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Purpose: To report dosimetric characteristics and early clinical outcomes in patients with pelvic Ewing sarcoma undergoing particle therapy. Methods: Patients ≥ 18 years old with pelvic Ewing sarcoma treated in adjuvant or definitive settings were considered for this retrospective analysis. Proton therapy was carried out with 45–60 Gy (RBE) (1.5–2 Gy (RBE) per fraction) and carbon ion therapy for recurrent disease with 51 Gy (RBE) (3 Gy (RBE) per fraction). Local control (LC), disease control (DC) and overall survival (OS) were calculated using the Kaplan–Meier method. Results: For our sample, 21 patients were available, 18 of whom were treated for primary, 3 for locally recurrent and 16 for inoperable disease. The median CTV and PTV were 1215 cm3 and 1630 cm3. Median Dmean values for the PTV, bladder and rectum and median V40 Gy for the bowel for patients undergoing proton therapy were 56 Gy (RBE), 0.6 Gy (RBE), 9 Gy (RBE) and 15 cm3, respectively. At the end of particle therapy, G 1–2 skin reactions (n = 16/21) and fatigue (n = 9/21) were the main reported symptoms. After a median follow-up of 21 months, the 2-year LC, DC and OS were 76%, 56% and 86%, respectively. Conclusions: Particle therapy in adult pelvic Ewing sarcoma is feasible and provides excellent dosimetric results. First clinical outcomes are promising; however, further long-term follow-up is needed.

Ependymomas are the third most-frequent pediatric brain tumors. To prevent local recurrence, the resection site should be irradiated. Compared to photon radiation treatment, proton therapy often achieves even better results regarding target coverage and organ-sparing. Due to their physical properties, helium ions could further reduce side effects, providing better protection of healthy tissue despite similar target coverage. In our in silico study, 15 pediatric ependymoma patients were considered. All patients underwent adjuvant radiotherapeutic treatment with active-scanned protons at Heidelberg Ion Beam Therapy Center (HIT). Both helium ion and highly conformal IMRT plans were calculated to evaluate the potential dosimetric advantage of ion beam therapy compared to the current state-of-the-art photon-based treatments. To estimate the potential clinical benefit of helium ions, normal tissue complication probabilities (NTCP) were calculated. Target coverage was comparable in all three modalities. As expected, the integral dose absorbed by healthy brain tissue could be significantly reduced with protons by up to −48% vs. IMRT. Even compared to actively scanned protons, relative dose reductions for critical neuronal structures of up to another −39% were achieved when using helium ions. The dose distribution of helium ions is significantly superior when compared to proton therapy and IMRT due to the improved sparing of OAR. In fact, previous studies could clearly demonstrate that the dosimetric advantage of protons translates into a measurable clinical benefit for pediatric patients with brain tumors. Given the dose–response relationship of critical organs at risk combined with NTCP calculation, the results of our study provide a strong rationale that the use of helium ions has the potential to even further reduce the risk for treatment related sequelae.

BackgroundTo report survival of craniofacial osteosarcoma patients treated by particle radiotherapy.MethodsBetween January 2010 and December 2021, 51 patients with primary (N = 35) or recurrent (N = 16) inoperable or incompletely resected craniofacial osteosarcoma were treated. In most cases, intracranial infiltration (59%) and macroscopic tumor on MRI/CT (75%) were present. Thirteen had a secondary osteosarcoma (25%). Treatment concepts included combined ion beam radiotherapy (CIBRT, N = 18), protons only (N = 3), carbon ions only (N = 12), IMRT with a carbon ion boost (N = 5), and carbon ion re-irradiation (N = 13). Eighty percent (N = 41) received additionally chemotherapy, most frequently EURAMOS-1 (47%) or EURO-B.O.S.S. (18%).ResultsThe median age was 38, and all patients finished treatment predominantly as outpatients (N = 44). Information on overall survival was available for N = 49 patients. The median follow-up of the survivors was 55 months. For the whole cohort 1-, 2-, 3-, and 5-year overall survival (OS) was 82.8%, 60.4%, 55.2%, and 51.7%, respectively. Those treated by CIBRT (N = 17) demonstrated a superior OS with 92.9% after 1 and 2 years and 83.6% after 3 and 5 years. The median clinical target volume (CTV) was 192.7 and 95.2 cc for the primary and boost plan, respectively. CIBRT, primary diagnosis, age ≤40a, and no macroscopic residual tumor were associated with improved survival in univariate analysis (p = 0.006, p = 0.004, p = 0.002, p = 0.026, respectively), while any foregoing resection compared to biopsy was not identified as a prognostic factor. CIBRT and no macroscopic residual tumor were confirmed as independent predictors of OS on multivariate analysis (HR = 0.107, 95% CI = [0.014, 0.797], p = 0.029 and HR = 0.130, 95% CI = [0.023, 0.724], p = 0.020, respectively). No acute toxicity > grade III was observed.ConclusionCIBRT shows promising results for patients with inoperable or incompletely resected craniofacial osteosarcoma.

