Checkpoint immunotherapy of cutaneous squamous cell carcinoma in patients suffering from chronic lymphocytic leukaemia: divergent outcomes in two men treated with PD-1 inhibitors.

Cutaneous squamous cell carcinoma (cSCC) numbers among the most common types of skin cancer and is known as one of the cancer entities with the highest mutational burden among all solid tumours. Due to the positive correlation between mutational burden and response rate to inhibitors of the programmed cell death 1 (PD-1), those inhibitors are considered promising candidates for the systemic therapy of cSCC. Recently, the PD-1 inhibitors pembrolizumab, nivolumab and cemiplimab demonstrated efficacy in the systemic treatment of locally advanced or metastatic cSCC leading to the approval of cemiplimab by the FDA (U.S. Food and Drug Administration) in 2018 and the EMA (European Medicines Agency) in 2019. Patients with haematological malignancies tend to develop skin cancers of high aggressiveness, enhanced cumulative recurrence rate and higher rates of metastases with subsequent death. Chronic lymphocytic leukaemia (CLL) is the most frequent type of leukaemia in the United States and Europe with the majority of patients older than 50 years of age. This neoplasm predominantly originates from B -cells leading to an impaired immune system of the patient. Although CLL is a B-cell malignancy, studies have also described the involvement of T cells in the pathogenesis and progression of the disease with contradictory findings on the effects of PD-1 inhibitors in CLL. Due to their underlying hematologic malignancy, these patients have commonly no access to PD-1 inhibitor trials for treatment of advanced cSCC. We report on two patients with locally advanced or metastatic cSCC. Both patients had been suffering from a CLL for many years without indication for treatment. Despite a potential immunosuppressive state of the patients due to their CLL, both were treated with the PD-1 inhibitor pembrolizumab resulting in different therapy outcomes.

Cardiac fibroblast activation detected by Ga-68 FAPI PET imaging as a potential novel biomarker of cardiac injury/remodeling.

BACKGROUND: Fibroblast activation protein (FAP) as a specific marker of activated fibroblasts can be visualized by positron emission tomography (PET) using Ga-68-FAP inhibitors (FAPI). Gallium-68-labeled FAPI is increasingly used in the staging of various cancers. In addition, the first cases of theranostic approaches have been reported. In this work, we describe the phenomenon of myocardial FAPI uptake in patients who received a Ga-68 FAPI PET for tumor staging. METHOD AND RESULTS: Ga-68 FAPI PET examinations for cancer staging were retrospectively analyzed with respect to cardiac tracer uptake. Standardized uptake values (SUV) were correlated to clinical covariates in a univariate regression model. From 09/2018 to 11/2019 N = 32 patients underwent FAPI PET at our institution. Six out of 32 patients (18.8%) demonstrated increased localized myocardial tracer accumulation, with remote FAPI uptake being significantly higher in patients with vs without localized focal myocardial uptake (SUVmax 2.2 ± .6 vs 1.5 ± .4, P < .05 and SUVmean 1.6 ± .4 vs 1.2 ± .3, P < .05, respectively). Univariate regression demonstrated a significant correlation of coronary artery disease (CAD), age and left ventricular ejection fraction (LVEF) with remote SUVmean uptake, the latter with a very strong correlation with remote uptake (R2 = .74, P < .01). CONCLUSION: Our study indicates an association of CAD, age, and LVEF with FAPI uptake. Further studies are warranted to assess if fibroblast activation can be reliably measured and may be used for risk stratification regarding early detection or progression of CAD and left ventricular remodeling.

