[Tracheal Tumours]. / Trachealtumoren.

Malignant primary tracheal tumours are rare. The most common histological subtypes are squamous cell carcinoma and adenoid cystic carcinoma. These two entities have different prognoses and growth patterns. Tracheobronchoscopy and thoracic sectional imaging are standard diagnostic tools for tumour staging and local evaluation. Complete surgical resection of the affected tracheal segment is the treatment of choice for limited disease without distant metastases. Incomplete gross tumour resection with additional irradiation is an acceptable therapeutic option for adenoid cystic carcinoma. Interventional endoscopy with tumour debulking or tracheal stenting and/or definitive mediastinal radiotherapy are treatment alternatives in either a locally advanced or palliative setting.

DNA-methylome-assisted classification of patients with poor prognostic subventricular zone associated IDH-wildtype glioblastoma.

Glioblastoma (GBM) derived from the "stem cell" rich subventricular zone (SVZ) may constitute a therapy-refractory subgroup of tumors associated with poor prognosis. Risk stratification for these cases is necessary but is curtailed by error prone imaging-based evaluation. Therefore, we aimed to establish a robust DNA methylome-based classification of SVZ GBM and subsequently decipher underlying molecular characteristics. MRI assessment of SVZ association was performed in a retrospective training set of IDH-wildtype GBM patients (n = 54) uniformly treated with postoperative chemoradiotherapy. DNA isolated from FFPE samples was subject to methylome and copy number variation (CNV) analysis using Illumina Platform and cnAnalysis450k package. Deep next-generation sequencing (NGS) of a panel of 130 GBM-related genes was conducted (Agilent SureSelect/Illumina). Methylome, transcriptome, CNV, MRI, and mutational profiles of SVZ GBM were further evaluated in a confirmatory cohort of 132 patients (TCGA/TCIA). A 15 CpG SVZ methylation signature (SVZM) was discovered based on clustering and random forest analysis. One third of CpG in the SVZM were associated with MAB21L2/LRBA. There was a 14.8% (n = 8) discordance between SVZM vs. MRI classification. Re-analysis of these patients favored SVZM classification with a hazard ratio (HR) for OS of 2.48 [95% CI 1.35-4.58], p = 0.004 vs. 1.83 [1.0-3.35], p = 0.049 for MRI classification. In the validation cohort, consensus MRI based assignment was achieved in 62% of patients with an intraclass correlation (ICC) of 0.51 and non-significant HR for OS (2.03 [0.81-5.09], p = 0.133). In contrast, SVZM identified two prognostically distinct subgroups (HR 3.08 [1.24-7.66], p = 0.016). CNV alterations revealed loss of chromosome 10 in SVZM- and gains on chromosome 19 in SVZM- tumors. SVZM- tumors were also enriched for differentially mutated genes (p < 0.001). In summary, SVZM classification provides a novel means for stratifying GBM patients with poor prognosis and deciphering molecular mechanisms governing aggressive tumor phenotypes.

Stereotactic radiotherapy of brain metastases: clinical impact of three-dimensional SPACE imaging for 3T-MRI-based treatment planning.

PURPOSE: For planning CyberKnife stereotactic radiosurgery (CK SRS) of brain metastases (BM), it is essential to precisely determine the exact number and location of BM in MRI. Recent MR studies suggest the superiority of contrast-enhanced 3D fast spin echo SPACE (sampling perfection with application-optimized contrast by using different flip angle evolutions) images over 3D gradient echo (GE) T1-weighted MPRAGE (magnetization-prepared rapid gradient echo) images for detecting small BM. The aim of this study is to test the usability of the SPACE sequence for MRI-based radiation treatment planning and its impact on changing treatment. METHODS: For MRI-based radiation treatment planning using 3T MRI in 199 patients with cerebral oligometastases, we compared the detectability of BM in post-gadolinium SPACE images, post-gadolinium MPRAGE images, and post-gadolinium late-phase MPRAGE images. RESULTS: When SPACE images were used for MRI-based radiation treatment planning, 29.8% and 16.9% more BM, respectively, were detected and included in treatment planning than in the post-gadolinium MPRAGE images and the post-gadolinium late-phase MPRAGE images (post-gadolinium MPRAGE imaging: ntotal = 681, mean ± SD 3.4 ± 4.2; post-gadolinium SPACE imaging: ntotal = 884, mean ± SD 4.4 ± 6.0; post-gadolinium late-phase MPRAGE imaging: ntotal = 796, mean ± SD 4.0 ± 5.3; Ppost-gadolinium SPACE imaging versus post-gadolinium MPRAGE imaging < 0.0001, Ppost-gadolinium SPACE imaging versus post-gadolinium late-phase MPRAGE imaging< 0.0001). CONCLUSION: For 3T MRI-based treatment planning of stereotactic radiosurgery of BM, we recommend the use of post-gadolinium SPACE imaging rather than post-gadolinium MPRAGE imaging.

