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Purpose: Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is associated with unfavorable prognosis, while independent prognostic markers remain to be defined., Experimental Design: We retrospectively performed miRNA expression profiling. Patients were operated for locally advanced HPV-negative HNSCC and had received radiochemotherapy in eight different hospitals (DKTK-ROG; n = 85). Selection fulfilled comparable demographic, treatment, and follow-up characteristics. Findings were validated in an independent single-center patient sample (LMU-KKG; n = 77). A prognostic miRNA signature was developed for freedom from recurrence and tested for other endpoints. Recursive-partitioning analysis was performed on the miRNA signature, tumor and nodal stage, and extracapsular nodal spread. Technical validation used qRT-PCR. An miRNA-mRNA target network was generated and analyzed., Results: For DKTK-ROG and LMU-KKG patients, the median follow-up was 5.1 and 5.3 years, and the 5-year freedom from recurrence rate was 63.5% and 75.3%, respectively. A five-miRNA signature (hsa-let-7g-3p, hsa-miR-6508-5p, hsa-miR-210-5p, hsa-miR-4306, and hsa-miR-7161-3p) predicted freedom from recurrence in DKTK-ROG [hazard ratio (HR) 4.42; 95% confidence interval (CI), 1.98-9.88, P < 0.001], which was confirmed in LMU-KKG (HR 4.24; 95% CI, 1.40-12.81, P = 0.005). The signature also predicted overall survival (HR 3.03; 95% CI, 1.50-6.12, P = 0.001), recurrence-free survival (HR 3.16; 95% CI, 1.65-6.04, P < 0.001), and disease-specific survival (HR 5.12; 95% CI, 1.88-13.92, P < 0.001), all confirmed in LMU-KKG data. Adjustment for relevant covariates maintained the miRNA signature predicting all endpoints. Recursive-partitioning analysis of both samples combined classified patients into low ( n = 17), low-intermediate ( n = 80), high-intermediate ( n = 48), or high risk ( n = 17) for recurrence ( P < 0.001)., Conclusions: The five-miRNA signature is a strong and independent prognostic factor for disease recurrence and survival of patients with HPV-negative HNSCC. See related commentary by Clump et al., p. 1441 ., (©2018 American Association for Cancer Research.)

Background: The dismal overall survival (OS) prognosis of glioblastoma, even after trimodal therapy, can be attributed mainly to the frequent incidence of intracranial relapse (ICR), which tends to present as an in-field recurrence after a radiation dose of 60 Gray (Gy). In this study, molecular marker-based prognostic indices were used to compare the outcomes of radiation with a standard dose versus a moderate dose escalation., Methods: This retrospective analysis included 156 patients treated between 2009 and 2016. All patients were medically fit for postoperative chemoradiotherapy. In the dose-escalation cohort a simultaneous integrated boost of up to 66 Gy (66 Gy RT) within small high-risk volumes was applied. All other patients received daily radiation to a total dose of 60 Gy or twice daily to a total dose of 59.2 Gy (60 Gy RT)., Results: A total of 133 patients received standard 60 Gy RT, while 23 received 66 Gy RT. Patients in the 66 Gy RT group were younger (p <  0.001), whereas concomitant temozolomide use was more frequent in the 60 Gy RT group (p <  0.001). Other intergroup differences in known prognostic factors were not observed. Notably, the median time to ICR was significantly prolonged in the 66 Gy RT arm versus the 60 Gy RT arm (12.2 versus 7.6 months, p = 0.011), and this translated to an improved OS (18.8 versus 15.3 months, p = 0.012). A multivariate analysis revealed a strong association of 66 Gy RT with a prolonged time to ICR (hazard ratio = 0.498, p = 0.01) and OS (hazard ratio = 0.451, p = 0.01). These differences remained significant after implementing molecular marker-based prognostic scores (ICR p = 0.008, OS p = 0.007) and propensity-scored matched pairing (ICR p = 0.099, OS p = 0.023)., Conclusion: Radiation dose escalation was found to correlate with an improved time to ICR and OS in this cohort of glioblastoma patients. However, further prospective validation of these results is warranted.

The MabThera and Involved field Radiotherapy study investigated efficacy and safety of involved field (IF) radiotherapy in combination with the anti-CD20 antibody Rituximab for early-stage follicular lymphoma (FL) in a prospective, single-arm multicenter phase 2 design. Eighty-five stage I-II FL patients received 8 cycles of Rituximab (375 mg/m 2 ) and IF irradiation (30/40 Gy). The primary endpoint was progression-free survival (PFS) 2 years from treatment start. Secondary endpoints were overall survival (OS), complete response rates, toxicity, quality of life, and minimal residual disease (MRD) response with protocol defined visits up to month 30. For the primary endpoint, PFS at 2 years was 85% for the intention-to-treat set. Long-term data were captured in selected sites and evaluated as post hoc analysis in the per protocol (PP) set: PFS and OS were 78% and 96% at 5 years with a median follow-up of 66 or 78 months, respectively. There were 17/76 recurrences in the PP set, of which 14 were outside the radiation volume only. MRD analyses revealed a clonal marker in 36% of patients at diagnosis. All but 1 marker positive patients experienced a molecular treatment response. There were 13 serious adverse events (4 related to the therapy) during the first 30 months. IF radiotherapy combined with Rituximab is well tolerated and highly efficient with low rates of recurrence in the first years in early-stage FL. The efficacy is comparable with more aggressive therapy approaches without compromising the quality of life and maintains for an extended follow-up of more than 5 years., Competing Interests: Peter Borchmann, Sven Schnaidt: No conflicts of interest., (Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

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.

Purpose The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer. Method The process of updating the S3 guideline published in 2012 was based on the adaptation of identified source guidelines. They were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and with the results of a systematic search of literature databases followed by the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point and used them to develop suggestions for recommendations and statements, which were then modified and graded in a structured consensus process procedure. Recommendations Part 2 of this short version of the guideline presents recommendations for the therapy of primary, recurrent and metastatic breast cancer. Loco-regional therapies are de-escalated in the current guideline. In addition to reducing the safety margins for surgical procedures, the guideline also recommends reducing the radicality of axillary surgery. The choice and extent of systemic therapy depends on the respective tumor biology. New substances are becoming available, particularly to treat metastatic breast cancer.

Purpose The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer. Methods The process of updating the S3 guideline dating from 2012 was based on the adaptation of identified source guidelines which were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and the results of a systematic search of literature databases and the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point to develop recommendations and statements which were modified and graded in a structured consensus procedure. Recommendations Part 1 of this short version of the guideline presents recommendations for the screening, diagnosis and follow-up care of breast cancer. The importance of mammography for screening is confirmed in this updated version of the guideline and forms the basis for all screening. In addition to the conventional methods used to diagnose breast cancer, computed tomography (CT) is recommended for staging in women with a higher risk of recurrence. The follow-up concept includes suggested intervals between physical, ultrasound and mammography examinations, additional high-tech diagnostic procedures, and the determination of tumor markers for the evaluation of metastatic disease.

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.

