App-Controlled Treatment Monitoring and Support for Patients With Head and Neck Cancer Undergoing Radiotherapy: Results From a Prospective Randomized Controlled Trial.

BACKGROUND: Head and neck cancers (HNCs) are very common malignancies, and treatment often requires multimodal approaches, including radiotherapy and chemotherapy. Patients with HNC often display a high symptom burden, both due to the disease itself and the adverse effects of the multimodal therapy. Close telemonitoring of symptoms and quality of life during the course of treatment may help to identify those patients requiring early medical support. OBJECTIVE: The App-Controlled Treatment Monitoring and Support for Patients With Head and Neck Cancer (APCOT) trial aimed to investigate the feasibility of integrating electronic patient-reported outcomes (ePROs) in the treatment surveillance pathway of patients with HNC during the course of their radiotherapy. Additionally, the influence of app-based ePRO monitoring on global and disease-specific quality of life and patient satisfaction with treatment was assessed. METHODS: Patients undergoing radiotherapy for histologically proven HNCs at the Department of Radiation Oncology, University Medical Center Freiburg, Germany, were enrolled in this trial and monitored by weekly physician appointments. Patients were randomized between additional ePRO monitoring on each treatment day or standard-of-care monitoring. Feasibility of ePRO monitoring was defined as ≥80% of enrolled patients answering ≥80% of their daily app-based questions. Quality of life and patient satisfaction were assessed by the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30), the head and neck cancer module (H&N35), and the validated Patient Satisfaction Questionnaire Short Form (PSQ-18) at the completion of treatment and compared between trial arms. RESULTS: A total of 100 patients were enrolled in this trial, and 93 patients were evaluable. All patients (100%) in the experimental arm answered ≥80% of the ePRO questions during treatment, reaching the predefined threshold for the feasibility of ePRO monitoring (P<.001 in the binomial test). No clinical or patient-specific factor was found to influence feasibility. Global health and most domains of the general quality of life were comparable between trial arms, but an increased HNC-specific symptom burden was reported by patients undergoing ePRO surveillance. ePRO monitoring resulted in improved patient satisfaction regarding interpersonal manners (P=.01), financial aspects (P=.01), and time spent with a doctor (P=.01). CONCLUSIONS: This trial demonstrated the feasibility of incorporating daily app-based ePRO surveillance for patients with HNC undergoing radiotherapy. Our data, for the first time, demonstrate that telemonitoring in this setting led to increased reporting of HNC-specific symptom burden and significantly improved several domains of patient satisfaction. Further analyses are needed to assess whether our findings hold true outside the context of a clinical trial. TRIAL REGISTRATION: German Clinical Trials Register DRKS00020491; https://drks.de/search/en/trial/DRKS00020491.

Comparison of intraoperative radiotherapy as a boost vs. simultaneously integrated boosts after breast-conserving therapy for breast cancer.

Background: Currently, there are no data from randomized trials on the use of intraoperative radiotherapy (IORT) as a tumor bed boost in women at high risk of local recurrence. The aim of this retrospective analysis was to compare the toxicity and oncological outcome of IORT or simultaneous integrated boost (SIB) with conventional external beam radiotherapy (WBI) after breast conserving surgery (BCS). Methods: Between 2009 and 2019, patients were treated with a single dose of 20 Gy IORT with 50 kV photons, followed by WBI 50 Gy in 25 or 40.05 in 15 fractions or WBI 50 Gy with SIB up to 58.80-61.60 Gy in 25-28 fractions. Toxicity was compared after propensity score matching. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Results: A 1:1 propensity-score matching resulted in an IORT + WBI and SIB + WBI cohort of 60 patients, respectively. The median follow-up for IORT + WBI was 43.5 vs. 32 months in the SIB + WBI cohort. Most women had a pT1c tumor: IORT group 33 (55%) vs. 31 (51.7%) SIB group (p = 0.972). The luminal-B immunophenotype was most frequently diagnosed in the IORT group 43 (71.6%) vs. 35 (58.3%) in the SIB group (p = 0.283). The most reported acute adverse event in both groups was radiodermatitis. In the IORT cohort, radiodermatitis was grade 1: 23 (38.3%), grade 2: 26 (43.3%), and grade 3: 6 (10%) vs. SIB cohort grade 1: 3 (5.1%), grade 2: 21 (35%), and grade 3: 7 (11.6%) without a meaningful difference (p = 0.309). Fatigue occurred more frequently in the IORT group (grade 1: 21.7% vs. 6.7%; p = 0.041). In addition, intramammary lymphedema grade 1 occurred significantly more often in the IORT group (11.7% vs. 1.7%; p = 0.026). Both groups showed comparable late toxicity. The 3- and 5-year local control (LC) rates were each 98% in the SIB group vs. 98% and 93% in the IORT group (LS: log rank p = 0.717). Conclusion: Tumor bed boost using IORT and SIB techniques after BCS shows excellent local control and comparable late toxicity, while IORT application exhibits a moderate increase in acute toxicity. These data should be validated by the expected publication of the prospective randomized TARGIT-B study.