DEGRO practical guideline for central nervous system radiation necrosis part 2: treatment.

PURPOSE: The Working Group for Neurooncology of the German Society for Radiation Oncology (DEGRO; AG NRO) in cooperation with members of the Neurooncological Working Group of the German Cancer Society (DKG-NOA) aimed to define a practical guideline for the diagnosis and treatment of radiation-induced necrosis (RN) of the central nervous system (CNS). METHODS: Panel members of the DEGRO working group invited experts, participated in a series of conferences, supplemented their clinical experience, performed a literature review, and formulated recommendations for medical treatment of RN, including bevacizumab, in clinical routine. CONCLUSION: Diagnosis and treatment of RN requires multidisciplinary structures of care and defined processes. Diagnosis has to be made on an interdisciplinary level with the joint knowledge of a neuroradiologist, radiation oncologist, neurosurgeon, neuropathologist, and neurooncologist. If the diagnosis of blood-brain barrier disruptions (BBD) or RN is likely, treatment should be initiated depending on the symptoms, location, and dynamic of the lesion. Multiple treatment options are available (such as observation, surgery, steroids, and bevacizumab) and the optimal approach should be discussed in an interdisciplinary setting. In this practice guideline, we offer detailed treatment strategies for various scenarios.

DEGRO practical guideline for central nervous system radiation necrosis part 1: classification and a multistep approach for diagnosis.

PURPOSE: The Working Group for Neuro-Oncology of the German Society for Radiation Oncology in cooperation with members of the Neuro-Oncology Working Group of the German Cancer Society aimed to define a practical guideline for the diagnosis and treatment of radiation-induced necrosis (RN) of the central nervous system (CNS). METHODS: Panel members of the DEGRO working group invited experts, participated in a series of conferences, supplemented their clinical experience, performed a literature review, and formulated recommendations for medical treatment of RN including bevacizumab in clinical routine. CONCLUSION: Diagnosis and treatment of RN requires multidisciplinary structures of care and defined processes. Diagnosis has to be made on an interdisciplinary level with the joint knowledge of a neuroradiologist, radiation oncologist, neurosurgeon, neuropathologist, and neuro-oncologist. A multistep approach as an opportunity to review as many characteristics as possible to improve diagnostic confidence is recommended. Additional information about radiotherapy (RT) techniques is crucial for the diagnosis of RN. Misdiagnosis of untreated and progressive RN can lead to severe neurological deficits. In this practice guideline, we propose a detailed nomenclature of treatment-related changes and a multistep approach for their diagnosis.

Symptom relief, prognostic factors, and outcome in patients receiving urgent radiation therapy for superior vena cava syndrome : A single-center retrospective analysis of 21 years' practice.

PURPOSE: Superior vena cava syndrome (SVCS) often results from external vessel compression due to tumor growth. Urgent symptom-guided radiotherapy (RT) remains a major treatment approach in histologically proven, rapidly progressive disease. Despite several publications, recent data concerning symptom relief and oncological outcome as well as potential confounders in treatment response are still scarce. METHODS: We performed a retrospective single-center analysis of patients receiving urgent RT between 2000 and 2021 at the University Medical Center Göttingen. Symptom relief was evaluated by CTCAE score during the RT course. Effects of variables on symptom relief were assessed by logistic regression. The impact of parameters on overall survival (OS) was evaluated using Kaplan-Meier plot along with the log-rank test and by Cox regression analyses. Statistically significant (p-value < 0.05) confounders were tested in multivariable analyses. RESULTS: A total of 79 patients were included. Symptom relief was achieved in 68.4%. Mean OS was 59 days, 7.6% (n = 6) of patients showed long-term survival (> 2 years). Applied RT dose > 39 Gy, clinical target volume (CTV) size < 387 ml, concomitant chemotherapy, and completion of the prescribed RT course were found to be statistically significant for OS; applied RT dose and completion of the prescribed RT course were found to be statistically significant for symptom relief. CONCLUSION: Symptom relief by urgent RT for SVCS was achieved in the majority of patients. RT dose and completion of the RT course were documented as predictors for OS and symptom relief, CTV < 387 ml and concomitant chemotherapy were predictive for OS.

