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Biomarkers with relevance for loco-regional therapy are needed in human papillomavirus negative aka HPV(-) head and neck squamous cell carcinoma (HNSCC). Based on the premise that DNA methylation pattern is highly conserved, we sought to develop a reliable and robust methylome-based classifier identifying HPV(-) HNSCC patients at risk for loco-regional recurrence (LR) and all-event progression after postoperative radiochemotherapy (PORT-C). The training cohort consisted of HPV-DNA negative HNSCC patients (n = 128) homogeneously treated with PORT-C in frame of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG) multicenter biomarker trial. DNA Methylation analysis was performed using Illumina 450 K and 850 K-EPIC microarray technology. The performance of the classifier was integrated with a series of biomarkers studied in the training set namely hypoxia-, 5-microRNA (5-miR), stem-cell gene-expression signatures and immunohistochemistry (IHC)-based immunological characterization of tumors (CD3/CD8/PD-L1/PD1). Validation occurred in an independent cohort of HPV(-) HNSCC patients, pooled from two German centers (n = 125). We identified a 38-methylation probe-based HPV(-) Independent Classifier of disease Recurrence (HICR) with high prognostic value for LR, distant metastasis and overall survival (P < 10 -9 ). HICR remained significant after multivariate analysis adjusting for anatomical site, lymph node extracapsular extension (ECE) and size (T-stage). HICR high-risk tumors were enriched for younger patients with hypoxic tumors (15-gene signature) and elevated 5-miR score. After adjustment for hypoxia and 5-miR covariates, HICR maintained predicting all endpoints. HICR provides a novel mean for assessing the risk of LR in HPV(-) HNSCC patients treated with PORT-C and opens a new opportunity for biomarker-assisted stratification and therapy adaptation in these patients., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Radiochemotherapy (RCT) has been shown to induce changes in immune cell homeostasis which might affect antitumor immune responses. In the present study, we aimed to compare the composition and kinetics of major lymphocyte subsets in the periphery of patients with non-locoregional recurrent (n = 23) and locoregional recurrent (n = 9) squamous cell carcinoma of the head and neck (SCCHN) upon primary RCT., Methods: EDTA-blood of non-locoregional recurrent SCCHN patients was collected before (t0), after application of 20-30 Gy (t1), in the follow-up period 3 (t2) and 6 months (t3) after RCT. In patients with locoregional recurrence blood samples were taken at t0, t1, t2 and at the time of recurrence (t5). EDTA-blood of age-related, healthy volunteers (n = 22) served as a control (Ctrl). Major lymphocyte subpopulations were phenotyped by multiparameter flow cytometry., Results: Patients with non-recurrent SCCHN had significantly lower proportions of CD19 + B cells compared to healthy individuals before start of any therapy (t0) that dropped further until 3 months after RCT (t2), but reached initial levels 6 months after RCT (t3). The proportion of CD3 + T and CD3 + /CD4 + T helper cells continuously decreased between t0 and t3, whereas that of CD8 + cytotoxic T cells and CD3 + /CD56 + NK-like T cells (NKT) gradually increased in the same period of time in non-recurrent patients. The percentage of CD4 + /CD25 + /FoxP3 + regulatory T cells (Tregs) decreased directly after RCT, but increased above initial levels in the follow-up period 3 (t2) and 6 (t3) months after RCT. Patients with locoregional recurrence showed similar trends with respect to B, T cells and Tregs between t0 and t5. CD4 + T helper cells remained stably low between t0 and t5 in patients with locoregional recurrence compared to Ctrl. NKT/NK cell subsets (CD56 + /CD69 + , CD3 - /CD56 + , CD3 - /CD94 + , CD3 - /NKG2D + , CD3 - /NKp30 + , CD3 - /NKp46 + ) increased continuously up to 6 months after RCT (t0-t3) in patients without locoregional recurrence, whereas in patients with locoregional recurrence, these subsets remained stably low until time of recurrence (t5)., Conclusion: Monitoring the kinetics of lymphocyte subpopulations especially activatory NK cells before and after RCT might provide a clue with respect to the development of an early locoregional recurrence in patients with SCCHN. However, studies with larger patient cohorts are needed., Trial Registration: Observational Study on Biomarkers in Head and Neck Cancer (HNprädBio), NCT02059668. Registered on 11 February 2014, https://clinicaltrials.gov/ct2/show/NCT02059668 ., (© 2021. The Author(s).)

