Therapy Center (HIT). All patients had a history of surgery and pelvic radiotherapy of at least 50.4 Gy. Median dose was 36 Gy [relative biologic efficacy (RBE)] [range 36-51 Gy(RBE)], and median planning target volume was 456 ml (range 75-1,597 ml). Some patients were treated in the recruiting phase I/II of the PANDORA study (NCT01528683). RESULTS: Median follow-up was 7.8 months. Four patients were diagnosed with local relapse after carbon ion radiotherapy, and three patients developed distant metastases. Estimated mean local progression-free survival was 20.6 months by the Kaplan-Meier estimator. Two patients had preexisting rectovaginal fistula, and another patient had a preexisting presacral localized abscess formation in which the local relapse took place. No grade III or higher toxicities were observed. CONCLUSIONS: Our first experiences in a pretreated patient group with a dismal prognosis are encouraging, and therapy-related side effects are mild. Longer follow-up is required to determine possible late effects and long-term disease control.

Adjuvant radiotherapy and chemoradiation with gemcitabine after R1 resection in patients with pancreatic adenocarcinoma.

BACKGROUND: The purpose of the study was to evaluate the effect of radiation therapy and chemoradiation with gemcitabine (GEM) after R1 resection in patients with pancreatic adenocarcinoma (PAC). METHODS: We performed a retrospective analysis of 25 patients who were treated with postoperative radiotherapy (RT) or chemoradiation (CRT) after surgery with microscopically positive resection margins for primary pancreatic cancer (PAC). Median age was 60 years (range 34 to 74 years), and there were 17 male and 8 female patients. Fractionated RT was applied with a median dose of 49.6 Gy (range 36 to 54 Gy). Eight patients received additional intraoperative radiotherapy (IORT) with a median dose of 12 Gy. RESULTS: Median overall survival (mOS) of all treated patients was 22 months (95% confidence interval (CI) 7.9 to 36.1 months) after date of resection and 21.1 months (95% CI 7.6 to 34.6 months) after start of (C)RT. Median progression-free survival (mPFS) was 13.0 months (95% CI 0.93 to 25 months). Grading (G2 vs. G3, P = 0.005) and gender (female vs. male, P = 0.01) were significantly correlated with OS. There was a significant difference in mPFS between male and female patients (P = 0.008). A total of 11 from 25 patients experienced local tumour progression, and 19 patients were diagnosed with either locoregional or distant failure. CONCLUSIONS: We demonstrated that GEM-based CRT can be applied in analogy to neoadjuvant protocols in the adjuvant setting for PAC patients at high risk for disease recurrence after incomplete resection. Patients undergoing additive CRT have a rather good OS and PFS compared to historical control patient groups.

Prognostic impact of CA 19-9 on outcome after neoadjuvant chemoradiation in patients with locally advanced pancreatic cancer.

BACKGROUND: To asses the impact of CA 19-9 and weight loss/gain on outcome after neoadjuvant chemoradiation (CRT) in patients with locally advanced pancreatic cancer (LAPC). METHODS: We analyzed 289 patients with LAPC treated with CRT for LAPC. All patients received concomitant chemotherapy parallel to radiotherapy and adjuvant treatments. CA 19-9 and body weight were collected as prognostic and predictive markers. All patients were included into a regular follow-up with reassessment of resectability. RESULTS: Median overall survival in all patients was 14 months. Actuarial overall survival was 37 % at 12 months, 12 % at 24 months, and 4 % at 36 months. Secondary resectability was achieved in 35 % of the patients. R0/R1 resection was significantly associated with increase in overall survival (p = 0.04). Intraoperative radiotherapy was applied in 50 patients, but it did not influence overall survival (p = 0.05). Pretreatment CA 19-9 significantly influenced overall survival using different cutoff values. With increase in CA 19-9 levels, the possibility of secondary surgical resection decreased from 46 % in patients with CA 19-9 levels below 90 U/ml to 31 % in the group with CA 19-9 levels higher than 269 U/ml. DISCUSSION: This large group of patients with LAPC treated with neoadjuvant CRT confirms that CA 19-9 and body weight are strong predictive and prognostic factors of outcome. In the future, individual patient factors should be taken into account to tailor treatment.