ANTECEDENTES: Proteína de activación de fibroblastos (FAP) como marcador específico de fibroblastos maduros activados se puede visualizar mediante tomografía por emisión de positrones (PET) usando inhibidores de Ga-68-FAP (FAPI). El FAPI marcado con galio 68 se usa cada vez más en la estatificación de varios tipos de cáncer.Además, se han reportado los primeros casos de abordajes teranósticos. En este trabajo describimos el fenómeno de la captación de FAPI miocárdica en pacientes que recibieron Ga-68 FAPI PET para estatificación tumoral. MéTODO Y RESULTADOS: Los exámenes de PET Ga-68 FAPI para estadificación de cáncer se analizaron retrospectivamente con respecto a la captación del marcador cardíaco. Los valores de absorción estandarizados (SUV) se correlacionaron con covariables clínicas en un modelo de regresión univariante. Del 09/2018 al 11/2019 con una n = 32 pacientes fueron sometidos a PET FAPI en nuestra institución. Seis de 32 pacientes (18.8%) demostraron un aumento de acumulación del marcador localizado en el miocardio, con la captación remota de FAPI siendo significativamente mayor en pacientes con aumento de la captación vs sin captación focalizada de miocardio (SUVmax 2.2 ± 0.6 vs. 1.5 ± 0.4, p <0.05 y SUV mean 1.6 ± 0.4 vs. 1.2 ± 0.3, p <0.05, respectivamente). La regresión univariante demostró una correlación significativa de la enfermedad de la arteria coronaria (CAD), la edad y la fracción de eyección ventricular izquierda (FEVI) con absorción SUV remota, esta última con una muy fuerte correlación con la captación remota (R² = 0.74, p <0.01). CONCLUSIóN: Nuestro estudio indica una asociación de CAD, edad y FEVI con la captación de FAPI. Se necesitan más estudios para evaluar si la activación de fibroblastos se puede medir de manera confiable y se puede usar para la estratificación de riesgo con respecto a la detección temprana o la progresión de la CAD y la remodelación ventricular izquierda.

CONTEXTE: La protéine d'activation des fibroblastes (FAP) activés et matures peut être visualisée par tomographie à émission de positons (TEP) à l'aide d'inhibiteurs de l'activation des fibroblastes (FAPI). FAPI marqué au gallium 68 est de plus en plus utilisé dans la stratification de divers cancers. De plus, les premiers exemples d'approches théranostiques ont été rapportés. Dans ce travail nous décrivons la captation myocardique de FAPI chez les patients qui bénéficié d'une TEP au Ga-68 FAPI pour stratification tumorale. MéTHODE ET RéSULTATS: Les examens TEP Ga-68 FAPI pour la stratification oncologique ont été analysés rétrospectivement pour l'absorption du traceur au niveau cardiaque. Les valeurs d'absorption normalisées (SUV) font été corrélées aux variables cliniques selon un modèle de régression univarié. A partir de septembre 2018 jusqu'en novembre 2019, 32 patients ont bénéficié d'une TEP FAPI dans notre établissement. Six de nos 32 patients (18,8%) ont démontré une augmentation focale de captation du tracer au niveau myocardique. Les foyers systémiques se sont révélés significativement plus élevé chez les patients avec foyers myocardiques localisés (SUV max 2,2 ± 0,6 vs 1,5 ± 0,4, p <0,05 et SUV mean 1,6 ± 0,4 vs 1,2 ± 0,3, p <0,05, respectivement). Nous avons observé une corrélation significative entre la maladie coronarienne, l'âge, la fraction d'éjection du ventricule gauche et la présence de foyer myocardiques FAPI (R² = 0,74, p <0,01) CONCLUSION: Notre étude indique une association entre la maladie cardiovasculaire coronarienne, l'âge et la FEVG et la captation myocardique de FAPI. Des études additionnelles sont nécessaires pour déterminer si l'activation des fibroblastes peut être mesurée de manière fiable et utilisée pour la détection et la progression de la maladie coronarienne et le remodelage du ventricule gauche.

[Head and neck cancer in the elderly-current aspects]. / Tumorerkrankungen des Kopf-Hals-Bereichs im höheren Lebensalter ­ aktuelle Aspekte.

BACKGROUND: The treatment of head and neck cancer is dominated by surgery and radiochemotherapy, which is in part associated with high morbidity. In elderly patients, however, the otorhinolaryngologist often has to question the rationality of invasive treatment. Although the proportion of geriatric patients with head and neck tumors is increasing, the paucity of data means that there are few consistent standards and recommendations in the literature and guidelines. OBJECTIVE: The aim of this paper is to provide concrete clinical recommendations for geriatric patients with head and neck tumors based on a systematic literature search. MATERIALS AND METHODS: A keyword-based literature search was performed to present the current level of evidence and provide a clinical algorithm. RESULTS: In addition to age, the pretreatment dispositional evaluation of geriatric patients should include psychosocial, functional, and medical (patient history) comorbidities. For pretreatment risk stratification, an algorithm was created on the basis of these data for individual evaluation of the patient's pretreatment risk. CONCLUSION: Pretreatment risk stratification of geriatric patients with head and neck malignancies is of high relevance for the individual decision for or against invasive treatment, but the currently available evidence is limited. This paper is based on a systematic literature review and provides a clinical algorithm for otorhinolaryngologists and head and neck surgeons.

Heart dose exposure as prognostic marker after radiotherapy for resectable stage IIIA/B non-small-cell lung cancer: secondary analysis of a randomized trial.