Background: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other., Methods: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies)., Findings: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRT P ) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRT P (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (IC TaxPF -LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and IC TaxPF followed by CLRT (80%)., Interpretation: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or IC TaxPF -CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer., Fundings: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC., Competing Interests: Declaration of interests CP reports a grant from Fondation ARC during the conduct of the study. J-PP reports grants from Ligue National Contre le Cancer, during the conduct of the study. AA reports grants from Ligue Contre le Cancer and Programme Hospitalier de Recherche Clinique en Cancérologie–Institut National du Cancer, during the conduct of the study; grants from F Hoffmann-La Roche, and from the French Radiation and Oncology Group for Head and Neck (GORTEC), outside the submitted work. EEV and QTL report personal fees AbbVie, Amgen, AstraZeneca, Biolumina, BMS, Celgene, Eli Lilly, EMD Serono, Genentech, Merck, Regeneron, Novartis for EEV, and Grail for QTL outside the submitted work. J-WL reports grants from the US National Institutes of Health, during the conduct of the study. JJCH reports other payment from Sanofi Aventis during the conduct of the study; payment for an advisory role and conferences from Merck, Bristol Myers Squibb, Merck Sharp & Dohme España, Novartis, and Roche Pharma outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Detection of patients with esophageal squamous cell carcinoma (ESCC) who do not benefit from standard chemoradiation (CRT) is an important medical need. Radiomics using 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a promising approach. In this retrospective study of 184 patients with locally advanced ESCC. 152 patients from one center were grouped into a training cohort (n = 100) and an internal validation cohort (n = 52). External validation was performed with 32 patients treated at a second center. Primary endpoint was disease-free survival (DFS), secondary endpoints were overall survival (OS) and local control (LC). FDG-PET radiomics features were selected by Lasso-Cox regression analyses and a separate radiomics signature was calculated for each endpoint. In the training cohort radiomics signatures containing up to four PET derived features were able to identify non-responders in regard of all endpoints (DFS p < 0.001, LC p = 0.003, OS p = 0.001). After successful internal validation of the cutoff values generated by the training cohort for DFS (p = 0.025) and OS (p = 0.002), external validation using these cutoffs was successful for DFS (p = 0.002) but not for the other investigated endpoints. These results suggest that pre-treatment FDG-PET features may be useful to detect patients who do not respond to CRT and could benefit from alternative treatment.

Purpose: [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) parameters have shown prognostic value in nasopharyngeal carcinomas (NPC), mostly in monocenter studies. The aim of this study was to assess the prognostic impact of standard and novel PET parameters in a multicenter cohort of patients., Methods: The established PET parameters metabolic tumor volume (MTV), total lesion glycolysis (TLG) and maximal standardized uptake value (SUVmax) as well as the novel parameter tumor asphericity (ASP) were evaluated in a retrospective multicenter cohort of 114 NPC patients with FDG-PET staging, treated with (chemo)radiation at 8 international institutions. Uni- and multivariable Cox regression and Kaplan-Meier analysis with respect to overall survival (OS), event-free survival (EFS), distant metastases-free survival (FFDM), and locoregional control (LRC) was performed for clinical and PET parameters., Results: When analyzing metric PET parameters, ASP showed a significant association with EFS (p = 0.035) and a trend for OS (p = 0.058). MTV was significantly associated with EFS (p = 0.026), OS (p = 0.008) and LRC (p = 0.012) and TLG with LRC (p = 0.019). TLG and MTV showed a very high correlation (Spearman's rho = 0.95), therefore TLG was subesequently not further analysed. Optimal cutoff values for defining high and low risk groups were determined by maximization of the p-value in univariate Cox regression considering all possible cutoff values. Generation of stable cutoff values was feasible for MTV (p<0.001), ASP (p = 0.023) and combination of both (MTV+ASP = occurrence of one or both risk factors, p<0.001) for OS and for MTV regarding the endpoints OS (p<0.001) and LRC (p<0.001). In multivariable Cox (age >55 years + one binarized PET parameter), MTV >11.1ml (hazard ratio (HR): 3.57, p<0.001) and ASP > 14.4% (HR: 3.2, p = 0.031) remained prognostic for OS. MTV additionally remained prognostic for LRC (HR: 4.86 p<0.001) and EFS (HR: 2.51 p = 0.004). Bootstrapping analyses showed that a combination of high MTV and ASP improved prognostic value for OS compared to each single variable significantly (p = 0.005 and p = 0.04, respectively). When using the cohort from China (n = 57 patients) for establishment of prognostic parameters and all other patients for validation (n = 57 patients), MTV could be successfully validated as prognostic parameter regarding OS, EFS and LRC (all p-values <0.05 for both cohorts)., Conclusions: In this analysis, PET parameters were associated with outcome of NPC patients. MTV showed a robust association with OS, EFS and LRC. Our data suggest that combination of MTV and ASP may potentially further improve the risk stratification of NPC patients., Competing Interests: Dr. Amthauer reports personal fees from SIRTEX Medical Europe, grants from GE Healthcare, grants and personal fees from Novartis, outside the submitted work; All other authors have declared that no competing interests exist. We ensure that Dr Amthauer´s fees and grants do not alter our adherence to PLOS ONE policies on sharing data and materials.