Stability of spinal bone metastases in breast cancer after radiotherapy: a retrospective analysis of 157 cases.

PURPOSE: This retrospective analysis was performed to evaluate osteolytic bone lesions of breast cancer in the thoracic and lumbar spine after radiotherapy (RT) in terms of stability using a validated scoring system. METHODS: The stability of 157 osteolytic metastases, treated from January 2000 to January 2012, in 115 patients with breast cancer was evaluated retrospectively using the Taneichi score. Predictive factors for stability were analyzed and survival rates were calculated. RESULTS: Eighty-five (54%) lesions were classified as unstable prior to RT. After 3 and 6 months, 109 (70%) and 124 (79%) lesions, respectively, were classified as stable. Thirty fractures were detected prior to RT, and after RT seven cases (4.5%) with pathologic fractures were found within 6 months. None of the examined predictive factors showed significant correlation with stability 6 months after RT. After a median follow-up of 16.7 months, Kaplan-Meier estimates revealed an overall survival of 83% after 5 years. CONCLUSION: The majority of patients showed an improved or unchanged stability of the involved vertebral bodies after 6 months. The patients showed only minor cancer-related morbidity during follow-up and reached comparably high survival rates.

Photon-induced cell migration and integrin expression promoted by DNA integration of HPV16 genome.

BACKGROUND: Persistent human papilloma virus 16 (HPV16) infections are a major cause of cervical cancer. The integration of the viral DNA into the host genome causes E2 gene disruption which prevents apoptosis and increases host cell motility. In cervical cancer patients, survival is limited by local infiltration and systemic dissemination. Surgical control rates are poor in cases of parametrial infiltration. In these patients, radiotherapy (RT) is administered to enhance local control. However, photon irradiation itself has been reported to increase cell motility. In cases of E2-disrupted cervical cancers, this phenomon would impose an additional risk of enhanced tumor cell motility. Here, we analyze mechanisms underlying photon-increased migration in keratinocytes with differential E2 gene status. METHODS: Isogenic W12 (intact E2 gene status) and S12 (disrupted E2 gene status) keratinocytes were analyzed in fibronectin-based and serum-stimulated migration experiments following single photon doses of 0, 2, and 10 Gy. Quantitative FACS analyses of integrin expression were performed. RESULTS: Migration and adhesion are increased in E2 gene-disrupted keratinocytes. E2 gene disruption promotes attractability by serum components, therefore, effectuating the risk of local infiltration and systemic dissemination. In S12 cells, migration is further increased by photon RT which leads to enhanced expression of fibronectin receptor integrins. CONCLUSION: HPV16-associated E2 gene disruption is a main predictor of treatment-refractory cancer virulence. E2 gene disruption promotes cell motility. Following photon RT, E2-disrupted tumors bear the risk of integrin-related infiltration and dissemination.

Feasibility of isometric spinal muscle training in patients with bone metastases under radiation therapy - first results of a randomized pilot trial.

BACKGROUND: Spinal bone metastases are commonly diagnosed in cancer patients. The consequences are pain both at rest and under exercise, impairment of activities of daily life (ADL), reduced clinical performance, the risk of pathological fractures, and neurological deficits. The aim of this randomized, controlled pilot trial was to investigate the feasibility of muscle-training exercises in patients with spinal bone metastases under radiotherapy. Secondary endpoints were local control, pain response and survival. METHODS: This study was a prospective, randomized, monocentre, controlled explorative intervention trial to determine the multidimensional effects of exercises for strengthening the paravertebral muscles. On the days of radiation treatment, patients in the control group were physically treated in form of respiratory therapy. Sixty patients were randomized between September 2011 and March 2013 into one of the two groups: differentiated resistance training or physical measure with thirty patients in each group. RESULTS: The resistance training of the paravertebral muscles was feasible in 83.3% of patients (n = 25). Five patients died during the first three months. The exercise group experienced no measurable side effects. "Chair stand test" in the intervention group was significant enhanced with additionally improved analgesic efficiency. Patients in intervention group improved in pain score (VAS, 0-10) over the course (p < .001), and was significant better between groups (p = .003) after 3 months. The overall pain response showed no significant difference between groups (p = .158) There was no significant difference in overall and bone survival (survival from first diagnosed bone metastases to death). CONCLUSIONS: Our trial demonstrated safety and feasibility of an isometric resistance training in patients with spinal bone metastases. The results offer a rationale for future large controlled investigations to confirm these findings.