Patient reported outcomes based on EQ-5D-5L questionnaires in head and neck cancer patients: a real-world study.

OBJECTIVE: Health economic comparisons of various therapies are often based on health-related quality of life (HRQOL) using EQ-5D questionnaires within the framework of clinical trials. This real-world study prospectively evaluates the patient reported outcomes (PROs)-based HRQOL of head-and-neck (H&N) cancer patients undergoing modern radiotherapy (RT) to reflect PRO trajectories. METHODS: All H&N cancer patients treated in our clinic between July 2019 and December 2020 who completed the self-reported validated EQ-5D-5L questionnaire (health state index (HI) and Visual Analog Scale (VAS)) at baseline, end of radiotherapy, and at each respective follow up (FU) were included. Descriptive analysis of clinical and sociodemographic data, the frequency and level of each dimension was conducted. To assess the significance of therapy-induced HRQOL changes within and between the group, a distribution-based approach was used. RESULTS: Altogether, 366 participants completed a total of 565 questionnaires. For the whole cohort, HI at baseline was 0.804 (±0.208), 0.830 (±0.162) at RT completion, 0.812 (±0.205) at the first follow-up, and 0.769 (±0.224) at the second follow-up. The respective VAS values were 62.06 (±23,94), 66.73 (±82.20), 63.30 (±22.74), and 65.48 (±23.39). Females showed significantly lower HI values compared to males, but only at baseline (p = 0.034). Significantly lower HI values were also seen in patients with definitive RT as compared to adjuvant RT at baseline (p = 0.023), the second follow-up (p = 0.047), and the third follow-up (p = 0.010). As compared to outpatients, inpatients had significantly lower HI values at RT completion (p = 0.017), the second follow-up (p = 0.007), and the third follow-up (p = 0.031). Subgroup analyses by age (< 65 vs. ≥65) and smoking status (smokers vs. non-smokers) showed no difference at any time point. CONCLUSION: PROs demonstrated detectability of time- and intra-/inter-group therapy-induced HRQOL changes. A further detailed exploration of EQ-5D-5L responsiveness for H&N cancer patients is required.

Palliative radiotherapy of bone metastases in octogenarians: How do the oldest olds respond? Results from a tertiary cancer center with 288 treated patients.