Purpose or Objective: A homogeneity index (HI) measures the uniformity of a dose distribution within a given target volume. Traditional HIs only use a limited number of dose-volume histogram data-points for calculation. A voxel-based homogeneity index (VHI) is proposed which utilizes the entire information of the three-dimensional dose distribution. We compared the VHI with existing HIs and analyzed if VHI results were associated with treatment outcomes in patients who underwent therapeutic WBRT., Material and Methods: The VHI analyzes deviations from the prescribed dose in each voxel of the target volume. We retrospectively analyzed WBRT treatment plans. Overall survival (OS), CNS progression-free-survival (CNS PFS) and hazard rates were compared for tertile-split levels of the VHI using the Kaplan-Meier methods and multivariable Cox-regression analysis., Results: WBRT treatment plans (n = 770) were used for HIs comparison. OS and CNS PFS were assessed for 430 patients. The VHI showed a higher sensitivity for dose inhomogeneities. Lower OS and CNS PFS were observed for higher levels of VHI Underdosage , particularly in patients with good performance status (KPS >70%) (OS: Log-rank P = .007, HR = 1.37 95%CI [1.09, 1.72])., Conclusion: Higher sensitivity and feasibility to assess treatment plan quality using the VHI were demonstrated. First clinical implications were found in terms of compromised OS/CNS PFS for WBRT with radiation underdosage., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Estimating efficacy, safety and outcome of frameless image-guided robotic radiosurgery for the treatment of recurrent brain metastases after whole brain radiotherapy (WBRT). We performed a retrospective single-center analysis including patients with recurrent brain metastases after WBRT, who have been treated with single session radiosurgery, using the CyberKnife® Radiosurgery System (CKRS) (Accuray Inc., CA) between 2011 and 2016. The primary end point was local tumor control, whereas secondary end points were distant tumor control, treatment-related toxicity and overall survival. 36 patients with 140 recurrent brain metastases underwent 46 single session CKRS treatments. Twenty one patients had multiple brain metastases (58%). The mean interval between WBRT and CKRS accounted for 2 years (range 0.2-7 years). The median number of treated metastases per treatment session was five (range 1-12) with a tumor volume of 1.26 ccm (mean) and a median tumor dose of 18 Gy prescribed to the 70% isodose line. Two patients experienced local tumor recurrence within the 1st year after treatment and 13 patients (36%) developed novel brain metastases. Nine of these patients underwent additional one to three CKRS treatments. Eight patients (22.2%) showed treatment-related radiation reactions on MRI, three with clinical symptoms. Median overall survival was 19 months after CKRS. The actuarial 1-year local control rate was 94.2%. CKRS has proven to be locally effective and safe due to high local tumor control rates and low toxicity. Thus CKRS offers a reliable salvage treatment option for recurrent brain metastases after WBRT.

Tumor cells frequently overexpress heat shock protein 70 (Hsp70) and present it on their cell surface, where it can be recognized by pre-activated NK cells. In our retrospective study the expression of Hsp70 was determined in relation to tumor-infiltrating CD56 + NK cells in formalin-fixed paraffin embedded (FFPE) tumor specimens of patients with SCCHN (N = 145) as potential indicators for survival and disease recurrence. All patients received radical surgery and postoperative cisplatin-based radiochemotherapy (RCT). In general, Hsp70 expression was stronger, but with variable intensities, in tumor compared to normal tissues. Patients with high Hsp70 expressing tumors (scores 3-4) showed significantly decreased overall survival (OS; p = 0.008), local progression-free survival (LPFS; p = 0.034) and distant metastases-free survival (DMFS; p = 0.044), compared to those with low Hsp70 expression (scores 0-2), which remained significant after adjustment for relevant prognostic variables. The adverse prognostic value of a high Hsp70 expression for OS was also observed in patient cohorts with p16- (p = 0.001), p53- (p = 0.0003) and HPV16 DNA-negative (p = 0.001) tumors. The absence or low numbers of tumor-infiltrating CD56 + NK cells also correlated with significantly decreased OS (p = 0.0001), LPFS (p = 0.0009) and DMFS (p = 0.0001). A high Hsp70 expression and low numbers of tumor-infiltrating NK cells have the highest negative predictive value (p = 0.00004). In summary, a strong Hsp70 expression and low numbers of tumor-infiltrating NK cells correlate with unfavorable outcome following surgery and RCT in patients with SCCHN, and thus serve as negative prognostic markers., (© 2017 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

The heterogeneity of high-grade glioma recurrences remains an ongoing challenge for the interdisciplinary neurooncology team. Response to re-irradiation (re-RT) is heterogeneous, and survival data depend on prognostic factors such as tumor volume, primary histology, age, the possibility of reresection, or time between primary diagnosis and initial RT and re-RT. In the present pooled analysis, we gathered data from radiooncology centers of the DKTK Consortium and used it to validate the established prognostic score by Combs et al. and its modification by Kessel et al. Data consisted of a large independent, multicenter cohort of 565 high-grade glioma patients treated with re-RT from 1997 to 2016 and a median dose of 36 Gy. Primary RT was between 1986 and 2015 with a median dose of 60 Gy. Median age was 54 years; median follow-up was 7.1 months. Median OS after re-RT was 7.5, 9.5, and 13.8 months for WHO IV, III, and I/II gliomas, respectively. All six prognostic factors were tested for their significance on OS. Aside from the time from primary RT to re-RT (P = 0.074) and the reresection status (P = 0.101), all factors (primary histology, age, KPS, and tumor volume) were significant. Both the original and new score showed a highly significant influence on survival with P < 0.001. Both prognostic scores successfully predict survival after re-RT and can easily be applied in the routine clinical workflow. Now, further prognostic features need to be found to even improve treatment decisions regarding neurooncological interventions for recurrent glioma patients., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To compare six HPV detection methods in pre-treatment FFPE tumour samples from patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who received postoperative (N = 175) or primary (N = 90) radiochemotherapy., Materials and Methods: HPV analyses included detection of (i) HPV16 E6/E7 RNA, (ii) HPV16 DNA (PCR-based arrays, A-PCR), (iii) HPV DNA (GP5+/GP6+ qPCR, (GP-PCR)), (iv) p16 (immunohistochemistry, p16 IHC), (v) combining p16 IHC and the A-PCR result and (vi) combining p16 IHC and the GP-PCR result. Differences between HPV positive and negative subgroups were evaluated for the primary endpoint loco-regional control (LRC) using Cox regression., Results: Correlation between the HPV detection methods was high (chi-squared test, p < 0.001). While p16 IHC analysis resulted in several false positive classifications, A-PCR, GP-PCR and the combination of p16 IHC and A-PCR or GP-PCR led to results comparable to RNA analysis. In both cohorts, Cox regression analyses revealed significantly prolonged LRC for patients with HPV positive tumours irrespective of the detection method., Conclusions: The most stringent classification was obtained by detection of HPV16 RNA, or combining p16 IHC with A-PCR or GP-PCR. This approach revealed the lowest rate of recurrence in patients with tumours classified as HPV positive and therefore appears most suited for patient stratification in HPV-based clinical studies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: Reirradiation (reRT) is a valid option with considerable efficacy in patients with recurrent high-grade glioma, but it is still not known which patients might be optimal candidates for a second course of irradiation. This study validated a newly developed prognostic score independently in an external patient cohort., Material and Methods: The reRT risk score (RRRS) is based on a linear combination of initial histology, clinical performance status, and age derived from a multivariable model of 353 patients. This score can predict post-recurrence survival (PRS) after reRT. The validation dataset consisted of 212 patients., Results: The RRRS differentiates three prognostic groups. Discrimination and calibration were maintained in the validation group. Median PRS times in the development cohort for the good/intermediate/poor risk categories were 14.2, 9.1, and 5.3 months, respectively. The respective groups within the validation cohort displayed median PRS times of 13.8, 8.8, and 3.8 months, respectively. Uno's C for development data was 0.64 (CI: 0.60-0.69) and for validation data 0.63 (CI: 0.58-0.68)., Conclusions: The RRRS has been successfully validated in an independent patient cohort. This linear combination of three easily determined clinicopathological factors allows for a reliable classification of patients and may be used as stratification factor for future trials., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: In patients with prostate cancer (PCa) and biochemical progression (BP) after radical prostatectomy (RP), salvage radiotherapy (sRT) improves prostate cancer-specific survival (PCSS), but this evidence is based only on retrospective data., Patients and Methods: In addition to our previous study of 151 patients with PCa and BP after RP, we performed univariate analyses of prostate-specific antigen (PSA) kinetics during sRT. In 11 patients with BP or initiation of hormonal treatment (HT) within 180 days after sRT, risk factors were assessed using Mann-Whitney U tests. PSA doubling times (PSADT) before and after sRT in 82 patients with BP after sRT were compared by a Wilcoxon test., Results: After a median follow-up of 82 months, analysis of PSA kinetics during sRT did not show a statistically significant impact on a subsequent BP, PCSS, or overall survival at an administered dose of 30 or 45 Gy. The subgroup analysis of patients with early BP or early HT revealed higher Gleason scores (p = 0.008) and preoperative PSA values (p = 0.005), shorter PSADT prior to sRT (p < 0.0005), and longer time intervals from RP until the start of sRT (p = 0.005) compared to all other patients. In patients with subsequent BP, PSADTs were significantly prolonged after sRT (median PSADT 4.5 months before and 9.9 months after sRT, p < 0.0005)., Conclusion: PSA monitoring during sRT did not predict the therapeutic success. Subgroup analysis suggests a lower probability of benefit for patients with the abovenamed risk factors . However, the prolonged PSADT after sRT reflects a benefit of sRT for the vast majority of patients.