Background: Heart exposure to ionizing irradiation can cause ischaemic heart disease. The partial heart volume receiving ≥5 Gy (heartV5) was supposed to be an independent prognostic factor for survival after radiochemotherapy for locally advanced non-small-cell lung cancer (NSCLC). But validation of the latter hypothesis is needed under the concurrent risks of lung cancer patients. Patients and methods: The ESPATUE phase III trial recruited patients with potentially operable IIIA(N2)/selected IIIB NSCLC between 01/2004 and 01/2013. Cisplatin/paclitaxel induction chemotherapy was given followed by neoadjuvant radiochemotherapy (RT/CT) to 45 Gy (1.5 Gy bid/concurrent cisplatin/vinorelbine). Operable patients were randomized to definitive RT/CT(arm A) or surgery (arm B) and therefore were treated at two different total dose levels of radiotherapy. HeartV5 and mean heart dose (MHD) were obtained from the 3D radiotherapy plans, the prognostic value was analysed using multivariable proportional hazard analysis. Results: A total of 161 patients were randomized in ESPATUE, heartV5 and MHD were obtained from the 3D radiotherapy plans for 155 of these [male/female:105/50, median age 58 (33-74) years, stage IIIA/IIIB: 54/101]. Power analysis revealed a power of 80% of this dataset to detect a prognostic value of heartV5 of the size found in RTOG 0617. Multivariable analysis did not identify heartV5 as an independent prognostic factor for survival adjusting for tumour and clinical characteristics with [hazard ratio 1.005 (0.995-1.015), P = 0.30] or without lower lobe tumour location [hazard ratio 0.999 (0.986-1.012), P = 0.83]. There was no influence of heartV5 on death without tumour progression. Tumour progression, and pneumonia were the leading causes of death representing 65% and 14% of the observed deaths. Conclusions: HeartV5 could not be validated as an independent prognostic factor for survival after neoadjuvant or definitive conformal radiochemotherapy. Tumour progression was the predominant cause of death. Register No: Z5 - 22461/2 - 2002-017 (German Federal Office for Radiation Protection).

Long-term results of definitive radiochemotherapy in locally advanced cancers of the cervical esophagus.

The aim of this study was to retrospectively analyze the long-term effectiveness of combined chemoradiation as the definitive treatment of locally advanced cancers of the cervical esophagus. Patients received high-dose external beam radiotherapy and concurrent cisplatin-based chemotherapy. Some patients received intraluminal brachytherapy as a boost. In addition, a majority of the patients received cisplatin-based induction chemotherapy before definitive chemoradiation. Fifty-five patients (46 men, 9 women, median age 58 years, range 35-72 years) with cancers of the cervical esophagus (stage II: 20; stage III: 35 patients) were treated with definitive chemoradiation (median dose 60 Gy, range 50-70 Gy). Actuarial overall survival rates at 2, 3, 5, and 10 years were 35%, 29%, 25%, and 10%, respectively. Thirteen long-term survivors were observed with a follow-up of more than 5 years. Neither gender nor age, tumor length, tumor grade, or clinically detectable lymph node metastases was significant prognostic factors for survival. Twenty-four patients (44%) developed local or regional recurrences, 15 (27%) distant metastases, and 8 (15%) patients developed a second malignancy. Acute and late toxicity of this treatment schedule was moderate. Concurrent chemoradiation offers a chance of long-term survival for locally advanced unresectable carcinomas of the cervical esophagus, with long-term survival rates above 24% and acceptable toxicity. These results substantiate the use of chemoradiation as a curative treatment option for cervical esophageal cancer.

Prospects for online adaptive radiation therapy (ART) for head and neck cancer.