BACKGROUND: Accompanied by the demographic change, the number of octogenarian cancer patients with bone metastases will increase in the future. Palliative radiotherapy constitutes an effective analgesic treatment; however, as pain perception and bone metabolism change with increasing age, the analgesic efficacy of radiotherapy may be altered in elderly patients. We therefore investigated the treatment outcomes of palliative radiotherapy for bone metastases in octogenarians. METHODS: Patients between 80 and 89 years undergoing radiotherapy for bone metastases between 2009 and 2019 at a tertiary cancer center were analyzed for patterns-of-care, pain response and overall survival (OS). Logistic regression analyses were carried out to examine parameters associated with pain response, and Cox analyses were conducted to reveal prognostic parameters for OS. RESULTS: A total of 288 patients with 516 irradiated lesions were included in the analysis. The majority (n = 249, 86%) completed all courses of radiotherapy. Radiotherapy led to pain reduction in 176 patients (61%) at the end of treatment. Complete pain relief at the first follow-up was achieved in 84 patients (29%). Bisphosphonate administration was significantly associated with higher rates of pain response at the first follow-up (p < 0.05). Median OS amounted to 9 months, and 1-year, 2-year and 3-year OS were 43%, 28% and 17%. In the multivariate analysis, ECOG (p < 0.001), Mizumoto score (p < 0.01) and Spinal Instability Neoplastic Score (SINS) (p < 0.001) were independent prognosticators for OS. CONCLUSION: Palliative radiotherapy for bone metastases constitutes a feasible and effective analgesic treatment in octogenarian patients. ECOG, Mizumoto score and SINS are prognosic variables for survival and may aid treatment decisions regarding radiotherapy fractionation in this patient group. Single-fraction radiotherapy with 8 Gy should be applied for patients with uncomplicated bone metastases and poor prognosis. Prospective trials focusing on quality of life of these very old cancer patients with bone metastases are warranted to reveal the optimal radiotherapeutic management for this vulnerable population.

Spleen Preserving, Splenic Vessels Spearing, Pure Laparoscopic Total Duodenopancreatectomy for Intraductal Papillary Mucinous Pancreatic Neoplasia (IPMN): Case Report and Technique.

Total duodenopancreatectomy (TDP), performed exclusively by laparoscopic approach is considered one of the most complex abdominal surgical procedures. TDP with preservation of spleen vessels (operation Kimura) is a more technically-demanding procedure, but is beneficial in selected cases. While some high-volume centers have gained experience in minimally-invasive pancreatectomies, laparoscopic approach remains a recommendation for well selected patients with benign or low-grade malignant tumors and should be performed with caution, by experienced HPB surgeons. In this paper, we present a spleen preserving, splenic vessels spearing, pure laparoscopic TDP on a 40-year-old patient diagnosed with diffuse IPMN performed in our center, illustrating the operative steps.

The value of plasma hypoxia markers for predicting imaging-based hypoxia in patients with head-and-neck cancers undergoing definitive chemoradiation.

BACKGROUND: Tumor hypoxia worsens the prognosis of head-and-neck squamous cell carcinoma (HNSCC) patients, and plasma hypoxia markers may be used as biomarkers for radiotherapy personalization. We therefore investigated the role of the hypoxia-associated plasma proteins osteopontin, galectin-3, vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) as surrogate markers for imaging-based tumor hypoxia. METHODS: Serial blood samples of HNSCC patients receiving chemoradiation within a prospective trial were analyzed for osteopontin, galectin-3, VEGF and CTGF concentrations. Tumor hypoxia was quantified in treatment weeks 0, 2 and 5 using [18F]FMISO PET/CT. The association between PET-defined hypoxia and the plasma markers was determined using Pearson's correlation analyses. Receiver-operating characteristic analyses were conducted to reveal the diagnostic value of the hypoxia markers. RESULTS: Baseline osteopontin (r = 0.579, p < 0.01) and galectin-3 (r = 0.429, p < 0.05) correlated with the hypoxic subvolume (HSV) prior to radiotherapy, whereas VEGF (r = 0.196, p = 0.36) and CTGF (r = 0.314, p = 0.12) showed no association. Patients with an HSV > 1 mL in week 2 exhibited increased VEGF (p < 0.05) and CTGF (p < 0.05) levels in week 5. Pretherapeutic osteopontin levels were higher in patients exhibiting residual hypoxia at the end of treatment (104.7 vs. 60.8 ng/mL, p < 0.05) and could therefore predict residual hypoxia (AUC = 0.821, 95% CI 0.604-1.000, p < 0.05). CONCLUSION: In this exploratory analysis, osteopontin correlated with the initial HSV and with residual tumor hypoxia; therefore, there may be a rationale to study hypoxic modification based on osteopontin levels. However, as plasma hypoxia markers do not correspond to any spatial information of tumor hypoxia, they have limitations regarding the replacement of [18F]FMISO PET-based focal treatments. The results need to be validated in larger patient cohorts to draw definitive conclusions.