Protocol of the TREASURE study: Thoracic RadiothErapy with Atezolizumab in Small cell lUng canceR Extensive disease - a randomized, open-label, multicenter phase II trial.

BACKGROUND: Recently, the combination of the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab with first-line chemotherapy has demonstrated to improve outcome for patients with advanced small cell lung cancer (SCLC), leading to approval of this regimen. At the same time, accumulating (pre-)clinical data suggest synergisms of radiotherapy and immunotherapy via the radiation-mediated induction of anti-tumor immunogenicity. Combining the recent findings, the TREASURE trial aims at further enhancing response to upfront chemo-immunotherapy by the addition of thoracic radiotherapy (TRT). METHODS/DESIGN: The TREASURE trial is a randomized, multicenter, phase II clinical trial ( ClinicalTrials.gov identifier, NCT04462276). One hundred four patients suffering from extensive disease (ED) SCLC, with any response to the standard of care induction chemo-immunotherapy will be randomized to receive atezolizumab maintenance therapy with or without TRT. The primary endpoint of this study is overall survival (OS). Secondary endpoints include further measures of efficacy, safety, and the collection of biomarker samples. A safety interim analysis will take place after n = 23 patients receiving TRT have been observed for three months after the end of TRT. DISCUSSION: This trial will investigate whether treatment efficacy can be improved by adding TRT to atezolizumab maintenance therapy in ED SCLC patients with any response after chemo-immunotherapy. Safety and feasibility of such a regimen will be evaluated, and biomaterials for a translational research project will be collected. Together, the results of this trial will deepen our comprehension of how checkpoint inhibition and radiotherapy interact and contribute to the evolving landscape of SCLC therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04462276 (Date of initial registration: 8th July 2020), https://clinicaltrials.gov/ct2/show/NCT04462276 Eudra-CT Number: 2019-003916-29 (Date of initial registration: 30th March 2020), https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003916-29/DE.

Inhibition of Wnt/ß-Catenin Signaling Sensitizes Esophageal Cancer Cells to Chemoradiotherapy.

The standard treatment of locally advanced esophageal cancer comprises multimodal treatment concepts including preoperative chemoradiotherapy (CRT) followed by radical surgical resection. However, despite intensified treatment approaches, 5-year survival rates are still low. Therefore, new strategies are required to overcome treatment resistance, and to improve patients' outcome. In this study, we investigated the impact of Wnt/ß-catenin signaling on CRT resistance in esophageal cancer cells. Experiments were conducted in adenocarcinoma and squamous cell carcinoma cell lines with varying expression levels of Wnt proteins and Wnt/ß-catenin signaling activities. To investigate the effect of Wnt/ß-catenin signaling on CRT responsiveness, we genetically or pharmacologically inhibited Wnt/ß-catenin signaling. Our experiments revealed that inhibition of Wnt/ß-catenin signaling sensitizes cell lines with robust pathway activity to CRT. In conclusion, Wnt/ß-catenin activity may guide precision therapies in esophageal carcinoma patients.

Age-dependent hemato- and nephrotoxicity in patients with head and neck cancer receiving chemoradiotherapy with weekly cisplatin.

BACKGROUND AND PURPOSE: In cases of simultaneous chemoradiotherapy (CRT), early recognition of toxic side effects is important, as drug discontinuation may prevent further injury. It appears favorable to undertake further steps to investigate whether patient subgroups behave differently depending on their toxicity profile. METHODS: We retrospectively analyzed 125 consecutive patients with non-metastasized carcinoma of the head and neck who were treated with CRT (cisplatin 40 mg/m2 weekly) in 2013/2014. Patients were planned to receive six cycles of cisplatin. Statistical analyses were performed using the chi2 test, t-test, Kaplan-Meier method, and the log-rank test, as appropriate. RESULTS: Eighty-six patients did not reach the intended sixth cycle (68.8%; 60.0% of whom were ≥60 years, p < 0.05). Acute kidney injury (glomerular filtration rate <60 mL/min/1.73m2) was the most common reason for drug discontinuation (26.7%; 82.6% of whom were ≥60 years; p < 0.01), followed by leukopenia <3/nL (23.3%; 75% of whom were <60 years; p < 0.01) and infection (11.6%). Patients who underwent ≥5 cycles were associated with prolonged overall survival and metastasis-free survival after CRT (p < 0.02; median follow-up 24 months), especially patients <60 years. CONCLUSION: Acute kidney injury was the most common side effect in patients ≥60 years, whereas leukopenia characteristically occurred significantly more often in younger patients. Discontinuing cisplatin during CRT was associated with a worse outcome, especially in patients <60 years.