Purpose: The aim of this study was to identify and independently validate a novel gene signature predicting locoregional tumor control (LRC) for treatment individualization of patients with locally advanced HPV-negative head and neck squamous cell carcinomas (HNSCC) who are treated with postoperative radio(chemo)therapy (PORT-C). Experimental Design: Gene expression analyses were performed using NanoString technology on a multicenter training cohort of 130 patients and an independent validation cohort of 121 patients. The analyzed gene set was composed of genes with a previously reported association with radio(chemo)sensitivity or resistance to radio(chemo)therapy. Gene selection and model building were performed comparing several machine-learning algorithms. Results: We identified a 7-gene signature consisting of the three individual genes HILPDA, CD24, TCF3 , and one metagene combining the highly correlated genes SERPINE1, INHBA, P4HA2 , and ACTN1 The 7-gene signature was used, in combination with clinical parameters, to fit a multivariable Cox model to the training data (concordance index, ci = 0.82), which was successfully validated (ci = 0.71). The signature showed improved performance compared with clinical parameters alone (ci = 0.66) and with a previously published model including hypoxia-associated genes and cancer stem cell markers (ci = 0.65). It was used to stratify patients into groups with low and high risk of recurrence, leading to significant differences in LRC in training and validation ( P < 0.001). Conclusions: We have identified and validated the first hypothesis-based gene signature for HPV-negative HNSCC treated by PORT-C including genes related to several radiobiological aspects. A prospective validation is planned in an ongoing prospective clinical trial before potential application in clinical trials for patient stratification. Clin Cancer Res; 24(6); 1364-74. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: For patients with recurrent prostate cancer after radical prostatectomy (RP), salvage radiotherapy (SRT) is a second chance of cure. However, depending on risk factors, 40-70% of the patients experience further progression. With a focus on the pre- and post-SRT serum level of the prostate-specific antigen (PSA), we assessed the determinants of the long-term outcome after SRT., Patient and Methods: Between 1997 and 2011, 464 patients received 3D-conformal SRT with median 66.6 Gy. The median PSA level before SRT was 0.31 ng/ml. In our retrospective analysis, post-SRT progression was defined as either a rising PSA >0.2 ng/ml above the nadir, or the application of anti-androgens or clinical recurrence. A PSA <0.1 ng/ml was termed undetectable. We analyzed the data with the Kaplan-Meier method (Logrank test) and multivariable Cox regression., Results: The median follow-up was 5.9 years. Overall, 178 patients had recurrence, 13 developed distant metastases and 30 died. Univariate, a pre-RP PSA <10 ng/ml, pathological stage pT <3, Gleason score <8, positive surgical margins, a pre-SRT PSA <0.2 ng/ml and a post-SRT PSA nadir <0.1 ng/ml correlated with fewer and later second recurrences. In a multivariable Cox model, pT, Gleason score, margin status and pre-SRT PSA were significant covariates of progression. If the post-SRT PSA response was included in the regression analysis, then a nadir ≥0.1 ng/ml was the strongest risk factor. Initiating SRT at a PSA <0.2 ng/ml correlated with a post-SRT PSA <0.1 ng/ml. Men who achieved an undetectable post-SRT PSA nadir also had lower rates of metastases and a better overall survival. However, there were too few events for Cox regression analysis of these two endpoints., Conclusions: Early SRT at a PSA <0.2 ng/ml correlates with re-achieving an undetectable PSA, which predicts improved freedom from progression and metastases and better overall survival.

Background: Malignant melanoma brain metastases (MBM) are the third most common cause for brain metastases (BM). Historically Whole-brain radiotherapy (WBRT) was considered the goldstandard of treatment even though melanoma cells are regarded as very radioresistant. Therapeutic possibilities have fundamentally changed since the availability of stereotactic radiotherapy (SRT), where it is possible to apply high ablative doses in a very precise manner. In this work we analyze prognostic factors of overall survival (OS) after SRT in patients with MBM and evaluate the applicability of popular prognostic indices that mainly stem from the WBRT-era., Materials and Methods: This work is a retrospective analysis of OS of 80 malignant melanoma (MM) patients who received SRT for intracranial melanoma metastases between 2004 and 2014 who had not received prior treatment for MBM in terms of surgery or WBRT. Potential prognostic factors were analyzed using univariable and multivariable analysis. Existing prognostic scores [Graded Prognostic Assessment (GPA), Diagnosis-Specific-GPA (DS-GPA), Golden Grading System (GGS) and RADES] were calculated and tested using log-rank analysis., Results: Eighty patients, respectively 177 brain metastases, were irradiated. The median survival time from radiation was 7.06 months. Overall, GGS, GPA and DS-GPA were significant predictors of survival. The MM-specific index DS-GPA showed the best p-value but did not show adequate division when looking at the two intermediate risk subgroups. RADES did not show any statistically significant prognostic value. In univariable as well as in multivariable analyses a higher Karnofsky-Index, a single BM, and non nodular melanoma (NM) histology were positive predictors of survival., Conclusion: The existing prognostic scores do not seem to ideally fit for this special group of patients. Our results indicate that the histologic subtype of MM could add to the prognostic value of specialized future indices.