Interleukin-6 as surrogate marker for imaging-based hypoxia dynamics in patients with head-and-neck cancers undergoing definitive chemoradiation-results from a prospective pilot trial.

PURPOSE: Intratumoral hypoxia increases resistance of head-and-neck squamous cell carcinoma (HNSCC) to radiotherapy. [18F]FMISO PET imaging enables noninvasive hypoxia monitoring, though requiring complex logistical efforts. We investigated the role of plasma interleukin-6 (IL-6) as potential surrogate parameter for intratumoral hypoxia in HNSCC using [18F]FMISO PET/CT as reference. METHODS: Within a prospective trial, serial blood samples of 27 HNSCC patients undergoing definitive chemoradiation were collected to analyze plasma IL-6 levels. Intratumoral hypoxia was assessed in treatment weeks 0, 2, and 5 using [18F]FMISO PET/CT imaging. The association between PET-based hypoxia and IL-6 was examined using Pearson's correlation and multiple regression analyses, and the diagnostic power of IL-6 for tumor hypoxia response prediction was determined with receiver-operating characteristic analyses. RESULTS: Mean IL-6 concentrations were 15.1, 19.6, and 31.0 pg/mL at baseline, week 2 and week 5, respectively. Smoking (p=0.050) and reduced performance status (p=0.011) resulted in higher IL-6 levels, whereas tumor (p=0.427) and nodal stages (p=0.334), tumor localization (p=0.439), and HPV status (p=0.294) had no influence. IL-6 levels strongly correlated with the intratumoral hypoxic subvolume during treatment (baseline: r=0.775, p<0.001; week 2: r=0.553, p=0.007; week 5: r=0.734, p<0.001). IL-6 levels in week 2 were higher in patients with absent early tumor hypoxia response (p=0.016) and predicted early hypoxia response (AUC=0.822, p=0.031). Increased IL-6 levels at week 5 resulted in a trend towards reduced progression-free survival (p=0.078) and overall survival (p=0.013). CONCLUSION: Plasma IL-6 is a promising surrogate marker for tumor hypoxia dynamics in HNSCC patients and may facilitate hypoxia-directed personalized radiotherapy concepts. TRIAL REGISTRATION: The prospective trial was registered in the German Clinical Trial Register (DRKS00003830). Registered 20 August 2015.

18F-FMISO-PET Hypoxia Monitoring for Head-and-Neck Cancer Patients: Radiomics Analyses Predict the Outcome of Chemo-Radiotherapy.

Tumor hypoxia is associated with radiation resistance and can be longitudinally monitored by 18F-fluoromisonidazole (18F-FMISO)-PET/CT. Our study aimed at evaluating radiomics dynamics of 18F-FMISO-hypoxia imaging during chemo-radiotherapy (CRT) as predictors for treatment outcome in head-and-neck squamous cell carcinoma (HNSCC) patients. We prospectively recruited 35 HNSCC patients undergoing definitive CRT and longitudinal 18F-FMISO-PET/CT scans at weeks 0, 2 and 5 (W0/W2/W5). Patients were classified based on peritherapeutic variations of the hypoxic sub-volume (HSV) size (increasing/stable/decreasing) and location (geographically-static/geographically-dynamic) by a new objective classification parameter (CP) accounting for spatial overlap. Additionally, 130 radiomic features (RF) were extracted from HSV at W0, and their variations during CRT were quantified by relative deviations (∆RF). Prediction of treatment outcome was considered statistically relevant after being corrected for multiple testing and confirmed for the two 18F-FMISO-PET/CT time-points and for a validation cohort. HSV decreased in 64% of patients at W2 and in 80% at W5. CP distinguished earlier disease progression (geographically-dynamic) from later disease progression (geographically-static) in both time-points and cohorts. The texture feature low grey-level zone emphasis predicted local recurrence with AUCW2 = 0.82 and AUCW5 = 0.81 in initial cohort (N = 25) and AUCW2 = 0.79 and AUCW5 = 0.80 in validation cohort. Radiomics analysis of 18F-FMISO-derived hypoxia dynamics was able to predict outcome of HNSCC patients after CRT.