This article compares the expression and applicability of biomarkers, from single genes and gene signatures, identified in patients with locally advanced head and neck squamous cell carcinoma using the GeneChip Human Transcriptome Array 2.0, nCounter, and real-time PCR analyses. Two multicenter, retrospective cohorts of patients with head and neck squamous cell carcinoma from the German Cancer Consortium Radiation Oncology Group who received postoperative radiochemotherapy or primary radiochemotherapy were considered. Real-time PCR was performed for a limited number of 38 genes of the cohort who received postoperative radiochemotherapy only. Correlations between the methods were evaluated by the Spearman rank correlation coefficient. Patients were stratified based on the expression of putative cancer stem cell markers, hypoxia-associated gene signatures, and a previously developed seven-gene signature. Locoregional tumor control was compared between these patient subgroups using log-rank tests. Gene expressions obtained from nCounter analyses were moderately correlated to GeneChip analyses (median ρ = approximately 0.68). A higher correlation was obtained between nCounter analyses and real-time PCR (median ρ = 0.84). Significant associations with locoregional tumor control were observed for most of the considered biomarkers evaluated by GeneChip and nCounter analyses. In general, all applied biomarkers (single genes and gene signatures) classified approximately 70% to 85% of the patients similarly. Overall, gene signatures seem to be more robust and had a better transferability among different measurement methods., (Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: This article aims to provide an overview of the role of combined radiation and androgen deprivation (ADT) therapy in patients with intermediate-risk prostate cancer., Materials and Methods: The current German, European, and NCCN (National Comprehensive Cancer Network) guidelines as well as relevant literature in the PubMed database which provide information on sub-classification within the intermediate-risk group and the use of ADT in terms of oncological outcome were reviewed., Results: Different recommendations for risk-group assessment of patients with localized prostate cancer are available. Subdivision of intermediate risk into a favorable and an unfavorable group seems to be justified to allow for a more individualized therapy in a quite heterogenous group of patients. So far, multiple randomized trials have shown a benefit when radiation therapy (RT) is combined with ADT. The use of dose-escalated RT without ADT also appears to be an adequate therapy associated with a very low rate of cancer-specific deaths. Therefore, taking into account the increased rate of toxicity associated with ADT, dose-escalated RT alone might be justified, especially in favorable intermediate-risk patients., Conclusion: Dose-escalated RT alone appears to be an appropriate treatment in favorable intermediate-risk patients. Addition of short course ADT (4-6 months) might improve outcomes in unfavorable intermediate-risk patients.

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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.

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.

Background: To determine the influence of baseline laboratory values on treatment outcome in patients with locally advanced head and neck cancer (HNSCC)., Methods: Data of the randomized trials ARO 95 -06 (n = 384) and SAKK 10 /94 (n = 224) were pooled for a total sample size of 608 patients. Haemoglobin (Hb) and creatinine (Cr) were available at baseline and their association with locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), cancer-specific survival (CSS), and overall survival (OS) was analyzed using univariable and multivariable Cox regression models., Results: A total of 580 and 564 patients were available with baseline Hb and Cr values in the pooled analysis. Univariable analyses revealed that lower baseline Hb values were significantly associated with decreased LRRFS, DMFS, CSS and OS. This effect remained significant for OS when the treatment arms (radiotherapy [RT] alone vs. chemoradiation [CRT]) were analyzed separately. Higher baseline Cr was associated with improved OS in the pooled analysis. Interestingly, the prognostic value of baseline Cr appeared to be limited to the subgroup of 284 patients who were treated with CRT. In the multivariable Cox regression model lower baseline Hb remained associated with decreased OS both in the patients who received CRT (HR 0.79, 95 % CI 0.66-0.94, p = 0.009) and in those patients who underwent RT alone (HR 0.67, 95 % CI 0.58-0.78, p < 0.001). Increased baseline Cr remained significantly associated with improved OS in patients who underwent CRT (HR 0.79, 95 % CI 0.69-0.92, p = 0.002) but not in those patients who underwent RT alone., Conclusions: An association between lower baseline Hb and inferior treatment outcome was confirmed. Baseline Cr was introduced as a prognosticator of outcome after CRT for locally advanced HNSCC.

