Integration of radiation oncology teaching in medical studies by German medical faculties due to the new licensing regulations : An overview and recommendations of the consortium academic radiation oncology of the German Society for Radiation Oncology (DEGRO).

The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included.

Robotic stereotactic ablative radiotherapy for renal cell carcinoma in patients with impaired renal function.

BACKGROUND: Robotic stereotactic ablative radiotherapy (SABR) is currently under investigation as a noninvasive treatment option for patients with renal cell carcinoma (RCC). For radiation therapy of RCC, tumor motion and the need for high ablative doses while preserving the remaining renal parenchyma is a challenge. We aimed to analyze the safety and efficacy of robotic radiosurgery in RCC in a specific difficult subgroup of patients with impaired renal function. METHODS: We retrospectively identified all patients with RCC, treated with robotic SABR and motion compensation in our institution between 2012 and 2017. Either single fraction SABR of 24 or 25 Gy or 3 fractions of 12 Gy prescribed to the 70% isodose line was applied. Local control, overall survival, radiation side effects were evaluated together with renal function and tumor motion. RESULTS: We analyzed data of 13 lesions treated in 10 patients with clear cell RCC and a mean age of 70.5 ± 13.6 years (range: 48-87). Prior to SABR, 8 patients underwent previous complete and/or partial nephrectomy, 7 patients presented with chronic kidney disease ≥ stage 3. The median of minimum, mean and maximum planning target volume doses were 23.2, 29.5 and 35.0 Gy for single fraction and 24.4, 42.5 and 51.4 Gy for the three fractions regime. Persistent local control by robotic SABR was achieved in 9 out of 10 patients (92.3% of all lesions) within a median follow-up period of 27 month (range: 15-54). One patient underwent nephrectomy due to progressive disease and sufficient renal function of the contralateral kidney. Renal function remained stable with a mean estimated glomerular filtration rate (eGFR) of 51.3 ± 19.7 ml/min at baseline and 51.6 ± 25.8 ml/min at follow-up. The largest respiratory-induced tumor motion was seen in superior-inferior direction, compensated by the CyberKnife with mean targeting errors of maximal 2.2 mm. CONCLUSIONS: Robotic SABR is technically feasible for the treatment of RCC in preexisting kidney disease with good local tumor control at about 2 years follow-up. Robotic SABR with motion tracking offers a valid treatment option for patients, who are at increased risk for progression to end-stage renal disease due to partial nephrectomy or ablative techniques.

Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy-final results of the larynx organ preservation trial DeLOS-II.

Background: The German multicenter randomized phase II larynx organ preservation (LOP) trial DeLOS-II was carried out to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC). Patients and methods: Treatment-naïve patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF [docetaxel (T) and cisplatin (P) 75 mg/m2/day 1, 5-FU (F) 750 mg/m2/day days 1-5] followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with ≥30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24 months LFS above 35% in arm B. Results: Of 180 patients randomized (July 2007 to September 2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24 months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). One hundred and twenty-three early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A versus 80%/86.0% in B. The 24 months overall survival (OS) rates were 68.2% and 69.3%. Conclusions: Despite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24 months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS. Clinical trial information: NCT00508664.

Age-corrected hearing loss after chemoradiation in cervical cancer patients.

OBJECTIVE: This study aimed to evaluate subjective and objective hearing loss in cervical cancer patients after chemoradiation with cisplatin (mono). PATIENTS AND METHODS: A total of 51 cervical cancer patients with indication for chemoradiation were included. Pure tone and impedance audiometry were performed before and after chemoradiation. Hearing loss was scaled according to ASHA criteria. Subjective hearing was assessed with the Oldenburger Sentence Test. To consider age-dependent changes, hearing loss was corrected for age and the time interval between measurements. RESULTS: Median age at diagnosis was 46 years, 46% were active/former smokers (n = 24), 28 (54%) patients were never-smokers. Median total weekly cisplatin dose was 70 ± 14.2 mg. Cumulative doses of cisplatin during chemoradiation ranged between 115.2 and 400 mg cisplatin (mean 336.1 mg, median 342 ± 52.7 mg). The median interval between last chemotherapy and second audiometry was 320 ± 538 days (35-2262 days). Changes in hearing threshold ≥20 dB were experienced by 32/52 patients (62%) following chemoradiation, 55% of them for frequencies ≥6000 Hz. No statistically significant hearing loss remained after chemoradiation upon correction for age and time interval. Patients >40 years had a higher risk of hearing loss than younger patients. Objective data on hearing function did not correlate with subjective hearing loss and did not impair daily activity in any patient. CONCLUSION: Chemoradiation with cumulative cisplatin doses up to 400 mg did not lead to significant impairment of objective or subjective hearing. For cervical cancer patients undergoing chemoradiation, standard audiometry is not indicated.