BACKGROUND: The aim of the present study is to examine the impact of kV-CBCT-based online adaptive radiation therapy (ART) on dosimetric parameters in comparison to image-guided-radiotherapy (IGRT) in consecutive patients with tumors in the head and neck region from a prospective registry. METHODS: The study comprises all consecutive patients with tumors in the head and neck area who were treated with kV-CBCT-based online ART or IGRT-modus at the linear-accelerator ETHOS™. As a measure of effectiveness, the equivalent-uniform-dose was calculated for the CTV (EUDCTV) and organs-at-risk (EUDOAR) and normalized to the prescribed dose. As an important determinant for the need of ART the interfractional shifts of anatomic landmarks related to the tongue were analyzed and compared to the intrafractional shifts. The latter determine the performance of the adapted dose distribution on the verification CBCT2 postadaptation. RESULTS: Altogether 59 consecutive patients with tumors in the head-and-neck-area were treated from 01.12.2021 to 31.01.2023. Ten of all 59 patients (10/59; 16.9%) received at least one phase within a treatment course with ART. Of 46 fractions in the adaptive mode, irradiation was conducted in 65.2% of fractions with the adaptive-plan, the scheduled-plan in the remaining. The dispersion of the distributions of EUDCTV-values from the 46 dose fractions differed significantly between the scheduled and adaptive plans (Ansari-Bradley-Test, p = 0.0158). Thus, the 2.5th percentile of the EUDCTV-values by the adaptive plans amounted 97.1% (95% CI 96.6-99.5%) and by the scheduled plans 78.1% (95% CI 61.8-88.7%). While the EUDCTV for the accumulated dose distributions stayed above 95% at PTV-margins of ≥ 3 mm for all 8 analyzed treatment phases the scheduled plans did for margins ≥ 5 mm. The intrafractional anatomic shifts of all 8 measured anatomic landmarks were smaller than the interfractional with overall median values of 8.5 mm and 5.5 mm (p < 0.0001 for five and p < 0.05 for all parameters, pairwise comparisons, signed-rank-test). The EUDOAR-values for the larynx and the parotid gland were significantly lower for the adaptive compared with the scheduled plans (Wilcoxon-test, p < 0.001). CONCLUSIONS: The mobile tongue and tongue base showed considerable interfractional variations. While PTV-margins of 5 mm were sufficient for IGRT, ART showed the potential of decreasing PTV-margins and spare dose to the organs-at-risk.

Feasibility of 6-month maintenance cetuximab after adjuvant concurrent chemoradiation plus cetuximab in squamous cell carcinoma of the head and neck.

BACKGROUND: Close resection margins < 5 mm (CM) or extra capsular extent at the lymph nodes (ECE) impair the prognosis of patients with squamous cell cancer of the head and neck (SCCHN) scheduled for adjuvant radiochemotherapy. We conducted a multicenter phase II study to investigate toxicity and efficacy of additional cetuximab administered concomitantly and as maintenance for the duration of 6 months following adjuvant radiochemotherapy., Ppreliminary results on feasibility and acute toxicity on skin and mucosa are presented in this article. METHODS: Patients with SCCHN following CM resection or with ECE were eligible for the study. In all, 61.6 Gy (1.8/2.0/2.2 Gy, days 1-36) were administered using an integrated boost intensity-modulated radiotherapy (IMRT) technique. Cisplatin (20 mg/m(2), days 1-5 and days 29-33) and 5-fluorouracil (5-FU) as continuous infusion (600 mg/m(2), days 1-5 + days 29-33) were given concurrently. Cetuximab was started 7 days prior to radiochemotherapy at 400 mg/m(2) followed by weekly doses of 250 mg/m(2). Maintenance cetuximab began after radiochemotherapy at 500 mg/m(2) every 2 weeks for 6 months. RESULTS: Of the 55 patients (46 male, 9 female, mean age 55.6, range 29-70 years) who finished radiochemotherapy, 50 were evaluable for acute toxicity concerning grade III/IV toxicities of skin and mucosa. Grade 3-4 (CTC 3.0) mucositis, radiation dermatitis, and skin reactions outside the radiation portals were documented for 46, 28, and 14 % of patients, respectively. One toxic death occurred (peritonitis at day 57). Cetuximab was terminated in 5 patients due to allergic reactions after the first application. In addition, 22 % of patients discontinued cetuximab within the last 2 weeks or at the end of radiochemotherapy. Of patients embarking on maintenance treatment, 80 % were still on cetuximab at 3 months and 63 % at 5 months. Concurrent and maintenance treatment with cetuximab could be administered as scheduled in 48 % of patients. CONCLUSION: Adjuvant radiochemotherapy with concomitant and maintenance cetuximab is feasible and acute toxicities are within the expected range. Compliance within the first 3-5 months is moderate.

Respiration-controlled radiotherapy in lung cancer: Systematic evaluation of the optimal application practice.