Background: Prostate cancer has the highest incidence of any type of cancer in Germany; an estimated 67 000 new diagnoses of prostate cancer will be made in 2016. In the current German S3 guideline for the treatment of prostate cancer, radiotherapy-sometimes in combination with androgen deprivation therapy (ADT)-is one of the two recommended options for treatment with curative intent (the other is radical prostatectomy). There have been many publications on this subject, yet it is still often unclear in routine practice how ADT should be administered, and for how long., Methods: This review is based on publications retrieved by a selective literature search, with special attention to controlled trials., Results: For low risk patients, radiotherapy without ADT is indicated (evidence level 1). Patients with localized prostate cancer and an intermediate risk benefit from radiotherapy combined with a four-to-six-month course of ADT. In this situation, a higher radiation dose might be an effective substitute for ADT (evidence level 1-2). For patients at high risk, radiotherapy combined with long-term hormonal treatment is the standard therapy, as it significantly improves all oncological end points (evidence level 1). For example, in the largest randomized and controlled trial, this form of treatment reduced cancer-specific mortality from 19% to 9% . Higher radiation doses of 66-74 Gy and longer ADT can improve local control at the cost of increased urethral toxicity., Conclusion: Androgen deprivation combined with external beam radiotherapy is a curative standard option for patients with prostate cancer who are at high risk of recurrence. The modern radiotherapeutic techniques that are now available, such as intensity-modulated radiotherapy, enable a further improvement of the risk/benefit ratio.

Aim: To compare simultaneous integrated boost plans for intensity-modulated proton therapy (IMPT), helical tomotherapy (HT), and RapidArc therapy (RA) for patients with head and neck cancer., Patients and Methods: A total of 20 patients with squamous cell carcinoma of the head and neck received definitive chemoradiation with bilateral (n = 14) or unilateral (n = 6) neck irradiation and were planned using IMPT, HT, and RA with 54.4, 60.8, and 70.4 GyE/Gy in 32 fractions. Dose distributions, coverage, conformity, homogeneity to planning target volumes (PTV)s and sparing of organs at risk and normal tissue were compared., Results: All unilateral and bilateral plans showed excellent PTV coverage and acceptable dose conformity. For unilateral treatment, IMPT delivered substantially lower mean doses to contralateral salivary glands (< 0.001-1.1 Gy) than both rotational techniques did (parotid gland: 6-10 Gy; submandibular gland: 15-20 Gy). Regarding the sparing of classical organs at risk for bilateral treatment, IMPT and HT were similarly excellent and RA was satisfactory., Conclusion: For unilateral neck irradiation, IMPT may minimize the dry mouth risk in this subgroup but showed no advantage over HT for bilateral neck treatment regarding classical organ-at-risk sparing. All methods satisfied modern standards regarding toxicity and excellent target coverage for unilateral and bilateral treatment of head and neck cancer at the planning level.