Targeted next-generation sequencing identifies molecular subgroups in squamous cell carcinoma of the head and neck with distinct outcome after concurrent chemoradiation.

BACKGROUND: Based on epidemiological (HPV status, smoking habits) and clinical risk factors (T/N stage), three subgroups of patients suffering from locally advanced oropharyngeal carcinoma with significantly different outcome after concurrent chemoradiation (cCRTX) can be distinguished. Mutational profiling by targeted next-generation sequencing (NGS) might further improve risk stratification. PATIENTS AND METHODS: Patients with stage IV squamous cell carcinoma of the oropharynx and hypopharynx who had been enrolled in a randomized phase III trial (ARO-0401) comparing two regimens of cCRTX and from whom archival tumor specimens were available were included. The HPV status was determined by p16 immunostaining and detection of HPV DNA. Targeted NGS covering 45 genes frequently altered in squamous cell carcinoma of the head and neck (SCCHN) was applied for detection of non-synonymous somatic and germline mutations. Interference of mutational profiles with cCRTX efficacy was determined. RESULTS: The prognostic value of the 'Ang' risk model could be confirmed in the total biomarker study cohort (N = 175) as well as the patient subgroup for which mutational profiles could be established (N = 97). Mutations in genes involved in phosphoinositide 3-kinase (PI3K), receptor tyrosine kinase (RTK), and p53 signaling pathways were significantly enriched in the low- (N = 7), intermediate- (N = 20), and high-risk group (N = 70), respectively. Mutations in TP53 identified a subgroup of high-risk patients with dismal outcome after cCRTX. No prognostic relevance was observed for mutations in PI3K and RTK signaling pathways in the low- and intermediate-risk groups, respectively. Mutated NOTCH1 and two functional KDR germline variants (rs2305948, rs1870377) were associated with improved outcome in all risk groups. All genetic markers (TP53, NOTCH1, KDR) remained independent prognosticators of OS in the multivariate model. CONCLUSION: A potential of targeted NGS for risk classification of SCCHN cases beyond HPV status and clinical factors was demonstrated.

[The role of microRNAs in head and neck squamous cell carcinoma : Biomarkers for prognosis, therapy selection, and novel therapeutics]. / Die Bedeutung von MiRNA für das Kopf-Hals-Karzinom : Biomarker für Prognose, Therapieselektion und neue Therapeutika.

Despite recent advances in radiochemotherapy, treatment of locally advanced head and neck squamous cell carcinoma is still challenging, and survival rates have improved only slightly. This is due to the high frequency of metastases and local and/or regional tumor recurrences that have acquired radio- or chemoresistance. MiRNAs regulate diverse processes in tumorigenesis, metastasis, and therapy resistance in head and neck squamous cell carcinoma. Hence, miRNAs are highly valued in biomarker studies. Establishment of the miRNA profiles of oropharyngeal tumors enables personalized treatment selection, since expression of distinct miRNAs can predict the response to two different radiochemotherapy regimens. Development of novel miRNA therapeutics has a high clinical potential for further improving treatment of cancerous disease. The use of nanoparticles with distinct surface modifications as miRNA vectors permits prolonged bioavailability, high efficacy in tumor targeting, and low toxicity. Nevertheless, the efficacy of miRNA therapy has only been shown in animal models to date.