Outcome of whole brain irradiation with a dose-escalated simultaneous-integrated boost in patients with multiple large and/or diffuse brain metastases: real live data and review of the literature.

BACKGROUND: We retrospectively investigate feasibility and safety of whole brain radiotherapy (WBRT) including a simultaneous-integrated boost technique (WBRT-SIB) in a cohort of patients with a very poor prognosis suffering from multiple and/or large brain metastases, unfavorable primary histology, poor performance status and/or symptomatic BMs. MATERIALS AND METHODS: Thirty-five patients with high brain tumor burden, extracranial metastases and low life-expectancy were treated with WBRT-SIB mostly with 35-42 Gy/14 fractions. All metastases were boosted in patients with up to 12 BMs. In patients with > 12 BM, large and/or small metastases in critical brain regions were boosted up to a maximum of 12 SIB volumes. RESULTS: The median number of BM was 8 (range 2-45) and the median BM diameter was 12 mm (range 4-90 mm). Fifteen (43%) patients had ≥ 10 BMs and 25 patients presented with a Karnofski index ≤ 80%. Primary tumor histology was NSCLC (n = 13), SCLC (n = 11), breast cancer (n = 7), melanoma (n = 2), other (n = 2). The median iPFS was not reached, and 12- and 18-months iPFS were 75% and 50%, respectively. Overall, seven patients had intracranial progression: two patients within the SIB and WBRT area, one patient only within the SIB region and four patients had new BMs in the WBRT volume alone. The median iPFS for non-SCLC patients was 17 months and the 12- and 18-month iPFS were 56.8% and 28.4%, respectively. There was no significant OS difference between SCLC-group and non-SCLC patients (p = 0.38). Overall, median OS was 8.7 months and 1-year OS was 25%. The treatment was generally well-tolerated with no observed cases of radionecrosis. CONCLUSION: Our WBRT-SIB approach involves a combination of whole brain radiotherapy and a simultaneous integrated boost to specific tumor volumes, and its effectiveness is compared with other treatment modalities in the literature. Further research, including prospective studies with larger patient cohorts, is necessary to validate and refine the findings.

Carbon ion radiotherapy of hepatocellular carcinoma provides excellent local control: The prospective phase I PROMETHEUS trial.

Background & Aims: Inoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing non-tumorous liver. High linear energy transfer could promote therapy efficacy. Japanese and Chinese studies on hypofractionated CIRT have yielded excellent results. Because of different radiobiological models and the different etiological spectrum of HCC, applicability of these results to European cohorts and centers remains questionable. The aim of this prospective study was to assess safety and efficacy and to determine the optimal dose of CIRT with active raster scanning based on the local effect model (LEM) I. Methods: CIRT was performed every other day in four fractions with relative biological effectiveness (RBE)-weighted fraction doses of 8.1-10.5 Gy (total doses 32.4-42.0 Gy [RBE]). Dose escalation was performed in five dose levels with at least three patients each. The primary endpoint was acute toxicity after 4 weeks. Results: Twenty patients received CIRT (median age 74.7 years, n = 16 with liver cirrhosis, Child-Pugh scores [CP] A5 [n = 10], A6 [n = 4], B8 [n = 1], and B9 [n = 1]). Median follow up was 23 months. No dose-limiting toxicities and no toxicities exceeding grade II occurred, except one grade III gamma-glutamyltransferase elevation 12 months after CIRT, synchronous to out-of-field hepatic progression. During 12 months after CIRT, no CP elevation occurred. The highest dose level could be applied safely. No local recurrence developed during follow up. The objective response rate was 80%. Median overall survival was 30.8 months (1/2/3 years: 75%/64%/22%). Median progression-free survival was 20.9 months (1/2/3 years: 59%/43%/43%). Intrahepatic progression outside of the CIRT target volume was the most frequent pattern of progression. Conclusions: CIRT of HCC yields excellent local control without dose-limiting toxicity. Impact and implications: To date, safety and efficacy of carbon ion radiotherapy for hepatocellular carcinoma have only been evaluated prospectively in Japanese and Chinese studies. The optimal dose and fractionation when using the local effect model for radiotherapy planning are unknown. The results are of particular interest for European and American particle therapy centers, but also of relevance for all specialists involved in the treatment and care of patients with hepatocellular carcinoma, as we present the first prospective data on carbon ion radiotherapy in hepatocellular carcinoma outside of Asia. The excellent local control should encourage further use of carbon ion radiotherapy for hepatocellular carcinoma and design of randomized controlled trials. Clinical Trials Registration: The study is registered at ClinicalTrials.gov (NCT01167374).