Purpose: The Uterus-11 trial was designed to evaluate the role of surgical staging in patients with cervical cancer before primary chemoradiation therapy (CRT). The present report provides the toxicity data stratified by the treatment arm and technique., Methods and Materials: A total of 255 patients with carcinoma of the uterine cervix (International Federation of Gynecology and Obstetrics stage IIB-IVA) were randomized to either surgical staging followed by CRT (arm A) or clinical staging followed by CRT (arm B). Patients with para-aortic metastases underwent extended field radiation therapy (RT). Brachytherapy was mandatory. The present report presents the acute therapy-related toxicities stratified by treatment arm and radiation technique., Results: A total of 240 patients were eligible (n=121 in arm A; n=119 in arm B). Of the 240 patients, 236 (98.3%) underwent external beam RT with a median total dose of 50.4 Gy. The mean treatment duration was 53 days. Of the patients, 60% underwent intensity modulated RT (IMRT). A total of 234 patients (97.5%) underwent chemotherapy, and 231 (96.3%) underwent brachytherapy, with a median single dose of 6 Gy covering the tumor to a median nominal total dose of 28 Gy. Treatment was well tolerated, with 0% grade ≥3 genitourinary and gastrointestinal toxicity, 6% grade 3 nausea, 3% grade 3 vomiting, and <2% grade 3 diarrhea. More patients after surgical staging experienced grade 2 anemia (54.3% in arm A vs 45.3% in arm B; P=.074) and grade 2 leukocytopenia (41.4% vs 31.6%; P=.56). Of the patients who received IMRT versus a 3-dimensional technique, 65.3% versus 33.7% presented with grade 2 anemia. Grade 3 gastrointestinal and grade 2 bladder toxicity were significantly reduced with the use of IMRT., Conclusions: The incidence and severity of acute therapy-related toxicity compared favorably with those from other randomized trials. Excellent adherence to treatment and treatment quality was achieved compared with patterns of care analyses. Surgical staging led to a doubled number of patients treated with extended field RT. The question of whether surgical staging is beneficial in the context of primary CRT requires further study., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aim: The purpose of this work was to compare sequential (SeqB) versus simultaneous integrated boost (SIB) radiotherapy plans delivered with volumetric modulated arc therapy (VMAT) for patients with locally advanced squamous cell cancer of the head and neck (HNSCC)., Patients and Methods: SeqB and SIB plans using VMAT for 10 HNSCC patients given definitive chemoradiation were generated and analysed for differences in dose distribution, coverage, conformity and homogeneity to the planning target volumes (PTV) 1-3 and sparing of organs at risk (OAR)., Results: The mean delineated volumes ± standard deviations were 137.7 ± 44.8, 351.3 ± 83.9 and 895.6 ± 120.5 cm3 for PTV1-3. The mean volumes encompassed by the corresponding 95 % isodoses were 281 (+ 110 %) ± 73.4, 712.2 (+ 115 %) ± 146.4 and 1381.1 (+ 54 %) ± 217.3 cm3 with SeqB and 138.2 (+ 7 %) ± 40.1, 380.4 (+ 11 %) ± 91.9 and 1057.3 (+ 21 %) ± 161.4 cm3 with SIB for PTV1-3, respectively. Both strategies achieved excellent PTV coverage. SeqB provided significantly better coverage of PTV1 and 3, worse conformity for PTV1-3 and a higher mean dose than prescribed (111-115 %) to PTV2 and 3 (p ≤ 0.007). Both strategies provided satisfactory OAR sparing., Conclusion: This study showed significant dosimetric differences with potential clinical relevance between two VMAT boost strategies regarding coverage, conformity and dose to the PTVs. SIB might cause less toxicity. A clinical phase III/IV trial endorsed by the German Head and Neck Clinical Trials Group (IAG-KHT) will evaluate differences in acute/late toxicity as well as in locoregional recurrences between the two boost techniques.

Background and Purpose: The purpose of this work was to evaluate the use of extended-field chemoradiation (EFRT) with concomitant chemotherapy in patients with histologically confirmed para-aortic metastases after laparoscopic para-aortic and pelvic lymphadenectomy (LAE) with regard to oncologic results and treatment-related toxicity., Patients and Methods: A total of 44 women with squamous cell carcinoma (82 %) and adenocarcinoma (18 %) of the cervix in FIGO stages IIA (n = 3), IIB (n = 29); IIIB (n = 9), and IVA (n = 3) and histologically proven para-aortic metastases underwent EFRT and chemotherapy. Laparoscopic LAE was performed in 40 patients. Patients underwent chemoradiation with conventional fractionation of 1.8-50.4 Gy to the para-aortic and pelvic region. In addition, MRI-guided brachytherapy was performed to the cervix with 5-6 single doses of 5 Gy for a total dose of 25-30 Gy., Results: The mean number of harvested lymph nodes was 17 in the pelvic as well as para-aortic regions, respectively. Laparoscopic intervention did not delay chemoradiation. Follow-up was 6-76 months (mean 25.1 months). There was no grade 4 or 5 acute radiation toxicity. In all, 8, 4, and 11 % grade 1, 2, and 3 gastrointestinal late toxicities and 7, 11, and 19 % grade 1, 2 and 3 genitourinary late toxicities were recorded. Despite the excellent locoregional (pelvic) control rates of 89.1 and 82.8 % after 2 and 5 years, respectively, the overall survival rates were 68.4 and 54.1 % after 2 and 5 years, respectively. Of the 44 patients, 43 remained tumor free in the para-aortic region., Conclusion: In patients with proven para-aortic disease, excellent pelvic and para-aortic control could be achieved by laparoscopic LAE followed by EFRT. More than half of the patients were long-term survivors. The high risk of distant metastases should be addressed by further improving systemic treatment.