Background and purpose: Definitive radiochemotherapy (RCT) for non-small cell lung cancer (NSCLC) in UICC/TNM I-IVA (singular, oligometastatic) is one of the treatment methods with a potentially curative concept. However, tumour respiratory motion during RT requires exact pre-planning. There are various techniques of motion management like creating internal target volume (ITV), gating, inspiration breath-hold and tracking. The primary goal is to cover the PTV with the prescribed dose while at the same time maximizing dose reduction of surrounding normal tissues (organs at risk, OAR). In this study, two standardized online breath-controlled application techniques used alternately in our department are compared with respect to lung and heart dose. Materials and methods: Twenty-four patients who were indicated for thoracic RT received planning CTs in voluntary deep inspiration breath-hold (DIBH) and in free shallow breathing, prospectively gated in expiration (FB-EH). A respiratory gating system by Varian (Real-time Position Management, RPM) was used for monitoring. OAR, GTV, CTV and PTV were contoured on both planning CTs. The PTV margin to the CTV was 5 mm in the axial and 6-8 mm in the cranio-caudal direction. The consistency of the contours was checked by elastic deformation (Varian Eclipse Version 15.5). RT plans were generated and compared in both breathing positions using the same technique, IMRT over fixed irradiation directions or VMAT. The patients were treated in a prospective registry study with the approval of the local ethics committee. Results: The PTV in expiration (FB-EH) was on average significantly smaller than the PTV in inspiration (DIBH): for tumours in the lower lobe (LL) 431.5 vs. 477.6 ml (Wilcoxon test for connected samples; p = 0.004), in the upper lobe (UL) 659.5 vs. 686.8 ml (p = 0.005). The intra-patient comparison of plans in DIBH and FB-EH showed superiority of DIBH for UL-tumours and equality of DIBH and FB-EH for LL-tumours. The dose for OAR in UL-tumours was lower in DIBH than in FB-EH (mean lung dose p = 0.011; lungV20, p = 0.002; mean heart dose p = 0.016). The plans for LL-tumours in FB-EH showed no difference in OAR compared to DIBH (mean lung dose p = 0.683; V20Gy p = 0.33; mean heart dose p = 0.929). The RT setting was controlled online for each fraction and was robustly reproducible in FB-EH. Conclusion: RT plans for treating lung tumours implemented depend on the reproducibility of the DIBH and advantages of the respiratory situation with respect to OAR. The primary tumour localization in UL correlates with advantages of RT in DIBH, compared to FB-EH. For LL-tumours there is no difference between RT in FB-EH and RT in DIBH with respect to heart or lung exposure and therefore, reproducibility is the dominant criterion. FB-EH is recommended as a very robust and efficient technique for LL-tumours.

Evaluation of prognostic factors after primary chemoradiotherapy of anal cancer: A multicenter study of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG).

BACKGROUND AND PURPOSE: Prognosis after chemoradiotherapy (CRT) for anal squamous cell carcinoma (ASCC) shows marked differences among patients according to TNM subgroups, however individualized risk assessment tools to better stratify patients for treatment (de-) escalation or intensified follow-up are lacking in ASCC. MATERIALS AND METHODS: Patients' data from eight sites of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG), comprising a total of 605 patients with ASCC, treated with standard definitive CRT with 5-FU/Mitomycin C or Capecitabine/Mitomycin C between 2004-2018, were used to evaluate prognostic factors based on Cox regression models for disease-free survival (DFS). Evaluated variables included age, gender, Karnofsky performance score (KPS), HIV-status, T-category, lymph node status and laboratory parameters. Multivariate cox models were separately constructed for the whole cohort and the subset of patients with early-stage (cT1-2 N0M0) tumors. RESULTS: After a median follow-up of 46 months, 3-year DFS for patients with early-stage ASCC was 84.9%, and 67.1% for patients with locally-advanced disease (HR 2.4, p < 0.001). T-category (HR vs. T1: T2 2.02; T3 2.11; T4 3.03), N-category (HR versus N0: 1.8 for N1-3), age (HR 1.02 per year), and KPS (HR 0.8 per step) were significant predictors for DFS in multivariate analysis in the entire cohort. The model performed with a C-index of 0.68. In cT1-2N0 patients, T-category (HR 2.14), HIV status (HR 2.57), age (1.026 per year), KPS (HR 0.7 per step) and elevated platelets (HR 1.3 per 100/nl) were associated with worse DFS (C-index of 0.7). CONCLUSION: Classical clinicopathologic parameters like T-category, N-category, age and KPS remain to be significant prognostic factors for DFS in patients treated with contemporary CRT for ASCC. HIV and platelets were significantly associated with worse DFS in patients with early stage ASCC.

Chaetocin induced chromatin condensation: effect on DNA repair signaling and survival.