Intraoperative radiotherapy boost as part of breast-conservation therapy for breast cancer: a single-institution retrospective analysis.

BACKGROUND: There are currently no data from randomized controlled trials on the use of intraoperative radiotherapy (IORT) as a tumor bed boost as part of a breast-conservation approach for breast cancer. This study retrospectively reviewed the safety and efficacy of IORT as a boost treatment at a tertiary cancer center. METHODS: From 2015 to 2019, patients underwent breast-conserving surgery with axillary lymph node staging and a single dose of 20 Gy IORT with 50-kV photons, followed by whole-breast irradiation (WBI) and adjuvant systemic therapy (if applicable). Patients were followed for assessment of acute and late toxicities (using the Common Terminology Criteria for Adverse Events version 5.0) at 3-6-month intervals. Outcomes included ipsilateral (IBTR) and contralateral breast progression-free survival (CBE), distant metastasis-free survival (DMFS), and overall survival (OS). RESULTS: Median follow-up for the 214 patients was 28 (range 2-59) months. Most patients had T1 disease (n = 124) and were clinically node negative. Only few patients had high-grade and/or triple-negative disease. The vast majority of patients underwent sentinel node biopsy, and 32 (15%) required re-resection for initially positive margins. Finally, all tumor bed margins were clear. Nine (4.2%) and 48 (22.4%) patients underwent neoadjuvant and adjuvant chemotherapy, respectively. WBI was predominantly performed as conventionally fractionated WBI (n = 187, 87.4%), and the median time from BCS to WBI was 54.5 days. IORT was delivered with a single dose of 20 Gy. The median WBI dose was 50 Gy (range 29.4-50.4 Gy). No patients experienced grade 4 events; acute grade 3 toxicities were limited to 17 (8%) cases of radiation dermatitis. Postoperative toxicities were mild. After WBI only one case of late grade ≥ 2 events was reported. There were two recurrences in the tumor bed and one contralateral breast event. CONCLUSION: This investigation provides additional preliminary data supporting the using of IORT in the boost setting and corroborates the existing literature. These encouraging results should be prospectively validated by the eventual publication of randomized studies such as TARGIT­B.

Surviving Elderly Patients with Head-and-Neck Squamous Cell Carcinoma-What Is the Long-Term Quality of Life after Curative Radiotherapy?

The effects of radiotherapy on the long-term quality of life (QoL) of surviving elderly HNSCC patients are not well understood, therefore, we analyzed QoL in this population. A cross-sectional analysis was performed at a tertiary cancer center to assess long-term QoL in elderly HNSCC patients. Eligible patients were ≥65 years at the time of treatment who had to be alive for ≥1 year after radiotherapy and without current anti-cancer treatment. QoL and patient satisfaction were assessed using the EORTC QLQ-C30, QLQ-H&N35 and ZUF-8 questionnaires, respectively, and treatment-related toxicities were graded according to CTCAE (Common Terminology Criteria of Adverse Effects) v.5.0. Seventy-four patients met the inclusion criteria, of which 50 consented to participate. Median time between radiotherapy and QoL assessment was 32 months (range 12-113). The QLQ-C30 global QoL median amounted to 66.7 points (interquartile range (IQR) 50.0-83.3), which was comparable to the age- and gender-adjusted German population (median 65.3). Median global QoL was similar between patients undergoing definitive (75.0, IQR 50.0-83.3) and adjuvant (chemo)radiotherapy (66.7, IQR 41.7-83.3, p = 0.219). HPV-positive HNSCC patients had superior global QoL after radiotherapy than their HPV-negative counterparts (p < 0.05), and concomitant chemotherapy did not influence the long-term QoL (p = 0.966). Median global QoL did not correspond with physician-assessed highest-graded chronic toxicities (p = 0.640). The ZUF-8 ranged at 29 points in median (IQR 27-31), showing high patient satisfaction. Surviving elderly HNSCC patients treated by radiotherapy exhibit a relatively high long-term global QoL which is a relevant information for clinicians treating elderly HNSCC patients.