Detection of circulating tumor cells for prediction of recurrence after adjuvant chemoradiation in locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: The prognostic role of persistence of circulating tumor cells (CTC) after upfront tumor surgery for outcome of adjuvant (chemo)radiation in locally advanced squamous cell carcinoma of the head and neck (LASCCHN) was evaluated. PATIENTS AND METHODS: In this prospective study, peripheral blood samples from 144 patients with LASCCHN presenting after tumor resection for adjuvant treatment were analyzed for CTC. Their detection was correlated with tumor site, clinical risk factors, disease-free (DFS) and overall survival (OS). RESULTS: CTC were detected in 42 of 144 patients (29%). CTC detection was higher in cases with nodal involvement and in carcinomas located at the tonsil or base of tongue but was not influenced by age, smoking history, T stage, extracapsular lymph node extension, surgical margins or the human papillomavirus status. Overall, the presence of CTC was not predictive for OS or DFS. However, while in oropharyngeal carcinomas (OPC, n = 63), the detection of CTC was associated per trend with improved DFS [CTC+ versus CTC- (% of patients without evidence of disease at 2 years): 100% versus 79%; log rank: P = 0.059]; the reverse was observed for carcinomas from other sites (non-OPC, n = 81; CTC+ versus CTC-: 29% versus 75%; P = 0.001). In multivariate analysis, CTC remained an independent prognostic marker for DFS [hazard ratio (HR) 4.3, 95% confidence interval (CI) 1.7-10.9, P = 0.002] and OS (HR 2.7, 95% CI 1.2-6.3, P = 0.016) in non-OPC. CONCLUSIONS: Assessment of CTC in non-OPC should prove useful for identification of patients who benefit from treatment intensification. The basis for the good prognostic value of CTC in OPC has to be elucidated in future studies.

Image-guided stereotactic radiotherapy for patients with vestibular schwannoma. A clinical study.

INTRODUCTION: Local tumor control and functional outcome after linac-based stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for vestibular schwannoma (VS) were assessed. METHODS: In all, 250 patients with VS were treated: 190 patients with tumors < 2 cm diameter underwent SRS and 60 patients with tumors >2 to 3.5 cm underwent FSRT. Dose prescription for all cases with SRS (n = 190, 76 %) was 13.5 Gy. For FSRT, mainly two hypofractionated schedules (n = 60, 24 %) with either 7 fractions of 5 Gy (total dose: 35 Gy; n = 35) or 11 fractions of 3.8 Gy (total dose: 41.8 Gy; n = 16) were used. The primary endpoint was local tumor control. Secondary endpoints were symptomatic control and morbidity. RESULTS: The median follow-up was 33.8 months. The 3-year local tumor control was 88.9 %. Local control for SRS and FSRT was 88 and 92 %, respectively. For FSRT with 35 and 41.8 Gy, local control was 90 and 100 %, respectively. There were no acute reactions exceeding grade I. In 61 cases (24.4 % of the entire cohort), trigeminal neuralgia was reported prior to treatment. At last follow-up, 16.3 % (10/61) of those patients reported relief of pain. Regarding facial nerve dysfunction, 45 patients (18 %) presented with symptoms prior to RT. At the last follow-up, 13.3% (6/45) of those patients reported a relief of dysesthesia. CONCLUSION: Using SRS to treat small VS results in good local control rates. FSRT for larger lesions also seems effective. Severe treatment-related complications are not frequent. Therefore, image-guided stereotactic radiotherapy is an appropriate alternative to microsurgery for patients with VS.

Protection of quality and innovation in radiation oncology: the prospective multicenter trial QUIRO of DEGRO: evaluation of time, attendance of medical staff, and resources during radiotherapy with tomotherapy.

PURPOSE: The technical progress in radiotherapy in recent years has been tremendous. This also implies a change of human and time resources. However, there is a lack of data on this topic. Therefore, the DEGRO initiated several studies in the QUIRO project on this subject. The present publication focuses on results for tomotherapy systems and compares them with other IMRT techniques. METHODS: Over a period of several months, time allocation was documented using a standard form at two university hospitals. The required time for individual steps in the treatment planning process was recorded for all involved professional groups (physicist, technician, and physician) by themselves. The time monitoring at the treatment machines was performed by auxiliary employees (student research assistants). Evaluation of the data was performed for all recorded data as well as by tumor site. A comparison was made between the two involved institutions. RESULTS: A total of 1,691 records were analyzed: 148 from head and neck (H&N) tumors, 460 from prostate cancer, 136 from breast cancer, and 947 from other tumor entities. The mean value of all data from both centers for the definition of the target volumes for H&N tumors took a radiation oncology specialist 75 min, while a physicist needed for the physical treatment planning 214 min. For prostate carcinomas, the times were 60 and 147 min, respectively, and for the group of other entities 63 and 192 min, respectively. For the first radiation treatment, the occupancy time of the linear accelerator room was 31, 26, and 30 min for each entity (H&N, prostate, other entities, respectively). For routine treatments 22, 18, and 21 min were needed for the particular entities. Major differences in the time required for the individual steps were observed between the two centers. CONCLUSION: This study gives an overview of the time and personnel requirements in radiation therapy using a tomotherapy system. The most representative analysis could be done for the room occupancy times during treatment in both centers. Due to the partly small amount of data and differing planning workflows between the two centers, it is problematic to draw a firm conclusion with regard to planning times. Overall, the time required for the tomotherapy treatment and planning is slightly higher compared to other IMRT techniques.