Purpose: To report the long-term results of the ARO 95-06 randomized trial comparing hyperfractionated accelerated chemoradiation with mitomycin C/5-fluorouracil (C-HART) with hyperfractionated accelerated radiation therapy (HART) alone in locally advanced head and neck cancer., Patients and Methods: The primary endpoint was locoregional control (LRC). Three hundred eighty-four patients with stage III (6%) and IV (94%) oropharyngeal (59.4%), hypopharyngeal (32.3%), and oral cavity (8.3%) cancer were randomly assigned to 30 Gy/2 Gy daily followed by twice-daily 1.4 Gy to a total of 70.6 Gy concurrently with mitomycin C/5-FU (C-HART) or 16 Gy/2 Gy daily followed by twice-daily 1.4 Gy to a total dose of 77.6 Gy alone (HART). Statistical analyses were done with the log-rank test and univariate and multivariate Cox regression analyses., Results: The median follow-up time was 8.7 years (95% confidence interval [CI]: 7.8-9.7 years). At 10 years, the LRC rates were 38.0% (C-HART) versus 26.0% (HART, P=.002). The cancer-specific survival and overall survival rates were 39% and 10% (C-HART) versus 30.0% and 9% (HART, P=.042 and P=.049), respectively. According to multivariate Cox regression analysis, the combined treatment was associated with improved LRC (hazard ratio [HR]: 0.6 [95% CI: 0.5-0.8; P=.002]). The association between combined treatment arm and increased LRC appeared to be limited to oropharyngeal cancer (P=.003) as compared with hypopharyngeal or oral cavity cancer (P=.264)., Conclusions: C-HART remains superior to HART in terms of LRC. However, this effect may be limited to oropharyngeal cancer patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Young patients with cervical cancer who undergo chemoradiation might be interested in fertility preservation, not only dependent upon the use of a gestational carrier as maybe achieved by the use of ovarian transposition and cryo-conservation of oocytes or ovarian tissue, but may prefer to carry pregnancy to term after cancer treatment. The latter approach is a non-established concept needing both modern radiation therapy approaches as well as modifications -if at all possible- in current recommendations for target volume delineation to spare dose to the unaffected uterus. Future strategies to serve selected patients in this respect should only be conducted in prospective clinical evaluations and are critically discussed in this article.

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.

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.

Purpose: The numbers of circulating tumor cells (CTCs) and their expression/activation of epidermal growth factor receptor (EGFR) during the course of combined chemo- or bioradiotherapy regimens as potential biomarkers of treatment efficacy in squamous cell carcinoma of the head and neck (SCCHN) were determined., Methods and Materials: Peripheral blood samples from SCCHN patients with locally advanced stage IVA/B disease who were treated with concurrent radiochemotherapy or induction chemotherapy followed by bioradiation with cetuximab were included in this study. Using flow cytometry, the absolute number of CTCs per defined blood volume as well as their expression of EGFR and its phosphorylated form (pEGFR) during the course of treatment were assessed., Results: Before treatment, we detected ≥1 CTC per 3.75 mL blood in 9 of 31 patients (29%). Basal expression of EGFR was detected in 100% and pEGFR in 55% of the CTC+ cases. The frequency of CTC detection was not influenced by induction chemotherapy. However, the number of CTC+ samples significantly increased after radiotherapy. This radiation-induced increase in CTC numbers was less pronounced when radiotherapy was combined with cetuximab compared to its combination with cisplatin/5-fluorouracil. The former treatment regimen was also more effective in reducing pEGFR expression in CTCs., Conclusions: Definitive radiotherapy regimens of locally advanced SCCHN can increase the number of CTCs and might thus contribute to a systemic spread of tumor cells. Further studies are needed to evaluate the predictive value of the radiation-induced increase in CTC numbers and the persistent activation of the EGFR signalling pathway in individual CTC+ cases., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To proof feasibility of hydrogel application in patients with advanced cervical cancer undergoing chemo-radiation in order to reduce rectal toxicity from external beam radiation as well as brachytherapy., Material and Methods: Under transrectal sonographic guidance five patients with proven cervical cancer underwent hydro gel (20 cc) instillation into the tip of rectovaginal septum adherent to posterior part of the visible cervical tumor. Five days after this procedure all patients underwent T2 weighted transversal and sagittal MRI for brachytherapy planning. MRI protocol included T2 weighted fast spin echo (FSE) imaging in sagittal, coronal and para-axial orientation using an 1.5 Tesla MRI. Separation of anterior rectal wall and cervix was documented., Results: Hydrogel application was uneventful in all patients and no toxicity was reported. Separation ranged from 7 to 26 mm in width (median 10 mm). The length of the separation varied between 18 and 38 mm (median 32 mm). In all patients displacement was seen in the posterior vaginal fornix, and/or at the deepest part of uterine cervix depending on the extension of the cul-de-sac in correlation to the posterior wall of the uterus. In patients with bulky tumor and/or deep (vaginal) extend of peritoneal cavity tumour was seen mainly cranial from the rectovaginal space and therefore above the hydrogeI application. Only in the extra-peritoneal (lower) part of the cervix a good separation could be achieved between the rectum and cervix., Conclusion: Hydrgel instillation in patients with cervial cancer undergoing chemoradiation is safe and feasible. Because of the loose tissue of the cul-de-sac and its intra- and extraperitoneal part, hydrogel instillation of 20 cc did not result in a sufficient separation of the cervix from anterior wall.