Phase I study evaluating the treatment of patients with locally advanced pancreatic cancer with carbon ion radiotherapy: the PHOENIX-01 trial.

BACKGROUND: Treatment options for patients with locally advanced pancreatic cancer include surgery, chemotherapy as well as radiotherapy. In many cases, surgical resection is not possible, and therefore treatment alternatives have to be performed. Chemoradiation has been established as a convincing treatment alternative for locally advanced pancreatic cancer. Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 1.16 and 2.46 depending on the pancreatic cancer cell line as well as the endpoint analyzed. Japanese Data on the evaluation of carbon ion radiation therapy showed promising results for patients with pancreatic cancer. METHODS AND DESIGN: The present PHOENIX-01 trial evaluates carbon ion radiotherapy using the active rasterscanning technique in patients with advanced pancreatic cancer in combination with weekly gemcitabine and adjuvant gemcitabine. Primary endpoint is toxicity, secondary endpoints are overall survival, progression-free survival and response. DISCUSSION: The physical and biological properties of the carbon ion beam promise to improve the therapeutic ratio in patients with pancreatic cancer: Due to the inverted dose profile dose deposition in the entry channel of the beam leads to sparing of normal tissue; the Bragg peak can be directed into the defined target volume, and the sharp dose fall-off thereafter again spares normal tissue behind the target volume. The higher RBE of carbon ions, which has been shown also for pancreatic cancer cell lines in the preclinical setting, is likely to contribute to an increase in local control, and perhaps in OS. Early data from Japanese centers have shown promising results. In conclusion, this is the first trial to evaluate actively delivered carbon ion beams in patients with locally advanced pancreatic cancer within a dose-escalation strategy. TRIAL REGISTRATION: NCT01795274.

Proton and carbon ion radiotherapy for primary brain tumors and tumors of the skull base.

UNLABELLED: To analyze clinical concepts, toxicity and treatment outcome in patients with brain and skull base tumors treated with photons and particle therapy. MATERIAL AND METHODS: In total 260 patients with brain tumors and tumors of the skull base were treated at the Heidelberg Ion Therapy Center (HIT). Patients enrolled in and randomized within prospective clinical trials as well as bony or soft tissue tumors are not included in this analysis. Treatment was delivered as protons, carbon ions, or combinations of photons and a carbon ion boost. All patients are included in a tight follow-up program. The median follow-up time is 12 months (range 2-39 months). RESULTS: Main histologies included meningioma (n = 107) for skull base lesions, pituitary adenomas (n = 14), low-grade gliomas (n = 51) as well as high-grade gliomas (n = 55) for brain tumors. In all patients treatment could be completed without any unexpected severe toxicities. No side effects > CTC Grade III were observed. To date, no severe late toxicities were observed, however, for endpoints such as secondary malignancies or neurocognitive side effects follow-up time still remains too short. Local recurrences were mainly seen in the group of high-grade gliomas or atypical meningiomas; for benign skull base meningiomas, to date, no recurrences were observed during follow-up. CONCLUSION: The specific benefit of particle therapy will potentially reduce the risk of secondary malignancies as well as improve neurocognitive outcome and quality of life (QOL); thus, longer follow-up will be necessary to confirm these endpoints. Indication-specific trials on meningiomas and gliomas are underway to elucidate the role of protons and carbon ions in these indications.