Concurrent hyperfractionated accelerated radiotherapy with 5-FU and once weekly cisplatin in locally advanced head and neck cancer. The 10-year results of a prospective phase II trial.

PURPOSE: In this study, the acute toxicity and long-term outcome of a hyperfractionated accelerated chemoradiation regimen with cisplatin/5-fluorouracil (5-FU) in patients with locally advanced squamous cell carcinomas of head and neck were evaluated. PATIENTS AND METHODS: From 2000-2002, 38 patients with stage III (5.3 %) and stage IV (94.7 %) head and neck cancer were enrolled in a phase II study. Patients received hyperfractionated-accelerated radiotherapy with 72 Gy in 15 fractions of 2 Gy followed by 1.4 Gy twice daily with concurrent, continuous infusion 5-FU of 600 mg/m(2) on days 1-5 and 6 cycles of weekly cisplatin (30 mg/m(2)). Acute toxicities (CTCAEv2.0), locoregional control (LRC), metastases-free (MFS), and overall survival (OS) were analyzed and exploratively compared with the ARO 95-06 trial. RESULTS: Median follow-up was 11.4 years (95 % CI 8.6-14.2) and mean dose 71.6 Gy. Of the patients, 82 % had 6 (n = 15) or 5 (n = 16) cycles of cisplatin, 5 and 2 patients received 4 and 3 cycles, respectively. Grade 3 anemia, leukopenia, and thrombocytopenia were observed in 15.8, 15.8, and 2.6 %, respectively. Grade 3 mucositis in 50 %, grade 3 and 4 dysphagia in 55 and 13 %. The 2-, 5-, and 10-year LRC was 65, 53.6, and 48.2 %, the MFS was 77.5, 66.7, and 57.2 % and the OS 59.6, 29.2, and 15 %, respectively. CONCLUSION: Chemoradiation with 5-FU and cisplatin seems feasible and superior in terms of LRC and OS to the ARO 95-06C-HART arm at 2 years. However, this did not persist at the 5- and 10-year follow-ups.

Patterns of care in patients with cervical cancer 2012: results of a survey among German radiotherapy departments and out-patient health care centers.

BACKGROUND: Platinum-based primary or adjuvant chemoradiation is the treatment of choice for patients with cervical cancer. However, despite national guidelines and international recommendations, many aspects in diagnosis, therapy, and follow-up of patients with cervical cancer are not based on valid data. METHODS: To evaluate the current patterns of care for patients with cervical cancer in Germany, a questionnaire with 25 items was sent to 281 radiooncologic departments and out-patient health care centers. RESULTS: The response rate was 51%. While 87% of institutions treat 0-25 patients/year, 12 % treat between 26 and 50 and only 1% treat more than 50 patients/year. In 2011, the stage distribution of 1,706 treated cervical cancers were IB1, IB2, IIA, IIB, IIIA/IIIB, and IV in 11, 12, 11, 22, 28, and 16%, respectively. CT (90%) and MRI (86%) are mainly used as staging procedures in contrast to PET-CT with 14%. Interestingly, 27% of institutions advocate surgical staging prior to chemoradiation. In the majority of departments 3D-based (70%) and intensity-modulated radiotherapy (76%) are used for percutaneous radiation, less frequently volumetric arc techniques (26%). Nearly all colleagues (99.3%) apply conventional fractioning of 1.8-2 Gy for external-beam radiotherapy, in 19% combined with a simultaneous integrated boost. Cisplatinum mono is used as a radiosensitizer with 40 mg/m(2) weekly by 90% of radiooncologists. For boost application in the primary treatment, HDR (high-dose rate) brachytherapy is the dominant technique (84%). In patients after radical hysterectomy pT1B1/1B2, node negative and resection in sound margins adjuvant chemoradiation is applied due to the occurrence of 1-4 other risk factors in 16-97%. There is a broad spectrum of recommended primary treatment strategies in stages IIB and IVA. CONCLUSION: Results of the survey underline the leading role but also differences in the use of chemoradiation in the treatment of cervical cancer patients in Germany.