Purpose: To demonstrate the feasibility and safety of the simultaneous integrated boost technique for dose escalation in combination with helical tomotherapy in patients with cervical cancer., Methods and Materials: Forty patients (International Federation of Gynecology and Obstetrics Stage IB1 pN1-IVA) underwent primary chemoradiation with helical tomotherapy. Before therapy, 29/40 patients underwent laparoscopic pelvic and para-aortic lymphadenectomy. In 21%, 31%, and 3% of the patients, pelvic, pelvic and para-aortic, and skip metastases in the para-aortic region could be confirmed. All patients underwent radiation with 1.8-50.4 Gy to the tumor region and the pelvic (para-aortic) lymph node region (planning target volume-A), and a simultaneous boost with 2.12-59.36 Gy to the boost region (planning target volume-B). The boost region was defined using titan clips during laparoscopic staging. In all other patients, standardized borders for the planning target volume-B were defined. High-dose-rate brachytherapy was performed in 39/40 patients. The mean biologic effective dose to the macroscopic tumor ranged from 87.5 to 97.5 Gy. Chemotherapy consisted of weekly cisplatin 40 mg/m(2). Dose-volume histograms and acute gastrointestinal, genitourinary, and hematologic toxicity were evaluated., Results: The mean treatment time was 45 days. The mean doses to the small bowel, rectum, and bladder were 28.5 ± 6.1 Gy, 47.9 ± 3.8 Gy, and 48 ± 3 Gy, respectively. Hematologic toxicity Grade 3 occurred in 20% of patients, diarrhea Grade 2 in 5%, and diarrhea Grade 3 in 2.5%. There was no Grade 3 genitourinary toxicity. All patients underwent curettage 3 months after chemoradiation, which confirmed complete pathologic response in 38/40 patients., Conclusions: The concept of simultaneous integrated boost for dose escalation in patients with cervical cancer is feasible, with a low rate of acute gastrointestinal and genitourinary toxicity. Whether dose escalation can be translated into improved outcome will be assessed after a longer follow-up time., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background Despite clear differences in clinical presentation and outcome, squamous cell carcinomas of the head and neck (SCCHN) arising from human papilloma virus (HPV) infection or heavy tobacco/alcohol consumption are treated equally. Next-generation sequencing is expected to reveal novel targets for more individualised treatment. Patients and methods Tumour specimens from 208 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity, all uniformly treated with adjuvant cisplatin-based chemoradiation, were included. A customised panel covering 211 exons from 45 genes frequently altered in SCCHN was used for detection of non-synonymous point and frameshift mutations. Mutations were correlated with HPV status and treatment outcome. Results Mutational profiles and HPV status were successfully established for 179 cases. HPV– tumours showed an increased frequency of alterations in tumour suppressor genes compared to HPV+ cases ( TP53 67% versus 4%, CDKN2A 18% versus 0%). Conversely, HPV+ carcinomas were enriched for activating mutations in driver genes compared to HPV– cases ( PIK3CA 30% versus 12%, KRAS 6% versus 1%, and NRAS 4% versus 0%). Hotspot TP53 missense mutations in HPV– carcinomas correlated with an increased risk of locoregional recurrence (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.5–12.1, P = 0.006) and death (HR 2.2, 95% CI 1.1–4.4, P = 0.021). In HPV+ SCCHN, driver gene mutations were associated per trend with a higher risk of death (HR 3.9, 95% CI 0.7–21.1, P = 0.11). Conclusions Distinct mutation profiles in HPV– and HPV+ SCCHN identify subgroups with poor outcome after adjuvant chemoradiation. Mutant p53 and the phosphoinositide 3-kinase pathway were identified as potential druggable targets for subgroup-specific treatment optimisation. [ABSTRACT FROM AUTHOR]