Purpose: Platinum-based drugs, in particular cisplatin (cis-diamminedichloridoplatinum(II), CDDP), are used for treatment of squamous cell carcinoma of the head and neck (SCCHN). Despite initial responses, CDDP treatment often results in chemoresistance, leading to therapeutic failure. The role of primary resistance at subclonal level and treatment-induced clonal selection in the development of CDDP resistance remains unknown. Experimental Design: By applying targeted next-generation sequencing, fluorescence in situ hybridization, microarray-based transcriptome, and mass spectrometry-based phosphoproteome analysis to the CDDP-sensitive SCCHN cell line FaDu, a CDDP-resistant subline, and single-cell derived subclones, the molecular basis of CDDP resistance was elucidated. The causal relationship between molecular features and resistant phenotypes was determined by siRNA-based gene silencing. The clinical relevance of molecular findings was validated in patients with SCCHN with recurrence after CDDP-based chemoradiation and the TCGA SCCHN dataset. Results: Evidence of primary resistance at clonal level and clonal selection by long-term CDDP treatment was established in the FaDu model. Resistance was associated with aneuploidy of chromosome 17, increased TP53 copy-numbers and overexpression of the gain-of-function (GOF) mutant variant p53 R248L siRNA-mediated knockdown established a causal relationship between mutant p53 R248L and CDDP resistance. Resistant clones were also characterized by increased activity of the PI3K-AKT-mTOR pathway. The poor prognostic value of GOF TP53 variants and mTOR pathway upregulation was confirmed in the TCGA SCCHN cohort. Conclusions: Our study demonstrates a link of intratumoral heterogeneity and clonal evolution as important mechanisms of drug resistance in SCCHN and establishes mutant GOF TP53 variants and the PI3K/mTOR pathway as molecular targets for treatment optimization. Clin Cancer Res; 24(1); 158-68. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose: Few studies have reported large inter-observer variations in target volume selection and delineation in patients treated with radiotherapy for head and neck squamous cell carcinoma. Consensus guidelines have been published for the neck nodes (see Grégoire et al., 2003, 2014), but such recommendations are lacking for primary tumour delineation. For the latter, two main schools of thoughts are prevailing, one based on geometric expansion of the Gross Tumour Volume (GTV) as promoted by DAHANCA, and the other one based on anatomical expansion of the GTV using compartmentalization of head and neck anatomy., Method: For each anatomic location within the larynx, hypopharynx, oropharynx and oral cavity, and for each T-stage, the DAHANCA proposal has been comprehensively reviewed and edited to include anatomic knowledge into the geometric Clinical Target Volume (CTV) delineation concept. A first proposal was put forward by the leading authors of this publication (VG and CG) and discussed with opinion leaders in head and neck radiation oncology from Europe, Asia, Australia/New Zealand, North America and South America to reach a worldwide consensus., Results: This consensus proposes two CTVs for the primary tumour, the so called CTV-P1 and CVT-P2, corresponding to a high and lower tumour burden, and which should be associated with a high and a lower dose prescription, respectively., Conclusion: Implementation of these guidelines in the daily practice of radiation oncology should contribute to reduce treatment variations from clinicians to clinicians, facilitate the conduct of multi-institutional clinical trials, and contribute to improved care of patients with head and neck carcinoma., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Preclinical and clinical data suggest that the chemokine pathway governed by SDF-1 and CXCR4 contributes to a resistant phenotype. This retrospective biomarker study aims to explore the specific prognostic value of SDF-1 and CXCR4 expression in locally advanced head and neck squamous cell carcinomas (HNSCC) treated with primary radiochemotherapy (RT-CT)., Material and Methods: Biopsies from 141 HNSCC tumours of the oral cavity, oropharynx and hypopharynx were evaluated for SDF-1 and CXCR4 expression by immunofluorescence. SDF-1 and CXCR4 expression was correlated with clinico-pathological characteristics and outcome after RT-CT., Results: Patients with tumours exhibiting overexpression of intracellular SDF-1 and CXCR4 have a higher risk for loco-regional relapse and a worse overall survival after RT-CT (multivariate analysis, hazard ratio 2.33, CI [1.18-4.62], p = 0.02 and hazard ratio 2.02, CI [1.13-3.59], p = 0.02, respectively). Similar results were observed when only the subgroup of HPV DNA negative patients were analysed (hazard ratio 2.23 and 2.16, p = 0.02 and p = 0.01, respectively)., Conclusions: Our data support the importance of SDF-1 and CXCR4 expression for loco-regional control and overall survival in HNSCC after primary radiochemotherapy. Prospective multivariate validation and further studies into CXCR4 inhibition to overcome radiation resistance are warranted., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: The aim of this study was to evaluate local tumour control, incidence of radiation-induced glaucoma and associated interventions of sector-based and whole anterior segment proton beam therapy (PBT) for the treatment of iris melanoma., Patients and Methods: We retrospectively analysed the data of 77 patients with iris melanoma who underwent PBT applied as 50 CGE in four daily fractions. Of the patients, 47 received PBT with a circular-shaped collimator and 30 with a conformal sector-shaped target volume. Local control, eye preservation and secondary glaucoma were evaluated., Results: Median follow-up time was 54.9 months. Local tumour control was 100% in patients receiving whole anterior segment irradiation. Two patients developed pigment dispersion in the non-irradiated area after sector-based PBT and received whole anterior segment salvage PBT. The mean volume of ciliary body irradiated was 89.0% and 34.9% for whole anterior segment and lesion-based irradiation, respectively. At the end of follow-up, secondary glaucoma was found in 74.3% of the patients with whole anterior segment irradiation and in 19.2% with sector-based irradiation. Patients with sector-based PBT had a stable visual acuity of logMAR 0.1, while it declined from logMAR 0.1 to 0.4 after whole anterior segment irradiation., Conclusion: We found a significant reduction in radiation-induced secondary glaucoma and glaucoma-associated surgical interventions and stable visual acuity after sector-based irradiation compared with whole anterior segment irradiation. Sector-based irradiation revealed a higher risk for local recurrence, but selected patients with well-circumscribed iris melanoma benefit from applying a lesion-based target volume when treated with sector-based PBT.

Objective: To conduct a central pathology review within a randomized clinical trial on salvage radiation therapy (RT) in the presence of biochemical recurrence after prostatectomy to assess whether this results in changes in histopathological prognostic factors, such as Gleason score., Patients and Methods: A total of 350 patients were randomized and specimens from 279 patients (80%) were centrally reviewed by a dedicated genitourinary pathologist. Gleason score, tumour classification and resection margin status were reassessed and compared with the results of local pathology review. Agreement was assessed using contingency tables and Cohen's kappa coefficient. The association between other histopathological features (e.g. largest diameter of carcinoma) and rapid biochemical progression (up to 6 months after salvage RT) was also investigated., Results: There was good concordance between central and local pathology review for seminal vesicle invasion (pT3b: 91%; κ = 0.95 [95% confidence interval {CI} 0.89, 1.00]), extraprostatic extension (pT3a/b: 94%; κ = 0.82 [95% CI 0.75, 0.89]) and positive surgical margin (PSM) status (87%; κ = 0.7 [95% CI 0.62, 0.79]). The rate of agreement was lower for Gleason score (78%; κ = 0.61 [95% CI 0.52, 0.70]). The median (range) largest diameter of carcinoma was 16 (3-38) mm. A total of 49 patients (18%) experienced rapid biochemical progression after salvage RT. Largest diameter of carcinoma (odds ratio [OR] 2.04 [95% CI 1.30, 3.20]; P = 0.002), resection margin status (OR 0.36 [95% CI 0.18, 0.72]; P = 0.004) and Gleason score (OR 1.55 [95% CI 1.00, 2.42]; P = 0.05) remained associated with rapid progression after salvage RT after backward selection., Conclusion: The results of the central pathology analyses showed concordance between central and local pathology review with regard to seminal vesicle invasion, extraprostatic extension and PSM status, but a lower rate of agreement for Gleason score. Largest diameter of carcinoma was found to be a potential prognostic factor for rapid biochemical progression after salvage RT., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

Radiomics applies machine learning algorithms to quantitative imaging data to characterise the tumour phenotype and predict clinical outcome. For the development of radiomics risk models, a variety of different algorithms is available and it is not clear which one gives optimal results. Therefore, we assessed the performance of 11 machine learning algorithms combined with 12 feature selection methods by the concordance index (C-Index), to predict loco-regional tumour control (LRC) and overall survival for patients with head and neck squamous cell carcinoma. The considered algorithms are able to deal with continuous time-to-event survival data. Feature selection and model building were performed on a multicentre cohort (213 patients) and validated using an independent cohort (80 patients). We found several combinations of machine learning algorithms and feature selection methods which achieve similar results, e.g., , Msr-Rf: C-Index = 0.71 and BT-COX: C-Index = 0.70 in combination with Spearman feature selection. Using the best performing models, patients were stratified into groups of low and high risk of recurrence. Significant differences in LRC were obtained between both groups on the validation cohort. Based on the presented analysis, we identified a subset of algorithms which should be considered in future radiomics studies to develop stable and clinically relevant predictive models for time-to-event endpoints.