Prospective evaluation of early treatment outcome in patients with meningiomas treated with particle therapy based on target volume definition with MRI and 68Ga-DOTATOC-PET.

PURPOSE: To evaluate early treatment results and toxicity in patients with meningiomas treated with particle therapy. MATERIAL AND METHODS: Seventy patients with meningiomas were treated with protons (n = 38) or carbon ion radiotherapy (n = 26). Median age was 49 years. Median age at treatment was 55 years, 24 were male (34%), and 46 were female (66%). Histology was benign meningioma in 26 patients (37%), atypical in 23 patients (33%) and anaplastic in four patients (6%). In 17 patients (24%) with skull base meningiomas diagnosis was based on the typical appearance of a meningioma. For benign meningiomas, total doses of 52.2-57.6 GyE were applied with protons. For high-grade lesions, the boost volume was 18 GyE carbon ions, with a median dose of 50 GyE applied as highly conformal radiation therapy. Nineteen patients were treated as re-irradiation. Treatment planning with MRI and 68-Ga-DOTATOC-PET was evaluated. RESULTS: Very low rates of side effects developed, including headaches, nausea and dizziness. No severe treatment-related toxicity was observed. Local control for benign meningiomas was 100%. Five of 27 patients (19%) developed tumor recurrence during follow-up. Of these, four patients had been treated as re-irradiation for recurrent high-risk meningiomas. Actuarial local control after re-irradiation of high-risk meningiomas was therefore 67% at six and 12 months. In patients treated with primary radiotherapy, only one of 13 patients (8%) developed tumor recurrence 17 months after radiation therapy (photon and carbon ion boost). CONCLUSION: Continuous prospective follow-up and development of novel study concepts are required to fully exploit the long-term clinical data after particle therapy for meningiomas. To date, it may be concluded that when proton therapy is available, meningioma patients can be offered a treatment at least comparable to high-end photon therapy.

Dosimetric Parameters After VMAT Adaptive Radiotherapy in Patients With Locally Advanced NSCLC Undergoing 4DCT.

BACKGROUND/AIM: To investigate dosimetric differences in organs at risk (OARs) and cardiac substructures in patients with locally advanced non-small cell lung cancer (NSCLC) between the adaptive radiotherapy (ART) and non-ART groups. PATIENTS AND METHODS: Thirty patients were treated with definitive radiotherapy +/- chemotherapy. Cardiac substructures including the left anterior descending coronary artery (LAD) and large vessels, were contoured. Eight patients experienced tumor shrinkage and were replanned (ART). Cumulative plans after ART were compared to the original plans (not considering volume reduction) in terms of dosimetric parameters. The cumulative plans of the ART group (n=8) and non-ART group (n=22) were compared in terms of the same dosimetric parameters. RESULTS: Within the ART group, the following parameters were found to be significantly improved after re-planning: mean lung dose (MLD) (13.79 Gy vs. 15.6 Gy), V20Gy both lungs (17.88% vs. 27.38%), ipsilateral MLD (20.87 Gy vs. 24.44 Gy), and esophagus mean dose (20.79 Gy vs. 24.2 Gy). No dosimetric differences were observed in heart substructures. Dosimetric parameters, particularly LAD, were significantly worse in the ART group than in the non-ART group. This is probably because this OAR was not considered in the plan optimization after re-planning, because it was not routinely contoured as an OAR. CONCLUSION: Our analysis showed an improvement in dosimetric parameters in the lungs and esophagus in the ART group. This approach may lead to a possible reduction in toxicity. Contouring of cardiac substructures could lead to a plan optimization of their parameters and eventually reduce the risk of cardiac toxicities in these patients.