PURPOSE: The aim of the present study was to evaluate the effect of the histone lysine-methyltransferase (HKMT) inhibitor chaetocin on chromatin structure and its effect on ionizing radiation (IR) induced DNA damage response. METHODS: Concentration and time-dependent effects of chaetocin on chromatin clustering and its reversibility were analyzed by immunofluorescent assays in the non-small cell lung carcinoma (NSCLC) cell lines H460 and H1299Q4 and in human skin fibroblasts. In addition, IR induced damage response (γH2AX, 53BP1, and pATM foci formation) was studied by immunofluorescent assays. The effect on survival was determined by performing single-cell clonogenic assays. RESULTS: Chaetocin significantly increased the radiation sensitivity of H460 (F test on nonlinear regression, p < .0011) and of H1299 (p = .0201). In addition, treatment with 15 nM chaetocin also decreased the total radiation doses that control 50% of the plaque monolayers (TCD50) from 17.2 ± 0.3 Gy to 7.3 ± 0.4 Gy (p < .0001) in H1299 cells and from 11.6 ± 0.1 Gy to 6.5 ± 0.3 Gy (p < .0001). Phenotypically, chaetocin led to a time and concentration-dependent clustering of the chromatin in H1299 as well as in fibroblasts, but not in H460 cells. This phenotype of chaetocin induced chromatin clustering (CICC) was reversible and depended on the expression of the HKMTs SUV39H1 and G9a. Treatment with siRNA for SUV39h1 and G9a significantly reduced the CICC phenotype. Immunofluorescent assay results showed that the CICC phenotype was enriched for the heterochromatic marker proteins H3K9me3 and HP1α. γH2AX foci formation was not affected, neither in cells with normal nor with CICC phenotype. In contrast, repair signaling with 53BP1 and pATM foci formation was significantly reduced in the CICC phenotype. CONCLUSIONS: Treatment with chaetocin increased the radiation sensitivity of cells in vitro and DNA damage response, especially of 53BP1 and ATM-dependent repair by affecting chromatin structure. The obtained results support the potential use of natural HKMT inhibitors such as chaetocin or other bioactive compounds in improving radiosensitivity of cancer cells.

Dose-escalated radiotherapy with PET/CT based treatment planning in combination with induction and concurrent chemotherapy in locally advanced (uT3/T4) squamous cell cancer of the esophagus: mature results of a phase I/II trial.

BACKGROUND: This prospective phase I/II trial assessed feasibility and efficacy of dose-escalated definitive chemoradiation after induction chemotherapy in locally advanced esophageal cancer. Primary study endpoint was loco-regional progression-free survival at 1 year. METHODS: Eligible patients received 2 cycles of induction chemotherapy with irinotecan, folinic acid and 5-fluorouracil weekly and cisplatin every 2 weeks (weeks 1-6, 8-13) followed by concurrent chemoradiation with cisplatin and irinotecan (weeks 14, 15, 17, 18, 20). Radiotherapy dose escalation was performed in three steps (60 Gy, 66 Gy, 72 Gy) using conventional fractionation, planning target volumes were delineated with the aid of 18F-FDG-PET/CT scans. During follow-up, endoscopic examinations were performed at regular intervals. RESULTS: Between 09/2006 and 02/2010, 17 patients were enrolled (male/female:13/4, median age: 59 [range 48-66] years, stage uT3N0/T3N1/T4N1: 4/12/1). One patient progressed during induction chemotherapy and underwent surgery. Of 16 patients treated with definitive chemoradiotherapy, 9 (56%) achieved complete response after completion of chemoradiation. One-, 2-, 3- and 5-year overall survival rates (OS) were 77% [95%CI: 59-100], 53% [34-83], 41% [23-73], and 29% [14-61], respectively. Loco-regional progression-free survival at 1, 3, and 5 years was 59% [40-88], 35% [19-67], and 29% [14-61], corresponding cumulative incidences of loco-regional progressions were 18% [4-39%], 35% [14-58%], and 41% [17-64%]. No treatment related deaths occurred. Grade 3 toxicities during induction therapy were: neutropenia (41%), diarrhoea (41%), during combined treatment: neutropenia (62%) and thrombocytopenia (25%). CONCLUSIONS: Dose-escalated radiotherapy and concurrent cisplatin/irinotecan after cisplatin/irinotecan/5FU induction chemotherapy was tolerable. The hypothesized phase II one-year loco-regional progression free survival rate of 74% was not achieved. Long-term survival compares well with other studies on definitive radiotherapy using irinotecan and cisplatin but is not better than recent trials using conventionally fractionated radiotherapy ad 50 Gy with concurrent paclitaxel or 5FU and platinum compound. Trial registration The present trial was registered as a phase I/II trial at the EudraCT database: Nr. 2005-006097-10 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-006097-10/DE ) and authorized to proceed on 2006-09-25.

Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial.

BACKGROUND: Glioblastoma is a rapidly proliferating tumor. Patients bear an inferior prognosis with a median survival time of 14-16 months. Proliferation and repopulation are a major resistance promoting factor for conventionally fractionated radiotherapy. Tumor-Treating-Fields (TTFields) are an antimitotic modality applying low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz) alternating electric-fields. More recently interference of TTFields with DNA-damage-repair and synergistic effects with radiotherapy were reported in the preclinical setting. This study aims at examining the dosimetric consequences of TTFields applied during the course of radiochemotherapy. METHODS: Cone-beam-computed-tomography (CBCT)-data from the first seven patients of the PriCoTTF-phase-I-trial were used in a predefined way for dosimetric verification and dose-accumulation of the non-coplanar-intensity-modulated-radiotherapy (IMRT)-treatment-plans as well as geometric analysis of the transducer-arrays by which TTFields are applied throughout the course of treatment. Transducer-array-position and contours were obtained from the low-dose CBCT's routinely made for image-guidance. Material-composition of the electrodes was determined and a respective Hounsfield-unit was assigned to the electrodes. After 6D-fusion with the planning-CT, the dose-distribution was recalculated using a Boltzmann-equation-solver (Acuros XB) and a Monte-Carlo-dose-calculation-engine. RESULTS: Overdosage in the scalp in comparison to the treatment plan without electrodes stayed below 8.5% of the prescribed dose in the first 2 mm below and also in deeper layers outside 1cm2 at highest dose as obtained from dose-volume-histogram comparisons. In the clinical target volume (CTV), underdosage was limited to 2.0% due to dose attenuation by the electrodes in terms of D95 and the effective-uniform-dose. Principal-component-analysis (PCA) showed that the first principal-position-component of the variation of repeated array-placement in the direction of the largest variations and the perpendicular second-component spanning a tangential plane on the skull had a standard deviation of 1.06 cm, 1.23 cm, 0.96 cm, and 1.11 cm for the frontal, occipital, left and right arrays for the first and 0.70 cm, 0.71 cm, 0.79 cm, and 0.68 cm, respectively for the second-principal-component. The variations did not differ from patient-to-patient (p > 0.8, Kruskal-Wallis-tests). This motion led to a diminution of the dosimetric effects of the electrodes. CONCLUSION: From a dosimetric point of view, dose deviations in the CTV due to transducer-arrays were not clinically significant in the first 7 patients and confirmed feasibility of combined adjuvant radiochemotherapy and concurrent TTFields. PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma. DRKS-ID: DRKS00016667. Date of Registration in DRKS: 2019/02/26. Investigator Sponsored/Initiated Trial (IST/IIT): yes. Ethics Approval/Approval of the Ethics Committee: Approved. (leading) Ethics Committee Nr.: 18-8316-MF, Ethik-Kommission der Medizinischen. Fakultät der Universität Duisburg-Essen. EUDAMED-No. (for studies acc. to Medical Devices act): CIV-18-08-025247.

Targeting ARID1A-mutant colorectal cancer: depletion of ARID1B increases radiosensitivity and modulates DNA damage response.

The SWI/SNF chromatin remodeling complex has been found mutated in a wide range of human cancers, causing alterations in gene expression patterns, proliferation and DNA damage response that have been linked to poor clinical prognosis. Here, we investigated weather knockdown of ARID1B, one of two mutually exclusive subunits within the SWI/SNF complex, can sensitize colorectal cancer cell lines mutated in the other subunit, ARID1A, to ionizing radiation (IR). ARID1A-mutated colorectal cancer (CRC) cell lines are selectively sensitized to IR after siRNA mediated ARID1B depletion, as measured by clonogenic survival. This is characterized by a decrease in the surviving cell fraction to 87.3% ± 2.1%, 86.0% ± 1.1% and 77.2% ± 1.5% per 1 Gy compared with control siRNA exposed cells in the dose range of 0-6 Gy for the LS180, RKO and SW48 lines, respectively (p < 0.0001, F-test). The magnitude of this dose modifying effect was significantly larger in ARID1A mutated than in non-mutated cell lines (Spearman rank correlation rs = 0.88, p = 0.02). Furthermore, initial formation of RAD51 foci at 4 h after IR, as a measure for homologous recombination repair, was significantly reduced in ARID1A-mutant CRC cell lines but not in the majority of wildtype lines nor in fibroblasts. These findings open up perspectives for targeting ARID1B in combination with radiotherapy to improve outcomes of patients with ARID1A-mutant CRC.