The QUIRO Study (assurance of quality and innovation in radiooncology): methodology, instruments and practices.

PURPOSE: The QUIRO study aimed to establish a secure level of quality and innovation in radiation oncology. Over 6 years, 27 specific surveys were conducted at 24 radiooncological departments. In all, 36 renowned experts from the field of radiation oncology (mostly head physicians and full professors) supported the realization of the study. METHODS: A salient feature of the chosen methodological approach is the "process" as a means of systematizing diversified medical-technical procedures according to standardized criteria. On the one hand, "processes" as a tool of translation are adapted for creating and transforming standards into concrete clinical and medical actions; on the other hand, they provide the basis for standardized instruments and methods to determine the required needs of physicians, staff, and equipment. In the foreground of the collection and measurement of resource requirements were the processes of direct service provision which were subdivided into modules for reasons of clarity and comprehensibility. Overhead tasks (i.e., participation in quality management) were excluded from the main study and examined in a separate survey with appropriate methods. RESULTS: After the exploration of guidelines, tumor- or indication-specific examination and treatment processes were developed in expert workshops. Moreover, those specific modules were defined which characterize these entities and indications in a special degree. Afterwards, these modules were compiled according to their time and resources required in the "reference institution", i.e., in specialized and as competent recognized departments (mostly from the university area), by various suitable survey methods. CONCLUSION: The significance of the QUIRO study and the validity of the results were optimized in a process of constant improvements and comprehensive checks. As a consequence, the QUIRO study yields representative results concerning the resource requirement for specialized, qualitatively and technologically highly sophisticated radiooncologic treatment in Germany.

Protection of quality and innovation in radiation oncology: the prospective multicenter trial the German Society of Radiation Oncology (DEGRO-QUIRO study). Evaluation of time, attendance of medical staff, and resources during radiotherapy with IMRT.

BACKGROUND: A number of national and international societies published recommendations regarding the required equipment and manpower assumed to be necessary to treat a number of patients with radiotherapy. None of these recommendations were based on actual time measurements needed for specific radiotherapy procedures. The German Society of Radiation Oncology (DEGRO) was interested in substantiating these recommendations by prospective evaluations of all important core procedures of radiotherapy in the most frequent cancers treated by radiotherapy. The results of the examinations of radiotherapy with intensity-modulated radiation therapy (IMRT) in patients with different tumor entities are presented in this manuscript. PATIENTS, MATERIAL, AND METHODS: Four radiation therapy centers [University Hospital of Marburg, University Hospital of Giessen, University Hospital of Berlin (Charité), Klinikum rechts der Isar der Technischen Universität München] participated in this prospective study. The workload of the different occupational groups and room occupancies for the core procedures of radiotherapy were prospectively documented during a 2-month period per center and subsequently statistically analyzed. RESULTS: The time needed per patient varied considerably between individual patients and between centers for all the evaluated procedures. The technical preparation (contouring of target volume and organs at risk, treatment planning, and approval of treatment plan) was the most time-consuming process taking 3 h 54 min on average. The time taken by the medical physicists for this procedure amounted to about 57%. The training part of the preparation time was 87% of the measured time for the senior physician and resident. The total workload for all involved personnel comprised 74.9 min of manpower for the first treatment, 39.7 min for a routine treatment with image guidance, and 22.8 min without image guidance. The mean room occupancy varied between 10.6 min (routine treatment without image guidance) and 23.7 min (first treatment with image guidance). CONCLUSION: The prospective data presented here allow for an estimate of the required machine time and manpower needed for the core procedures of radiotherapy in an average radiation treatment with IMRT. However, one should be aware that a number of necessary and time-consuming activities were not evaluated in the present study.

Design and evaluation of a deep learning-based automatic segmentation of maxillary and mandibular substructures using a 3D U-Net.