Purpose: The role of radiotherapy for unresectable pancreatic cancer is controversial. A benefit of additional radiotherapy is supported by some observations. A dose-effect relationship was recently found by dose escalation employing image guided and intensity modulated radiotherapy., Methods: We retrospectively evaluated 28 consecutive patients, all with history of extensive prior therapies for unresectable locally advanced/ recurrent pancreatic cancer (LAPC/LRPC). Treatment was delivered by helical tomotherapy after daily position verification with computed tomography. Dose to the planned target volume (PTV) was 51 Gy, while the dose to the macroscopic tumor was escalated by a simultaneous integrated boost to a median cumulative dose of 66 Gy (60-66 Gy). Concomitant chemotherapy consisted mainly of capecitabine (n = 23)., Results: 10 of 28 patients presented acute toxicities > grade 2, one patient succumbed to gastrointestinal bleeding after treatment. No correlations of toxicities and dose volume histograms (DVH) of retrospectively delineated small bowel loops were observed, although average small bowel volume receiving ≥ 20 Gy was 374 ml. DVH analyses revealed a correlation of splenic parameters and acute toxicity: Vomiting, anorexia, dehydration, hematologic toxicity, fatigue, combined gastro-intestinal toxicity wit R-values between 0.392 and 0.561 (all p-values > 0.05). Only one patient developed late toxicities > grade 2. With an average follow-up time in surviving patients of 14 months median overall survival time was 19 months and median time to local recurrence 13 months. In 8 patients with available imaging of local recurrence: 5 in field recurrences, 2 marginal recurrences and one lymph node recurrence outside the high dose radiation field were observed. In univariate analysis only ΔCA-19-9 during radiotherapy was associated with local control (p = 0.029) and overall survival (p = 0.049)., Conclusion: Dose escalated normo-fractionated radiotherapy for LAPC/LRPC seems feasible and suitable to prolong local control and in consequence long-term survival. However, in-field local progression is still frequently observed and possibilities to increase the local effectiveness should be evaluated. Exposure of the spleen was predictive for acute toxicity and should be further investigated.

Background: The optimal prostate-specific antigen (PSA) level after radical prostatectomy (RP) for defining biochemical recurrence and initiating salvage radiation therapy (SRT) is still debatable. Whereas adjuvant or extremely early SRT irrespective of PSA progression might be overtreatment for some patients, SRT at PSA >0.2 ng/ml might be undertreatment for others. The current study addresses the optimal timing of radiation therapy after RP., Patients and Methods: Cohort 1 comprised 293 men with PSA 0.1-0.19 ng/ml after RP. Cohort 2 comprised 198 men with SRT. PSA progression and metastases were assessed in cohort 1. In cohort 2, we compared freedom from progression according to pre-SRT PSA (0.03-0.19 vs. 0.2-0.499 ng/ml). Multivariable Cox regression analyses predicted progression after SRT., Results: In cohort 1, 281 (95.9%) men had further PSA progression ≥0.2 ng/ml and 27 (9.2%) men developed metastases within a median follow-up of 74.3 months. In cohort 2, we recorded improved freedom from progression according to lower pre-SRT PSA (0.03-0.19 vs. 0.2-0.499 ng/ml: 69 vs. 53%; log-rank p = 0.051). Patients with higher pre-SRT PSA ≥0.2 ng/ml were at a higher risk of progression after SRT (hazard ratio: 1.8; p < 0.05)., Conclusion: The vast majority of patients with PSA ≥0.1 ng/ml after RP will progress to PSA ≥0.2 ng/ml. Additionally, early administration of SRT at post-RP PSA level <0.2 ng/ml might improve freedom from progression. Consequently, we suggest a PSA threshold of 0.1 ng/ml to define biochemical recurrence after RP.

Introduction: For high-dose radiation therapy (RT) of prostate cancer, image-guided (IGRT) and intensity-modulated RT (IMRT) approaches are standard. Less is known regarding comparisons of different IGRT techniques and the resulting residual errors, as well as regarding their influences on dose distributions., Patients and Methods: A total of 58 patients who received tomotherapy-based RT up to 84 Gy for high-risk prostate cancer underwent IGRT based either on daily megavoltage CT (MVCT) alone (n = 43) or the additional use of gold markers (n = 15) under routine conditions. Planned Adaptive (Accuray Inc., Madison, WI, USA) software was used for elaborated offline analysis to quantify residual interfractional prostate positioning errors, along with systematic and random errors and the resulting safety margins after both IGRT approaches. Dosimetric parameters for clinical target volume (CTV) coverage and exposition of organs at risk (OAR) were also analyzed and compared. Interfractional as well as intrafractional displacements were determined., Results: Particularly in the vertical direction, residual interfractional positioning errors were reduced using the gold marker-based approach, but dosimetric differences were moderate and the clinical relevance relatively small. Intrafractional prostate motion proved to be quite high, with displacements of 1-3 mm; however, these did not result in additional dosimetric impairments., Conclusion: Residual interfractional positioning errors were reduced using gold marker-based IGRT; however, this resulted in only slightly different final dose distributions. Therefore, daily MVCT-based IGRT without markers might be a valid alternative.

Background: By the use of PSMA positron emission tomography (PET) detection of prostate cancer lesions with a high sensitivity and specificity combined with a favorable lesion to background contrast is feasible. Therefore, PSMA-PET is increasingly used for planning of radiotherapy treatment; however, any data on intermediate-term outcome is missing so far., Methods: Patients with high-risk or very high risk prostate cancer, referred for salvage radiotherapy (SRT, n = 22) between 2013 and 2015, underwent PSMA-PET prior to therapy. Irradiation was planned on PET data with boost to macroscopic tumors/metastases. Treatment related toxicity was measured using Common Terminology Criteria for Adverse Events (CTCAE, v4.0)., Result: Findings in PSMA-PET led to treatment modifications in 77% of SRT patients compared to available CT information. One patient did not receive irradiation due to disseminated disease, the other patients received increased boost doses to macroscopic disease and/or inclusion of additional target volumes. Toxicity was low as only 2 patients reported toxicities > grade 1. With a Median follow-up time of 29 in patients that were not lost to follow-up, prolonged PSA responses below baseline were observed in the majority of patients (14 of 20). In hormone-naïve SRT patients (n = 11), radiotherapy led to prolonged PSA decrease in 8/11 patients, however with 3 of these 8 patients receiving repeated PSMA based irradiation of novel lesions during follow-up., Conclusion: PSMA-PET guided planning of radiotherapy led to change of treatment in the majority of patients. Treatment related toxicity was well tolerated and promising results regarding intermediate-term PSA decrease were observed., Trial Registration: No trial registration was performed due to retrospective evaluation.