BackgroundRadiotherapy plays an important role in the management of skull base meningioma. The aim of the study was to investigate patient-reported outcomes.MethodsA questionnaire of 20 items was sent to 192 patients with meningioma of the skull base who have been treated with proton therapy at a single institution. The survey included dichotomous, scaling, and open questions about symptoms, social distancing, rehabilitation, work, reintegration, limitations in recreational activities, as well as daily life activities and correlating diagnoses. Additionally, symptoms were reported retrospectively by the patients at different time points. In total, 128 patients (66.7%) responded. The median age at the time of RT was 55 years (range: 28-91); the majority were female (79%). The median time between the treatment of meningioma and the survey was 38.5 months (range: 7-100).ResultsThe most common initial symptoms were visual impairment (N=54, 42.2%), dizziness (N=38, 29.7%), and double vision (N=32, 25%). The most limiting symptom in daily life at the time of the survey was fatigue (N=31, 24.2%); a significant proportion of patients reported depression as associated with diagnosis (31.3%). Only 53% of patients reported occupational activity before treatment, this number did not increase with time. Only N= 40 (31.3%) and N=35 (27.3%) patients reported no limitations in daily household chores or recreational activities by the disease and treatment. The course of cognitive function after treatment showed a temporary deterioration with subsequent improvement. Except for the improvement in emotional functioning, most domains showed a temporary deterioration during radiotherapy, still, the values reached after 6 months differed weekly or moderately from the initial values.ConclusionBesides neurological deficits, patients with skull base meningioma experience a variety of unspecific symptoms, which can be most limiting in daily life. Even successful treatment does not necessarily translate into the alleviation of those symptoms. A greater focus on the characterization of those symptom complexes is necessary. Greater focus on functional structures such as the hippocampus might improve the results. Due to the retrospective character, this study is hypothesis-generating.

Background: To report the final results of a prospective, one-armed, single-center phase I/II trial (NCT01566123). Methods: Between 2007 and 2017, 37 patients with primary or recurrent (N = 6) retroperitoneal sarcomas were enrolled. Treatment included preoperative IMRT of 45–50 Gy with a simultaneous integrated boost of 50–56 Gy, surgery and IORT. The primary endpoint was local control (LC) at 5 years. The most common histology was dedifferentiated liposarcoma (51%), followed by leiomyosarcoma (24%) and well-differentiated liposarcoma (14%). The majority of lesions were high-grade (FNCLCC G1: 30%, G2: 38%, G3: 27%, two missing). Five patients were excluded from LC analysis per protocol. Results: The minimum follow-up of the survivors was 62 months (median: 109; maximum 162). IORT was performed for 27 patients. Thirty-five patients underwent gross total resection; the pathological resection margin was mostly R+ (80%) and, less often, R0 (20%). We observed 10 local recurrences. The 5-year LC of the whole cohort was 59.6%. Eleven patients received a dose > 50 Gy plus IORT boost; LC was 64.8%; the difference, however, was not significant (p = 0.588). Of 37 patients, 15 were alive and 22 deceased at the time of final analysis. The 5-year OS was 59.5% (68.8% per protocol). Conclusions: The primary endpoint of a 5-year LC of 70% was not met. This might be explained by the inclusion of recurrent disease and the high rate of G3 lesions and leiomyosarcoma, which have been shown to profit less from radiotherapy. Stratification by grading and histology should be considered for future studies.

Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both relapse rates and treatment sequelae. The PROSPER study is a tricontinental, nonrandomized, prospective, three-arm, pragmatic trial evaluating treatments of pelvic sarcoma involving the bone. Patients aged at least 15 years are eligible for inclusion. Participants must have an Eastern Cooperative Oncology Group Performance Status score of two or less, newly diagnosed disease, and histopathologic confirmation of pelvic chordoma, chondrosarcoma, osteosarcoma, Ewing sarcoma with bone involvement, rhabdomyosarcoma (RMS) with bone involvement, or non-RMS soft tissue sarcoma with bone involvement. Treatment arms include (1) CIRT (n = 30) delivered in Europe and Asia, (2) surgical treatment with or without adjuvant radiotherapy (n = 30), and (3) proton therapy (n = 30). Arms two and three will be conducted at Mayo Clinic campuses in Arizona, Florida, and Minnesota. The primary end point is to compare the 1-year change in functional QOL between CIRT and surgical treatment. Additional comparisons among the three arms will be made between treatment sequelae, local control, and other QOL measures.

Purpose/Objective: Oligometastatic disease (OMD) and oligoprogressive disease (OPD) describe tumor states with a limited metastasization. In contrast to other disease states, treatment of OMD or OPD has not yet become common for breast cancer. We sought to understand the outcomes and toxicities of this treatment paradigm. Material/Methods: We retrospectively analyzed female breast cancer patients with OMD (≤3 metastases) or OPD (1 progressive lesion) who received stereotactic body radiotherapy (SBRT) for their respective extracranial metastatic lesions between 01/2002 and 07/2019. Survival analysis was performed using the Kaplan-Meier method with log-rank test being used for evaluation of significance. Cox regression was used to detect prognostic outcome factors. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE v. 5.0). Results: Forty-six patients (70% OMD; 30% OPD) with 58 lesions met criteria for inclusion. The majority of treatments (34 out of 58; 58.6%) were delivered from 2017 to 2018. Treatment sites were bone, liver, lung [n = 19 (33%) for each site], and adrenal gland [n = 1 (1%)]. Median biologically effective dose (BED at α/β = 10) was 81.6 Gy (range: 45–112.5 Gy) and median planning target volume was 36.60 mL (range: 3.76–311.00 mL). At 2 years, local control (LC) was 89%, distant control (DC) was 44%, progression free survival (PFS) was 17% and overall survival (OS) was 62%. Multivariate analysis identified the diagnosis of a solitary metastasis as an independent prognostic factor for superior DC (HR = 0.186, CI [0.055; 0.626], p = 0.007) and PFS (HR = 0.363, CI [0.152; 0.863], p = 0.022). OS was independently inferior for patients treated at a higher age (HR = 5.788, CI [1.077; 31.119] p = 0.041). Nine (15.5%) grade I° and one (1.7%) grade II° toxicities were recorded, with no grade III° or higher toxicities. Conclusion: Extracranial SBRT in breast cancer patients with OMD or OPD was well-tolerated with excellent LC. SBRT should especially be offered to younger OMD and OPD breast cancer patients with only one metastasis. The increase in utilization since 2017 points toward a growing acceptance of SBRT for OMD and OPD in breast cancer.

Purpose: Several prognostic indexes for overall survival (OS) after radiotherapy of brain metastases in breast cancer patients exist but are mainly validated for whole-brain radiotherapy or not specifically for breast cancer patients. To date, no such index provides information beyond mere OS. Methods: We retrospectively analyzed 95 breast cancer patients treated with stereotactic radiosurgery for 203 brain metastases. The Kaplan-Meier method with log-rank test was used to assess OS, local control (LC), distant cranial control (DCC), and extracranial control (EC). Cox regression was applied to detect prognostic outcome factors. A point scoring system was designed to stratify patients based on outcome. Nine established prognostic indexes were analyzed using the concordance index (c-index). Results: Two out of nine analyzed prognostic indexes for OS showed a significant c-index, the breast graded prognostic assessment (bGPA; 0.631; 95% CI, 0.514-0.748; p = 0.037) and the modified bGPA (mod-bGPA; 0.662; 95% CI, 0.547-0.777; p = 0.010). Significant results from multivariate analysis (Karnofsky Performance Score, Her2/neu receptor status, extracranial control) were used to generate a new point system: the breast cancer stereotactic radiotherapy score (bSRS), which discriminated three significantly different prognostic groups, for LC, DCC, EC, and OS, respectively. However, the c-index was only significant for OS (0.689; 95% CI, 0.577-0.802; p = 0.003). Conclusions: The new bSRS score was superior to the bGPA and mod-bGPA scores for prognosis of OS. The bSRS is easy to use and the first tool, which might also provide outcome assessment beyond mere OS. Future studies need to validate these findings.