Interference of tumour mutational burden with outcome of patients with head and neck cancer treated with definitive chemoradiation: a multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group.

BACKGROUND: Tumour mutational burden (TMB) estimated from whole exome sequencing or comprehensive gene panels has previously been established as predictive factor of response to immune checkpoint inhibitors (ICIs). Its predictive value for the efficacy of concurrent chemoradiation (cCRTX), a potential combination partner of ICI, remains unknown. METHODS: The accuracy of TMB estimation by an in-house 327-gene panel was established in the Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) data set. Interference of TMB with outcome after cCRTX was determined in a multicentre cohort of patients with locally advanced HNSCC uniformly treated with cCRTX. Targeted next-generation sequencing was successfully applied in 101 formalin-fixed, paraffin-embedded pretreatment tumour samples. In a subset of cases (n = 40), tumour RNA was used for immune-related gene expression profiling by the nanoString platform. TMB was correlated with TP53 genotype, human papilloma virus (HPV) status, immune expression signatures and survival parameters. Results were validated in the TCGA HNSCC cohort. RESULTS: A high accuracy of TMB estimation by the 327-gene panel was established. High TMB was significantly associated with an increased prevalence of TP53 mutations and immune gene expression patterns unrelated to T cell-inflamed gene expression profiles. Kaplan-Meier analysis revealed significantly reduced overall survival in the patient group with high TMB (hazard ratio for death: 1.79, 95% confidence interval: 1.02-3.14; P = 0.042) which remained significant after correcting for confounding factors in the multivariate model. The prognostic value of TMB was confirmed in the TCGA HNSCC cohort. CONCLUSION: High TMB identifies HNSCC patients with poor outcome after cCRTX who might preferentially benefit from CRTX-ICI combinations.

Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma.

INTRODUCTION: Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common. METHODS & RESULTS: Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFV600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor-pretreated compared with MAPK-inhibitor-naïve intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1Bhigh cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death. CONCLUSION: The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.

[Proapoptotic antibodies as new therapeutic agents for tumor treatment]. / Proapoptotische Antikörper als neue Tumortherapeutika.

To convert the concept already successful in mice into clinical practice and commercialize it, a human anti-CD95-antibody must be produced. In a second step experiments must be performed on various normal healthy cells and tissues to determine whether these human anti-CD95-antibodies administered in very low doses have any effect on human cells (particularly hepatocytes) or at least cause only minimal side effects. If these studies yield positive results, then clinical trials can be conducted in which increasing doses are given to exclude an acute hepatotoxic effect and then the effect exerted by the antibody in combination with irradiation on tumor growth can be investigated.The advantage of this concept lies in the fact that systemic stimulus (low doses of anti-CD95-antibodies) is highly intensified by local radiotherapy and only then initiates cell death. Since the anti-CD95-antibodies trigger apoptosis primarily in tumor endothelia, this approach could be employed not only for prostate cancer and melanomas, which have already been tested, but also for many other tumors.

[Accelerated hyperfractionated radiotherapy with concurrent chemotherapy in locally advanced nasopharyngeal carcinomas]. / Lokal fortgeschrittene Nasopharynxkarzinome. Hyperfraktioniert-akzelerierte Radiotherapie mit simultaner Chemotherapie.

BACKGROUND: The excellent results yielded by hyperfractionated and accelerated radiotherapy associated with concurrent chemotherapy in locally advanced oropharyngeal and hypopharyngeal carcinomas led to investigation of this therapeutic regimen in nasopharyngeal carcinomas also. METHODS: Thirty-five patients with stage III and IV nasopharyngeal carcinomas received accelerated hyperfractionated radiotherapy with concurrent chemotherapy (5-FU, mitomycin C + leucovorin). In the first 3 weeks of treatment five 2-Gy doses per week were delivered to the primary tumour and regional lymph nodes. The fractionation was then accelerated, with 1.4 Gy given twice daily until a total dose of 72 Gy had been administered. RESULTS: The overall objective response rate was 100%. The median follow-up period was 71 months. Salvage surgery of the lymph nodes was performed in 10 patients, revealing vital tumour tissue in 6 of these. The actuarial 5-year local control rate was 64% (95%CI: 47-81%), while overall actuarial survival at 5 years was 70% (95%CI: 53-86%). CONCLUSION: Hyperfractionated accelerated radiotherapy with concurrent chemotherapy is effective and feasible in locally advanced nasopharyngeal carcinoma.