Background: Postoperative adjuvant radiation therapy (ART) in T3 and R1 prostate cancer as well as salvage radiation therapy (SRT) in case of postoperative biochemical failure (BF) are established treatments. Dose-intensified postoperative radiation therapy (RT) schemes have shown superior biochemical control accompanied by increased toxicity rates. In our study we evaluate a novel risk adapted dose-intensified postoperative RT scheme., Methods: A consecutive series of prostate cancer patients receiving postoperative RT after radical prostatectomy using helical Tomotherapy between 04/2012 and 04/2015 was analyzed retrospectively. RT was administered using a simultaneous integrated boost (SIB) to the area at risk (37 fractions of 1.9 Gy, total dose: 70.3 Gy) being defined based on histopathological findings (T3/R1 region) and in few cases according to additional diagnostic imaging. The whole prostate bed was treated with a dose of 66.6 Gy (37 fractions of 1.8 Gy). Primary endpoints were acute and late genitourinary (GU) and gastrointestinal (GI) toxicities. Secondary endpoints included patient reported outcome as assessed by the International Prostate Symptom Score (IPSS), the International Consultation on Incontinence questionnaire (ICIQ) and prostate cancer specific Quality of Life questionnaire QLQ-PR25, as well as rates of BF., Results: A total of 69 patients were analyzed. Sixteen patients underwent ART and 53 patients SRT, respectively. The median follow-up was 20 months (range, 8-41 months). Seven (10.1%) and four (5.8%) patients experienced acute grade 2 GU and GI toxicity. Two patients (2.9%) had late grade 2 GU toxicity, whereas no late grade 2 GI nor any grade 3 acute or late GU or GI events were observed. When compared to the baseline IPSS scores (p = 1.0) and ICIQ scores (p = 0.87) were not significantly different at the end of follow-up. Patient reported Quality of life (QoL) showed also no significant difference. A total of seven patients (10.1%) experienced a biochemical recurrence with the 2-year biochemical progression-free survival (bPFS) being 91%., Conclusions: Postoperative RT for prostate cancer patients with a risk adapted dose-intensified SIB using helical tomotherapy is feasible and associated with favorable acute and late GU and GI toxicity rates, no significant change of IPSS-, ICIQ scores and patient reported QoL and results in promising bPFS rates.

We examined the prognostic role of PD-1+ and CD8+ tumor infiltrating lymphocytes (TILs), and PD-L1+ cells in patients with squamous cell carcinoma of the head and neck (SCCHN) treated with surgery and postoperative chemoradiotherapy (CRT). FFPE samples from 161 patients were immunohistochemically stained for PD-1, CD8 and PD-L1. The immune marker expression was correlated with clinicopathologic characteristics, and overall survival (OS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of HPV16 DNA/p16 status. The median follow-up was 48 months (range: 4-100). The 2-year-OS was 84.1% for the entire cohort. High PD-1 and PD-L1 expression were more common in patients with positive HPV16 DNA (p < 0.001 and p = 0.008, respectively) and high infiltration by CD8+ TILs (p < 0.001 for both markers). High PD-L1 expression correlated with superior OS (p = 0.025), LPFS (p = 0.047) and DMFS (p = 0.048) in multivariable analysis, whereas no significance could be demonstrated for PD-1. Patients with CD8 high /PD-L1 high expression had favorable outcome (p < 0.001 for all endpoints) compared to other groups. We validated the superior OS data on CD8 high /PD-L1 high using the Cancer Genome Atlas TCGA dataset (n = 518; p = 0.032). High PD-L1 expression was a favorable prognostic marker in HPV16-negative but not HPV16-positive patients. In conclusion, HPV-positive tumors showed higher expression of immune markers. PD-L1 expression constitutes an independent prognostic marker in SCCHN patients post-adjuvant CRT. In conjunction with CD8 status, these data provide an important insight on the immune contexture of SCCHN and are directly relevant for future treatment stratification with PD-1/PD-L1 immune checkpoint inhibitors to complement CRT., (© 2017 UICC.)

Introduction: Outcome after postoperative radiochemotherapy (RT-CT) for patients with advanced head and neck squamous cell carcinomas (HNSCC) remains unsatisfactory, especially among those with HPV negative tumours. Therefore, new biomarkers are needed to further define subgroups for individualised therapeutic approaches. Preclinical and first clinical observations showed that the chemokine receptor CXCR4 and its ligand SDF-1 (CXCL12) play an important role in tumour cell proliferation, survival, cancer progression, metastasis and treatment resistance. However, the data on the prognostic value of SDF-1/CXCR4 expression for HNSCC are conflicting. The aim of our hypothesis-generating study was to retrospectively explore the prognostic potential of SDF-1/CXCR4 in a well-defined cohort of HNSCC patients collected within the multicenter biomarker study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG)., Material and Methods: Patients with stage III and IVA HNSCC of the oral cavity, oropharynx and hypopharynx were treated with resection and adjuvant radiotherapy (RT) with ≥60 Gy and concurrent cisplatin-based chemotherapy (CT). Tissue micro-arrays (TMAs) from a total of 221 patients were generated from surgical specimens, 201 evaluated for the SDF-1 and CXCR4 expression by immunofluorescence and correlated with clinico-pathological and outcome data., Results: In univariate and multivariate analyses intracellular SDF-1 expression was associated with lower loco-regional control (LRC) in the entire patient group as well as in the HPV16 DNA negative subgroup. CXCR4 expression showed a trend for lower LRC in the univariate analysis which was not confirmed in the multivariate analysis. Neither for SDF-1 nor CXCR4 expression associations with distant metastasis free or overall survival were found., Conclusions: Our exploratory data support the hypothesis that overexpression of intracellular SDF-1 is an independent negative prognostic biomarker for LRC after postoperative RT-CT in high-risk HNSCC. Prospective validation is warranted and further exploration of SDF-1/CXCR4 as a potential therapeutic target to overcome treatment resistance in HNSCC appears promising.

Objective: Current constraints aim to minimize the risk of radiation myelitis by the use of restrictive maximal spinal cord doses, commonly 50 Gy. However, several studies suggested that a dose-volume effect could exist. Based on these observations, we evaluated patients receiving potentially excessive doses to the spinal cord within minimal volumes., Patients and Methods: Patients receiving radiotherapy between June 2010 and May 2015 using the Novalis TM (Varian, Palo Alto, CA, USA; Brainlab, Heimstetten, Germany) radiosurgery system were retrospectively analyzed. A total of 56 patients with 62 treated lesions that had been prescribed radiation doses close to the spinal cord potentially higher than the common 50 Gy 2‑Gy equivalent-dose (EQD2) constraint were selected for further analysis. Of these patients, 26 with 31 lesions had no history of previous irradiation, while 30 patients with 31 lesions had been previously irradiated within the treatment field., Results: According to different dose evaluation approaches (spinal canal, spinal cord contour), 16 and 10 out of 31 primary irradiated lesions infringed constraints. For the 16 lesions violating spinal canal doses, the maximum doses ranged from 50.5 to 61.9 Gy EQD2. Reirradiated lesions had an average and median cumulative dose of 70.5 and 69 Gy, respectively. Dose drop-off was steep in both groups. Median overall survival was 17 months. No radiation myelitis or radiomorphological alterations were observed during follow-up., Conclusion: This study adds to the increasing body of evidence indicating that excessive spinal cord doses within a minimal volume, especially in a reirradiation setting with topographically distinct high-point doses, may be given to patients after careful evaluation of treatment- and tumor-associated risks.