Thoracic radiotherapy plus Durvalumab in elderly and/or frail NSCLC stage III patients unfit for chemotherapy - employing optimized (hypofractionated) radiotherapy to foster durvalumab efficacy: study protocol of the TRADE-hypo trial.

BACKGROUND: Non-small cell lung cancer is the most common cause of cancer death worldwide, highlighting the need for novel therapeutic concepts. In particular, there is still a lack of treatment strategies for the group of elderly and frail patients, who are frequently not capable of receiving standard therapy regimens. Despite comprising the majority of lung cancer patients, this group is underrepresented in clinical trials. This applies also to elderly and frail patients suffering from unresectable stage III NSCLC, who are unfit for chemotherapy, and, therefore, cannot receive the standard therapy comprising of radiochemotherapy and the recently approved subsequent durvalumab consolidation therapy. These patients often receive radiotherapy only, which raises the concern of undertreatment. The TRADE-hypo trial aims at optimizing treatment of this patient group by combining radiotherapy with concomitant durvalumab administration, thereby employing the immune-promoting effects of radiotherapy, and determining safety, feasibility, and efficacy of this treatment. METHODS/ DESIGN: In this prospective phase II clinical trial, durvalumab therapy will be combined with either conventionally fractionated (CON-group) or hypofractionated (HYPO-group) thoracic radiotherapy. A safety stop-and-go lead-in phase will assess safety of hypofractionated radiotherapy with respect to severe pneumonitis in small patient cohorts before opening full enrollment. Tumor tissue, blood and stool samples will be collected before and during the study period to investigate the immunological mechanisms responsible for checkpoint inhibitor efficacy and immune-promoting effects of radiotherapy. DISCUSSION: Preclinical data suggests that irradiation-induced immunogenicity can be further increased if applied in a hypofractionated setting, potentially boosting the expected synergistic effect with immune checkpoint inhibition in restoring the immune anti-tumor response. If proven safe and efficient, a hypofractionated radiation schedule can provide a considerably more practicable option for the patient. Taking into consideration the intend to develop a combination treatment strategy that can be made available to patients soon after proving to be efficient and the potentially elevated toxicity of a hypofractionated radiotherapy approach, this trial was designed as a two-trials-in-one design. An accompanying translational research program is planned striving to gain insights into the tumor-host biology and to identify suitable biomarkers to predict therapy response. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04351256 . Registered 17 April 2020, Eudra-CT, 2019-002192-33 . Registered 24 October 2019.

A matched-pair analysis comparing stereotactic radiosurgery with whole-brain radiotherapy for patients with multiple brain metastases.

INTRODUCTION: Stereotactic radiosurgery (SRS) is an emerging treatment for patients with multiple brain metastases (BM). The present work compares the SRS of multiple brain metastases with whole-brain radiotherapy (WBRT). METHODS: We performed a matched-pair analysis for 128 patients with multiple BM treated with either SRS or WBRT over a 5-year period. Patients were matched pairwise for seven potential prognostic factors. A mixed Cox Proportional Hazards model with univariate and multivariate analysis was fitted for overall survival (OS). Distant intracranial progression-free survival (icPFS) and local control were assessed using a Fine and Gray subdistribution hazard model and considering death as competing event. RESULTS: Patients undergoing SRS had a median of 4 BM (range 3-16). 1-year local control of individual BM following SRS was 91.7%. Median OS in the SRS subgroup was 15.7 months (IQR 9.7-36.4) versus 8.0 months (interquartile range, IQR 3.8-18.0) in the WBRT subgroup (HR 2.25, 95% CI [1.5; 3.5], p < 0.001). Median icPFS was 8.6 (IQR 3.4-18.0) versus 22.4 (IQR 5.6-28.6) months, respectively (HR for WBRT 0.41, 95% CI [0.24; 0.71], p = 0.001). Following SRS, synchronous BM diagnosis (HR 2.51, 95% CI [1.30; 4.70], p = 0.004), higher initial number of BM (HR 1.21, 95% CI [1.10; 1.40], p = 0.002) and lung cancer histology (HR 2.05, 95% CI [1.10; 3.80], p = 0.024) negatively impacted survival. Excellent clinical performance (KPI 90%) was a positive prognosticator (HR 0.38, 95% CI [0.20; 0.72], p = 0.003), as was extracerebral tumor control (HR 0.48, 95% CI [0.24; 0.97], p = 0.040). Higher initial (HR 1.19, 95% CI [1.00; 1.40], p < 0.013) and total number of BM (HR 1.23, 95% CI [1.10; 1.40], p < 0.001) were prognostic for shorter icPFS. CONCLUSION: This is the first matched-pair analysis to compare SRS alone versus WBRT alone for multiple BM. OS was prolonged in the SRS subgroup and generally favorable in the entire cohort. Our results suggest SRS as a feasible and effective treatment for patients with multiple BM.