While the proportion of elderly head-and-neck squamous cell carcinoma (HNSCC) patients is increasing, the evidence regarding the ideal treatment for this patient cohort is limited. The benefit of concomitant chemotherapy (CT) has been reported to decrease in elderly HNSCC patients; however, it remains unknown whether modern supportive treatments, state-of-the art radiotherapy (RT) techniques and the generally improved performance status of elderly patients nowadays may have altered this observation. Elderly (≥65 years) patients with locoregionally advanced HNSCCs of the oral cavity, oropharynx, hypopharynx or larynx (cT3-4 and/or cN+) receiving definitive RT, with or without concomitant CT, between 2005 and 2019 were eligible for this analysis. Exclusion criteria were recurrent HNSCCs, distant metastases at the time of RT, or HNSCCs from the nasopharynx, salivary glands or the skin. A total of 824 elderly HNSCC patients from nine tertiary cancer centers met the inclusion criteria and were analyzed. The median age amounted to 72 years (range 65-96 years), and 568 patients (80% of the patients with known ECOG status, n=708) exhibited an ECOG performance status of 0 or 1. The median age-adjusted Charlson Comorbidity Index (CCI) ranged at 4 points (IQR 3-5). Only a minority of HNSCCs (n=140, 17%) exhibited p16 positivity. About half of the cohort suffered from oropharyngeal carcinomas (n=418, 51%), followed by cancers of the hypopharynx (n=151, 18%), oral cavity (n=124, 15%), larynx (n=102, 12%) and multi-level carcinomas (n=29, 4%). A positive smoking history was present in 473 patients (70% of the patients with known smoking status, n=674). Seven hundred thirty-six (89%) of the analyzed patients completed the pre-specified RT dose. OS/PFS amounted to 71%/56% at 1 year, 56%/45% at 2 years, and 46%/38% at 3 years, respectively. Chemoradiation (CRT) resulted in significantly improved OS (HR=0.49, p <0.05) and PFS (HR=0.53, p <0.05) compared to RT. Even for patients aged ≥75 years (n=329), CRT was associated with superior OS (HR=0.57, p <0.05) and PFS (HR=0.61, p <0.05). However, patients receiving concomitant CT were significantly younger (p <0.05), exhibited a better ECOG performance status (p <0.05) and fewer comorbidities (p <0.05). In order to control for these disparities, a matched-pair analysis with the matching variables ECOG, CCI and age was conducted, resulting in 98 matching pairs (n=196): Here, both OS (HR=0.44, p <0.05) and PFS (HR=0.45, p <0.05) remained superior in the CRT compared to the RT group. This analysis suggests a benefit of concomitant CT in elderly HNSCC patients receiving RT and does not support the usage of a strict age cut-off for CT. Structured assessment of patient performance and comorbidities may help to guide treatment decisions regarding CRT in elderly HNSCC patients. [ABSTRACT FROM AUTHOR]

The European Organization for Research and Treatment of Cancer (EORTC) 22861 randomised trial established that combined radiochemotherapy is the standard treatment for locally advanced anal cancer. This EORTC phase II study (#22953) tests the feasibility of reducing the gap between sequences to 2 weeks, to deliver Mitomycin C (MMC) in each radiotherapy sequence and 5-FU continuously during the treatment. The first sequence consisted of 36 Gy over 4 weeks. 5-FU 200 mg/m2/days 1–26, MMC 10 mg/m2/day 1 gap 16 days. Then a second sequence of 23.4 Gy over 17 days, 5-FU 200 mg/m2/days 1–17 and, MMC 10 mg/m2/day 1 was given. 43 patients with a World Health Organization (WHO) status of 0 (n=27) or 1 (n=16) and with T2-T4, N0-3 tumours were included. Compliance with the planned treatment, doses and duration was 93%. The complete response rate was 90.7%. Grade 3 toxicities of 28, 12 and 2% were observed for skin, diarrhoea and haematological toxicities, respectively. The 3-year estimated rates for trials 22861 and 22953 are: 68 and 88% for local control; 72 and 81% for colostomy-free interval, 62 and 84% for severe late toxicity-free interval, and 70 and 81% for survival, respectively. The 22953 scheme is feasible and the results are promising. This is now considered as the new standard scheme by the EORTC. [Copyright &y& Elsevier]