Background: The predictive value of microRNAs (miRNAs) in tumour cells and infiltrating immune cells for the efficacy of chemoradiation (CRTX) in locally advanced head and neck squamous cell carcinoma (HNSCC) was evaluated., Methods: Formalin-fixed, paraffin-embedded tumour material was collected from patients with locally advanced HNSCC treated within the ARO-0401 phase III trial with radiotherapy in combination with either 5-fluorouracil/cisplatin (CDDP-CRTX) or 5-fluorouracil/mitomycin C (MMC-CRTX). MiRNA and immune profiles were established in a test cohort of 48 oropharyngeal carcinoma (OPSCC) cases by Affymetrix miRNA microarrays and the nanoString PanCancer Immune Panel, respectively. Expression of miRNA candidates was measured in 149 HNSCC patients by real-time PCR. Interference of miRNA profiles with CRTX efficacy was determined by Kaplan-Meier and Cox regression analysis., Results: Expression levels of five miRNAs (miR-27b, -130b, -200b, -451 and -532-5p) were significantly associated with overall survival after MMC-CRTX. Six different miRNAs (miR-125b, -146a, -150, -155, -187 and -342-5p) were correlated with overall survival after CDDP-CRTX. Validation by real-time PCR confirmed the predictive value of miR-200b and miR-155 in OPSCC, which was absent in hypopharyngeal carcinomas. MiR-146a was revealed as a prognostic marker for both CRTX regimens. MiR-200b expression was mainly associated with distant metastasis, whereas miR-155 correlated with local recurrence. MiR-155 and miR-146a were identified as surrogate markers for tumour-infiltrating lymphocytes., Conclusions: MiR-200b and miR-155 were established as potential markers for personalised treatment selection of two standard regimens of CRTX. The predictive role of miR-155 deserves further investigation, especially within the framework of clinical trials of CRTX/immune checkpoint inhibitor combinations., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: To investigate the potential of human satellite cells in muscle regeneration small animal models are useful to evaluate muscle regeneration. To suppress the inherent regeneration ability of the tibialis muscle of mice before transplantation of human muscle fibers, a localized irradiation of the mouse leg should be conducted. We analyzed the feasibility of an image-guided robotic irradiation procedure, a routine treatment method in radiation oncology, for the focal irradiation of mouse legs., Methods: After conducting a planning computed tomography (CT) scan of one mouse in its customized mold a three-dimensional dose plan was calculated using a dedicated planning workstation. 18 Gy have been applied to the right anterior tibial muscle of 4 healthy and 12 mice with immune defect in general anesthesia using an image-guided robotic linear accelerator (LINAC). The mice were fixed in a customized acrylic mold with attached fiducial markers for image guided tracking., Results: All 16 mice could be irradiated as prevised without signs of acute radiation toxicity or anesthesiological side effects. The animals survived until scarification after 8, 21 and 49 days as planned. The procedure was straight forward and the irradiation process took 5 minutes to apply the dose of 18 Gy., Conclusions: Localized irradiation of mice legs using a robotic LINAC could be conducted as planned. It is a feasible procedure without recognizable side effects. Image guidance offers precise dose delivery and preserves adjacent body parts and tissues., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Purpose: To develop a technique for radiation (RT) of in-transit path ways (IT) in Merkel cell carcinoma., Method: In the planning study, IT were ink-marked on the skin during sentinel lymphscintigraphy and wire-marked in planning-CT. Pre- and post-operative planning-CTs were acquired. The clinical target volume (CTV) included tumor bed plus safety margin, IT and draining nodes, the planning volume (PTV) the CTV plus 0.5-1cm margin. VMAT plans with 2-3 arcs were analyzed., Results: A planning study was performed for five pts. including two pts. with primary tumor (PT) in head and neck, 1 pt. each with PT of elbow, forearm and upper leg respectively. Plans showed satisfactory PTV coverage: D mean 100%±0%, D 98% 92.4%±2.24%, homogeneity index (HI) 0.095±0.01, conformation number (CN) 0.84±0.01 and conformality index (CI) 0.95±0.01., Conclusion: The planning study confirms feasibility of highly conformal irradiation of IT pathways based on individualized target delineation. Currently, patients referred for non-metastatic MCC are encouraged to enroll in a prospective clinical study that evaluates the feasibility of radiation of IT pathways., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To investigate the impact of the tumour volume, HPV status, cancer stem cell (CSC) marker expression and hypoxia gene signatures, as potential markers of radiobiological mechanisms of radioresistance, in a contemporary cohort of patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who received primary radiochemotherapy (RCTx)., Materials and Methods: For 158 patients with locally advanced HNSCC of the oral cavity, oropharynx or hypopharynx who were treated at six DKTK partner sites, the impact of tumour volume, HPV DNA, p16 overexpression, p53 expression, CSC marker expression and hypoxia-associated gene signatures on outcome of primary RCTx was retrospectively analyzed. The primary endpoint of this study was loco-regional control (LRC)., Results: Univariate Cox regression revealed a significant impact of tumour volume, p16 overexpression, and SLC3A2 and CD44 protein expression on LRC. The tumour hypoxia classification showed a significant impact only for small tumours. In multivariate analyses an independent correlation of tumour volume, SLC3A2 expression, and the 15-gene hypoxia signature with LRC was identified (CD44 protein n/a because of no event in the CD44-negative group). Logistic modelling showed that inclusion of CD44 protein expression and p16 overexpression significantly improved the performance to predict LRC at 2years compared to the model with tumour volume alone., Conclusions: Tumour volume, HPV status, CSC marker expression and hypoxia gene signatures are potential prognostic biomarkers for patients with locally advanced HNSCC, who were treated by primary RCTx. The study also supports that the individual tumour volumes should generally be included in biomarker studies and that panels of biomarkers are superior to individual parameters., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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 Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In solid tumours millions of cells are shed into the blood circulation each day. Only a subset of these circulating tumour cells (CTCs) survive, many of them presumable because of their potential to form multi-cellular clusters also named spheroids. Tumour cells within these spheroids are protected from anoikis, which allows them to metastasize to distant organs or re-seed at the primary site. We used spheroid cultures of head and neck squamous cell carcinoma (HNSCC) cell lines as a model for such CTC clusters for determining the role of the epidermal growth factor receptor (EGFR) in cluster formation ability and cell survival after detachment from the extra-cellular matrix. The HNSCC cell lines FaDu, SCC-9 and UT-SCC-9 (UT-SCC-9P) as well as its cetuximab (CTX)-resistant sub-clone (UT-SCC-9R) were forced to grow in an anchorage-independent manner by coating culture dishes with the anti-adhesive polymer poly-2-hydroxyethylmethacrylate (poly-HEMA). The extent of apoptosis, clonogenic survival and EGFR signalling under such culture conditions was evaluated. The potential of spheroid formation in suspension culture was found to be positively correlated with the proliferation rate of HNSCC cell lines as well as their basal EGFR expression levels. CTX and gefitinib blocked, whereas the addition of EGFR ligands promoted anchorage-independent cell survival and spheroid formation. Increased spheroid formation and growth were associated with persistent activation of EGFR and its downstream signalling component (MAPK/ERK). Importantly, HNSCC cells derived from spheroid cultures retained their clonogenic potential in the absence of cell-matrix contact. Addition of CTX under these conditions strongly inhibited colony formation in CTX-sensitive cell lines but not their resistant subclones. Altogether, EGFR activation was identified as crucial factor for anchorage-independent survival of HNSCC cells. Targeting EGFR in CTC cluster formation might represent an attractive anti-metastatic treatment approach in HNSCC., Competing Interests: The authors have declared that no competing interests exist.

Background: Treatment of locally advanced squamous cell carcinomas of the head and neck (SCCHN) remains unsatisfactory. Although the addition of concurrent radiochemotherapy (RCT) or the combination of radiotherapy with blockade of the epidermal growth factor receptor (EGFR) have improved outcomes over radiotherapy alone, further optimization is urgently needed. The introduction of immune checkpoint inhibitors is currently revolutionizing cancer treatment. Clinical evidence has recently been provided in melanoma that immune checkpoint blockade may cooperate with radiation. Therefore, we searched in the literature for the evidence of combining immune checkpoint inhibitors with radiotherapy in primary treatment of SCCHN., Discussion: A substantial amount of previous studies has dissected the molecular mechanisms of immune evasion in SCCHN. The biological effects of radio- and chemotherapy in tumor cells and the immune cell microenvironment were characterized in detail, revealing significant interference of both types of treatment with anti-tumor immunity. This extensive review of the literature revealed considerable amount of evidence that addition of immune checkpoint inhibitors might boost the immunomodulatory potential of radiotherapy and RCT regimens in SCCHN., Summary: Promising activity of immune checkpoint inhibitors has already been reported for metastatic/recurrent SCCHN. Given the immunogenic effect of radiotherapy and its enhancement by chemotherapy, combination of radiotherapy or RCT with this new type of immunotherapy might represent a valuable option for improvement of curative treatment modalities in SCCHN.