Neurocognitive functioning and health-related quality of life in adult medulloblastoma patients: long-term outcomes of the NOA-07 study.

BACKGROUND: Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL). METHODS: Neurocognitive functioning and HRQoL scores over time were determined, and differences between the post-treatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL. RESULTS: 28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (≥ 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below - 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range. CONCLUSIONS: This long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment.

Re-irradiation in locally recurrent lung cancer patients.

PURPOSE: Lung cancer remains one of the tumour diagnoses with high lethality, although innovative treatment approaches have yielded improvements in local control and survival rates. There is still no consensus on how to treat local relapse in patients after first-line treatments. Radiotherapy may be considered in this situation; however, data supporting its effectiveness are rare. The purpose of this retrospective analysis was to evaluate outcomes of patients re-irradiated for thoracic tumours in terms of overall survival (OS), local progression-free survival (LPFS), toxicity and dose-volume parameters. PATIENTS AND METHODS: Sixty-two patients with locally recurrent previously irradiated lung cancer were analysed retrospectively (NSCLC n = 52, SCLC n = 10). Target volumes both in lung and mediastinum were re-irradiated with conventional three-dimensional or intensity-modulated radiotherapy techniques. Median overall dose of re-irradiation was 38.5 Gy (range 20-60 Gy) with a median single dose per fraction of 2 Gy (1.8-3.0 Gy). Clinical documents and treatment plans were evaluated. RESULTS: Median follow-up was 8.2 months (range 0-27 months). OS following re-irradiation was 9.3 months (range: 0-27 months) and LPFS was 6.5 months (range: 0-24 months). OS and LPFS were not affected by histology, total dose or patient age and gender. OS was improved in patients whose re-irradiation volumes included less than two mediastinal lymph node stations (p = 0.016). Twelve patients suffered from pneumonitis ≥grade II (19%) and two from pneumonitis grade III. One patient presumably died from pneumonitis grade V. A slight decline in forced expiratory volume (FEV1) was detected in post-re-irradiation lung function testing. CONCLUSIONS: Re-irradiation is an option for patients with tumour recurrence to control local progression and lower the symptom burden. Oncological outcome appears to be affected by size, location of mediastinal target volumes and lung function. Prospective clinical trials are warranted to substantiate the role of re-irradiation in recurrent lung cancer.

Consolidative mediastinal irradiation of malignant lymphoma using active scanning proton beams: clinical outcome and dosimetric comparison.

PURPOSE: Current research approaches in lymphoma focus on reduction of therapy-associated long-term side effects. Especially in mediastinal lymphoma, proton beam radiotherapy (PT) may be a promising approach for reducing the dose to organs at risk (OAR). PATIENTS: In total, 20 patients were irradiated with active scanning PT at Heidelberg Ion Beam Therapy Center (HIT) between September 2014 and February 2017. For comparative analysis, additional photon irradiation plans with helical intensity-modulated radiotherapy (IMRT) were calculated and quantitative and qualitative dose evaluations were made for both treatment modalities. Toxicity and survival outcomes were evaluated. RESULTS: Clinical target volume coverage was comparable in both treatment modalities and did not significantly differ between IMRT and PT. Nevertheless, PT showed superiority regarding the homogeneity index (HIPT = 1.041 vs. HIIMRT = 1.075, p < 0.001). For all OAR, PT showed significantly higher dose reductions compared with IMRT. In particular, the dose to the heart was reduced in PT (absolute dose reduction of Dmean of 3.3 Gy [all patients] and 4.2 Gy [patients with pericardial involvement]). Likewise, the subgroup analysis of female patients, who were expected to receive higher doses to the breast, showed a higher dose reduction in Dmean of 1.2 Gy (right side) and 2.2 Gy (left side). After a median follow-up of 32 months (range 21-48 months), local and distant progression free survival (LPFS and DPFS) were 95.5% and 95.0%, respectively. Radiotherapy was tolerated well with only mild (grade 1-2) radiation-induced acute and chronic side effects. CONCLUSION: A significant reduction in the dose to the surrounding OAR was achieved with PT compared with photon irradiation, without compromising target volume coverage. Dosimetric advantages may have the potential to translate into a reduction of long-term radiation-induced toxicity in young patients with malignant lymphoma of the mediastinum.