Background: Current segmentation approaches for radiation treatment planning in head and neck cancer patients (HNCP) typically consider the entire mandible as an organ at risk, whereas segmentation of the maxilla remains uncommon. Accurate risk assessment for osteoradionecrosis (ORN) or implant-based dental rehabilitation after radiation therapy may require a nuanced analysis of dose distribution in specific mandibular and maxillary segments. Manual segmentation is time-consuming and inconsistent, and there is no definition of jaw subsections. Materials and methods: The mandible and maxilla were divided into 12 substructures. The model was developed from 82 computed tomography (CT) scans of HNCP and adopts an encoder-decoder three-dimensional (3D) U-Net structure. The efficiency and accuracy of the automated method were compared against manual segmentation on an additional set of 20 independent CT scans. The evaluation metrics used were the Dice similarity coefficient (DSC), 95% Hausdorff distance (HD95), and surface DSC (sDSC). Results: Automated segmentations were performed in a median of 86 s, compared to manual segmentations, which took a median of 53.5 min. The median DSC per substructure ranged from 0.81 to 0.91, and the median HD95 ranged from 1.61 to 4.22. The number of artifacts did not affect these scores. The maxillary substructures showed lower metrics than the mandibular substructures. Conclusions: The jaw substructure segmentation demonstrated high accuracy, time efficiency, and promising results in CT scans with and without metal artifacts. This novel model could provide further investigation into dose relationships with ORN or dental implant failure in normal tissue complication prediction models.

Oligometastases: the new paradigm and options for radiotherapy. A critical review.

Traditional oncology distinguishes between two separate and incommensurable states in the evolution of solid malignancies: the localized disease, which is curable; and the disseminated status, which is per se palliative. Recently, a huge body of evidence suggests a fundamental change in the understanding of cancer, indicating an intermediate state in the trajectory of solid malignancies: the oligometastatic state. The following review will critically analyse existing hypotheses and facts from the basic sciences and try to contextualize it in regard to the clinical evidence available to date. Consecutively, it will try to draw possible clinical consequences for application of radiotherapy in this specific clinical scenario.

Blisters - an unusual effect during radiotherapy.

The skin reaction to radiation is regularly monitored in order to detect enhanced radiosensitivity of the patient, unexpected interactions (e.g. with drugs) or any inadvertent overdosage. It is important to distinguish secondary disease from radiation reaction to provide adequate treatment and to avoid unnecessary discontinuation of radiotherapy. A case of bullous eruption or blisters during radiotherapy of the breast is presented. Differential diagnoses bullous pemphigoid, pemphigus vulgaris, and bullous impetigo are discussed and treatment described.

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.

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.

The presence of circulating tumor cells (CTCs) correlates with lymph node metastasis in nonresectable squamous cell carcinoma of the head and neck region (SCCHN).

BACKGROUND: The mechanisms regulating tumor cell dissemination in locally advanced squamous cell carcinoma of the head and neck region (SCCHN) are largely unresolved. We assessed the frequency of circulating tumor cells (CTCs), their association with clinicopathologic parameters and their kinetics during radiochemotherapy. PATIENTS AND METHODS: Peripheral blood samples from 42 patients with locally advanced SCCHN were included. CTCs were detected using flow cytometric analysis of CD45-epithelial cell adhesion molecule+cytokeratin+ cells and results were validated by nested RT-PCR analysis of circulating epidermal growth factor receptor transcripts. The association between the presence of CTCs and T stage, tumor volume, N stage and human papillomavirus status was evaluated. The influence of radiochemotherapy on CTC numbers was determined. RESULTS: CTCs were detected in 18 of 42 SCCHN patients (43%), with a mean ± standard deviation of 1.7 ± 0.9 CTCs per 3.75 ml blood. We observed no significant correlation between the presence of CTCs and T stage or tumor volume. However, a nodal stage of N2b or higher was associated with higher frequency of CTCs. Though concurrent radiochemotherapy reduced their frequency, CTCs persisted during treatment in 20% of cases. CONCLUSIONS: Detection of CTCs correlates with regional metastasis in inoperable SCCHN. Further follow-up is needed to evaluate the prognostic significance of CTC detection, in addition to clinical staging of lymph nodes, for regional or distant recurrence.

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.