Background The improved efficacy of tyrosine kinase inhibitors (TKI) mandates reappraisal of local therapy (LT) for brain metastases (BM) of oncogene-driven non-small-cell lung cancer (NSCLC). Patients and methods This study included all epidermal growth factor receptor-mutated (EGFR+, n = 108) and anaplastic lymphoma kinase-rearranged (ALK+, n = 33) TKI-naive NSCLC patients diagnosed with BM in the Thoraxklinik Heidelberg between 2009 and 2019. Eighty-seven patients (62%) received early LT, while 54 (38%) received delayed (n = 34; 24%) or no LT (n = 20; 14%). LT comprised stereotactic (SRT; n = 40; 34%) or whole-brain radiotherapy (WBRT; n = 77; 66%), while neurosurgical resection was carried out in 19 cases. Results Median overall survival (OS) was 49.1 months for ALK+ and 19.5 months for EGFR+ patients (P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM (P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and ‘short’ EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial progression (HR 2.97; P = 0.001). The longer icPFS with early LT was also evident in separate analyses of the EGFR+ and ALK+ subsets. Conclusions Despite preferential use for cases with poor prognostic factors, early LT prolongs the icPFS, but not OS, in TKI-treated EGFR+/ALK+ NSCLC. Considering the lack of survival benefit, and the neurocognitive effects of WBRT, patients presenting with polytopic BM may benefit from delaying radiotherapy, or from radiosurgery of multiple or selected lesions. For SRT candidates, the improved tumor control with earlier radiotherapy should be weighed against the potential toxicity and the enhanced intracranial activity of newer TKI. High-risk EGFR/ALK variants are associated with earlier intracranial failure and identify patients who could benefit from more aggressive management., Highlights • Upfront LT delay intracranial progression, but do not prolong OS in oncogene-driven NSCLC. • Use of stereotactic versus whole-brain radiotherapy and primary tumor TP53 status do not significantly affect brain control. • Non-del19 EGFR mutations and ‘short’ EML4-ALK fusions are independent predictors of earlier intracranial failure.

Background An inverse correlation between expression of the aldehyde dehydrogenase 1 subfamily A2 (ALDH1A2) and gene promoter methylation has been identified as a common feature of oropharyngeal squamous cell carcinoma (OPSCC). Moreover, low ALDH1A2 expression was associated with an unfavorable prognosis of OPSCC patients, however the causal link between reduced ALDH1A2 function and treatment failure has not been addressed so far. Methods Serial sections from tissue microarrays of patients with primary OPSCC (n = 101) were stained by immunohistochemistry for key regulators of retinoic acid (RA) signaling, including ALDH1A2. Survival with respect to these regulators was investigated by univariate Kaplan-Meier analysis and multivariate Cox regression proportional hazard models. The impact of ALDH1A2-RAR signaling on tumor-relevant processes was addressed in established tumor cell lines and in an orthotopic mouse xenograft model. Results Immunohistochemical analysis showed an improved prognosis of ALDH1A2high OPSCC only in the presence of CRABP2, an intracellular RA transporter. Moreover, an ALDH1A2highCRABP2high staining pattern served as an independent predictor for progression-free (HR: 0.395, p = 0.007) and overall survival (HR: 0.303, p = 0.002), suggesting a critical impact of RA metabolism and signaling on clinical outcome. Functionally, ALDH1A2 expression and activity in tumor cell lines were related to RA levels. While administration of retinoids inhibited clonogenic growth and proliferation, the pharmacological inhibition of ALDH1A2-RAR signaling resulted in loss of cell-cell adhesion and a mesenchymal-like phenotype. Xenograft tumors derived from FaDu cells with stable silencing of ALDH1A2 and primary tumors from OPSCC patients with low ALDH1A2 expression exhibited a mesenchymal-like phenotype characterized by vimentin expression. Conclusions This study has unraveled a critical role of ALDH1A2-RAR signaling in the pathogenesis of head and neck cancer and our data implicate that patients with ALDH1A2low tumors might benefit from adjuvant treatment with retinoids. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0476-0) contains supplementary material, which is available to authorized users.