Definitive radiotherapy vs. postoperative radiotherapy for lower gingival carcinomas of the mandible : A single-center report about outcome and toxicity.

PURPOSE: To assess radiotherapy (RT) outcomes in patients with gingival carcinoma and growth up to or involvement of the lower jaw bone. METHODS: This was a retrospective analysis of 51 patients with squamous cell carcinomas of the gingiva. Patients received definitive (group 1, 31.4%) or postoperative (group 2, 66.7%) RT between 2005 and 2017 at the Department of Radiation Oncology, University Hospital Heidelberg. The primary endpoint was overall survival (OS) in both treatment groups. Other endpoints were local-disease-free survival (LDFS), progression-free survival (PFS) and treatment-related toxicity (Common Terminology Criteria for Adverse Events, CTCAE, Version 4.03). RESULTS: Median age at first diagnosis was 63 years. All patients had a local advanced disease (American Joint Commission on Cancer [AJCC] stage III-IV). After a median follow-up of 22 months (range 3-145 months), 20 patients (39.2%) were still alive. At 5 years, OS rate was 36.6%. No significant differences in OS (p = 0.773), PFS (p = 0.350) and LDFS (p = 0.399) were observed between the two groups. Most common higher-grade acute RT-related complications (≥ grade 3) were dermatitis (78.2%), oral mucositis (61.7%), xerostomia (51.5%), and loss of taste (74.6%). Three cases (5.8%) of osteoradionecrosis (ORN) of the lower jaw were detected after 15-31 months. CONCLUSIONS: Definitive and postoperative RT have similar treatment outcomes for patients with lower gingiva carcinomas of the lower jaw. The most common acute complications (grade ≥3) were dermatitis, oral mucositis, xerostomia and loss of taste.

Fostering efficacy of anti-PD-1-treatment: Nivolumab plus radiotherapy in advanced non-small cell lung cancer - study protocol of the FORCE trial.

BACKGROUND: Hypofractionated palliative radiotherapy for metastatic lung cancer patients is frequently used in order to ease pain, to increase bone stability, to treat local mass effects, or to prolong progression-free survival at critical sites. Recently introduced, immunotherapy for patients with non-squamous non-small cell lung carcinoma (NSCLC) has significantly improved outcome in this cohort. Preclinical and early clinical data suggest that the combination of photon radiation with programmed death-1 (PD-1) targeting immunotherapies may promote a strong and durable immune response against tumor manifestations both within and beyond radiation targets. METHODS/DESIGN: In the present prospective, two-group, non-randomized, open-label phase II trial, 130 patients with stage IV non-squamous NSCLC in 2nd-line or 3rd-line treatment will be included. 65 patients with a clinical indication for palliative radiotherapy to non-cerebral/non-pulmonary metastatic sites will receive 240 mg nivolumab followed by palliative radiotherapy with 5 × 4 Gray (Gy) = 20 Gy photon radiation, which will be initiated within 72 h after first nivolumab administration (Group A). 65 patients without an indication for radiotherapy will only receive nivolumab (Group B). Nivolumab will be further administered every two weeks in both groups and will be continued until progression and loss of clinical benefit or until occurrence of limiting toxicities. The primary endpoint will be the objective response rate (ORR) according to response evaluation criteria in solid tumors (RECIST) 1.1. Secondary endpoints will be progression-free survival (PFS) according to RECIST 1.1, overall survival, descriptive subgroup analyses according to PD-L1 expression, toxicity and quality of life. Since response patterns following immunotherapies differ from those after conventional cytostatic agents, both objective response rate and progression-free survival will additionally be assessed according to immune-related RECIST (irRECIST) criteria. DISCUSSION: The FORCE study will prospectively investigate response rates, progression-free and overall survival (OS), and toxicity of nivolumab with and without hypofractionated palliative radiotherapy in a group of 130 patients with metastatic non-small cell lung cancer (non-squamous histology) in 2nd-line or 3rd-line treatment. This trial will contribute prospective data to the repeatedly published observation that the combination of hypofractionated photon radiotherapy and medical immunotherapy is not only safe but will also promote antitumoral immune responses. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03044626 (Date of initial registration: 05 January 2017). Eudra-CT Number: 2015-005741-31 (Date of initial registration: 18 December 2015).