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.

Purpose: To investigate the impact of hypoxia-induced gene expression and cancer stem cell (CSC) marker expression on outcome of postoperative cisplatin-based radiochemotherapy (PORT-C) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC)., Experimental Design: Expression of the CSC markers CD44, MET, and SLC3A2, and hypoxia gene signatures were analyzed in the resected primary tumors using RT-PCR and nanoString technology in a multicenter retrospective cohort of 195 patients. CD44 protein expression was further analyzed in tissue microarrays. Primary endpoint was locoregional tumor control., Results: Univariate analysis showed that hypoxia-induced gene expression was significantly associated with a high risk of locoregional recurrence using the 15-gene signature (P = 0.010) or the 26-gene signature (P = 0.002). In multivariate analyses, in patients with HPV16 DNA-negative but not with HPV16 DNA-positive tumors the effect of hypoxia-induced genes on locoregional control was apparent (15-gene signature: HR 4.54, P = 0.006; 26-gene signature: HR 10.27, P = 0.024). Furthermore, MET, SLC3A2, CD44, and CD44 protein showed an association with locoregional tumor control in multivariate analyses (MET: HR 3.71, P = 0.016; SLC3A2: HR 8.54, P = 0.037; CD44: HR 3.36, P = 0.054; CD44 protein n/a because of no event in the CD44-negative group) in the HPV16 DNA-negative subgroup., Conclusions: We have shown for the first time that high hypoxia-induced gene expression and high CSC marker expression levels correlate with tumor recurrence after PORT-C in patients with HPV16 DNA-negative HNSCC. After validation in a currently ongoing prospective trial, these parameters may help to further stratify patients for individualized treatment de-escalation or intensification strategies. Clin Cancer Res; 22(11); 2639-49. ©2016 AACR., (©2016 American Association for Cancer Research.)

Introduction: Hyperfractionated (HFRT) or accelerated hyperfractionated radiotherapy (AHFRT) have been discussed as a potential treatment for glioblastoma based on a hypothesized reduction of late radiation injury and prevention of repopulation. HFRT and AHFRT have been examined extensively in the pre-Temozolomide era with inconclusive results. In this study we examined the role of accelerated hyperfractionation in the Temozolomide era., Materials and Methods: Sixty-four patients who underwent AHFRT (62 of which received Temozolomide) were compared to 67 patients who underwent normofractionated radiotherapy (NFRT) (64 of which received TMZ) between 02/2009 and 10/2014. Follow-up data were analyzed until 01/2015., Results: Median progression-free survival (PFS) was 6 months for the entire cohort. For patients treated with NFRT median PFS was 7 months, for patients treated with AHFRT median PFS was 6 months. Median overall survival (OS) was 13 months for all patients. For patients treated with NFRT median OS was 15 months, for patients treated with AHFRT median OS was 10 months. The fractionation regimen was not a predictor of PFS or OS in univariable- or multivariable analysis. There was no difference in acute toxicity profiles between the two treatment groups., Conclusions: Univariable and multivariable analysis did not show significant differences between NFRT and AHFRT fractionation regimens in terms of PFS or OS. The benefits are immanent: the regimen does significantly shorten hospitalization time in a patient collective with highly impaired life expectancy. We propose that the role of AHFRT + TMZ should be further examined in future prospective trials.

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.

Here we evaluate the current status of clinical research on regional hyperthermia (RHT) in combination with chemotherapy or radiation therapy in paediatric oncology.Data were identified in searches of MEDLINE, Current Contents, PubMed, and references from relevant articles using medical subject headings including hyperthermia, cancer, paediatric oncology, children, radiation therapy and chemotherapy. Currently, only two RHT centres exist in Europe which treat children. Clinical RHT research in paediatric oncology has as yet been limited to children with sarcomas and germ cell tumours that respond poorly to or recur after chemotherapy. RHT is a safe and effective treatment delivering local thermic effects, which may also stimulate immunological processes via heat-shock protein reactions. RHT is used chiefly in children and adolescents with sarcomas or germ cell tumours located in the abdomino-pelvic region, chest wall or extremities to improve operability or render the tumour operable. It could potentially be combined with radiation therapy in a post-operative R1 setting where more radical surgery is not possible or combined with chemotherapy instead of radiation therapy in cases where the necessary radiation dose is impossible to achieve or would have mutilating consequences. RHT might also be an option for chemotherapy intensification in the neoadjuvant first-line treatment setting for children and adolescents, as was recently reflected in the promising long-term outcome data in adults with high-risk soft tissue sarcomas (EORTC 62961/ESHO trial).The limited data available indicate that combining RHT with chemotherapy is a promising option to treat germ cell tumours and, potentially, sarcomas. RHT may also be beneficial in first-line therapy in children, adolescents and young adults. The research should focus on optimising necessary technical demands and then initiate several clinical trials incorporating RHT into interdisciplinary treatment of children, adolescents and young adults that include translational research components exploring potential immunological mechanisms of action.

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.

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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

For primary radiation therapy (RT) of prostate cancer, dose intensification is established as standard of care. Less is known on the role of dose intensification in the postprostatectomy setting for salvage RT. Thus, we aimed to identify and summarize the existing literature. In retrospective analyses, dose-intensified salvage RT showed a superior biochemical control compared to standard dose salvage radiation with favorable acute and late gastrointestinal and genitourinary toxicity rates, especially when modern radiation techniques such as intensity modulated RT were applied. We identified one randomized phase III trial addressing the potential benefits of dose-intensified salvage RT (SAKK 09/10). Recently, acute gastrointestinal and genitourinary toxicities and early quality of life data of this trial were reported, and no significant difference in acute toxicities between both treatment arms were found; however, a significant worsening of genitourinary quality of life was noted in the dose-intensified treatment arm. Whereas dose-intensified salvage RT appears to be feasible and well tolerated, the improved biochemical control rates using dose intensified RT as suggested by retrospective analyses have yet to be validated by prospective trials.

Objective: The purpose of this study was to evaluate risk factors for and the incidence of osteoradionecrosis (ORN) of the jaw in patients with head and neck cancer., Study Design: This study was a retrospective analysis of the risk for ORN and outcome for 149 of 540 patients with head and neck cancer of the oral cavity (65%), oropharynx (26%), or other head and neck sites (9%) treated with radiotherapy between 2004 and 2009. ORN was graded according to Late Effects of Normal Tissues/Somatic Objective Management Analytic Scale (LENT/SOMA) criteria., Results: Within a median follow-up of 41 months (95% confidence interval: 27.4-54.6), 38 patients (25.5%) had developed ORN, 37 patients (25%) had a local recurrence, and 53 patients (36%) had died. The median time to diagnosis of ORN was 14.5 months (range: 3-80), and 79% were diagnosed within 2 years of RT. Eleven of these patients had undergone previous mandibular surgery. Univariate significant risk factors for ORN were any comorbidity, poor oral hygiene, pre-radiotherapy osteotomy, close tumor-to-bone proximity, post-radiotherapy dentoalveolar surgery (DAS), DAS without sufficient wound closure, alcohol consumption, and denture pressure sores. In multivariate analysis, comorbidities, pre-radiotherapy mandibular surgery, poor oral hygiene, and insufficient DAS remained significant., Conclusions: Reducing the risk of ORN calls for maintaining optimal oral hygiene, ensuring good denture fit, receiving proper training in DAS, and helping patients to stop drinking and smoking., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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.)