EML4-ALK fusion variant V3 is a high-risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK+ non-small cell lung cancer.

In order to identify anaplastic lymphoma kinase-driven non-small cell lung cancer (ALK+ NSCLC) patients with a worse outcome, who might require alternative therapeutic approaches, we retrospectively analyzed all stage IV cases treated at our institutions with one of the main echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variants V1, V2 and V3 as detected by next-generation sequencing or reverse transcription-polymerase chain reaction (n = 67). Progression under tyrosine kinase inhibitor (TKI) treatment was evaluated both according to Response Evaluation Criteria in Solid Tumors (RECIST) and by the need to change systemic therapy. EML4-ALK fusion variants V1, V2 and V3 were found in 39%, 10% and 51% of cases, respectively. Patients with V3-driven tumors had more metastatic sites at diagnosis than cases with the V1 and V2 variants (mean 3.3 vs. 1.9 and 1.6, p = 0.005), which suggests increased disease aggressiveness. Furthermore, V3-positive status was associated with earlier failure after treatment with first and second-generation ALK TKI (median progression-free survival [PFS] by RECIST in the first line 7.3 vs. 39.3 months, p = 0.01), platinum-based combination chemotherapy (median PFS 5.4 vs. 15.2 months for the first line, p = 0.008) and cerebral radiotherapy (median brain PFS 6.1 months vs. not reached for cerebral radiotherapy during first-line treatment, p = 0.028), and with inferior overall survival (39.8 vs. 59.6 months in median, p = 0.017). Thus, EML4-ALK fusion variant V3 is a high-risk feature for ALK+ NSCLC. Determination of V3 status should be considered as part of the initial workup for this entity in order to select patients for more aggressive surveillance and treatment strategies.

Response rates and recurrence patterns after low-dose radiotherapy with 4 Gy in patients with low-grade lymphomas.

PURPOSE: Retrospective study of effectiveness, toxicity, and relapse patterns after low-dose radiotherapy (LDRT) in patients with low-grade lymphomas. METHODS: 47 patients (median age 64 years) with 50 lesions were treated with LDRT (2â€¯× 2 Gy). In 60%, LDRT was the primary and curative treatment, in 40% offered as second-line therapy in recurrent disease. Histology included follicular (57%) and marginal zone lymphomas (43%). Patients were followed-up regularly clinically (skin) and with CT or MRI scans. RESULTS: Median follow-up was 21 months. 84% of the lesions were extranodal disease (32% orbit, 14% salivary glands, 30% skin, and 8% others). Most lesions were ≤5 cm (90%) with a singular affection (74%). 26% of the patients received rituximab simultaneously. Overall response rate (ORR) was 90% (all lesions), 93.3% (primary treatment), and 85% (recurrence treatment); p = 0.341. 2­year Local progression-free survival (LPFS) for all, curative, and palliative patients was 91.1%, 96.7%, and 83.8%, respectively; p = 0.522. Five relapses were detected: three infield only, and were therefore treated with LDRT or subsequent local RT of 30 Gy. Two patients showed an in- and outfield progression and were consequently treated with chemotherapy. Predictive factors for higher LPFS were tumor size ≤5 cm (p = 0.003), ≤2 previous treatments (p = 0.027), no skin involvement (p = 0.05), singular affection (p = 0.075), and simultaneous rituximab application (p = 0.148). LDRT was tolerated well, without detectable acute or long-term side effects. CONCLUSION: Primary LDRT is an effective treatment with high ORR and long-lasting remissions in a subset of patients with low-grade lymphoma, and may therefore be a curative treatment option for patients with low tumor burden. LDRT with the CD20 antibody obinutuzumab will soon be tested in a prospective multicenter trial.