Immunohistochemistry-based hypoxia-immune prognostic classifier for head-and-neck cancer patients undergoing chemoradiation - Post-hoc analysis from a prospective imaging trial.

PURPOSE: As both tumor hypoxia and an immunosuppressing tumor microenvironment hamper the anti-tumor activity of radiotherapy in head-and-neck squamous cell carcinoma (HNSCC), we aimed to develop an immunohistochemistry-based hypoxia-immune classifier. METHODS: 39 patients receiving definitive chemoradiation for HNSCC within a prospective trial were included in this analysis. Baseline tumor samples were analyzed for the hypoxia marker carbonic anhydrase IX (CAIX) and tumor-infiltrating lymphocytes (TILs) and were correlated with [18F]-misonidazole ([18F]FMISO) PET measurements. The impact of the biomarkers on the locoregional control (LRC) was examined using Cox analyses and concordance index statistics. RESULTS: Low CAIX (HR = 0.352, 95%CI 0.124-1.001, p = 0.050) and high TIL levels (HR = 0.308, 95%CI 0.114-0.828, p = 0.020) were independent parameters for improved LRC and did not correlate with each other (Spearman's ρ = 0.034, p = 0.846). Harrell's C was 0.66 for CAIX and TIL levels alone and 0.71 for the combination. 2-year LRC was 73%, 62% and 11% for the prognostically good (CAIXlow/TILhigh), intermediate (CAIXlow/TILlow or CAIXhigh/TILhigh) and poor groups (CAIXhigh/TILlow), respectively (p = 0.001). Focusing on T lymphocytes, the hypoxia-immune classifier could still stratify between favorable (CAIXlow/CD3 + TILhigh), intermediate (CAIXlow/CD3 + TILlow or CAIXhigh/CD3 + TILhigh) and poor subgroups (CAIXhigh/CD3 + TILlow) with a 2-year LRC of 80%, 59% and 14%, respectively (p = 0.001). There was a positive correlation between baseline CAIX levels and [18F]FMISO SUV in week 2 of chemoradiation (ρ = 0.324, p = 0.050), indicating an association between higher baseline CAIX expression and tumor hypoxia persistence. CONCLUSION: We developed a clinically feasible hypoxia-immune prognostic classifier for HNSCC patients based on pre-treatment immunohistochemistry. However, external validation is required to determine the prognostic value and the potential usage for personalized radiation oncology.

Development and validation of a novel prognostic score for elderly head-and-neck cancer patients undergoing radiotherapy or chemoradiation.

BACKGROUND AND PURPOSE: To establish a clinically feasible prognostic score and nomogram based on easily accessible clinical data that will aid decision-making in elderly head-and-neck squamous cell carcinoma (HNSCC) patients undergoing (chemo)radiotherapy. MATERIAL AND METHODS: 284 elderly HNSCC patients (≥65 years) undergoing curative (chemo)radiotherapy were included for the development of a score predicting overall survival (OS) based on the beta regression coefficients from significant parameters in a multivariate Cox regression analysis with p < 0.1 as inclusion criterion. A second, external cohort of 217 elderly HNSCC patients receiving (chemo)radiotherapy was used for validation. Using the aggregated data (n = 501), a nomogram was developed to predict 2- and 4-year OS. RESULTS: Karnofsky Performance Status (HR = 2.654; p < 0.001), Charlson Comorbidity Index (HR = 2.598; p < 0.001) and baseline C-reactive protein (CRP) level (HR = 1.634; p = 0.068) were prognostic for OS in the multivariate analysis. An OS score based on beta regression coefficients was created, in which reduced performance status, increased comorbidity burden and increased CRP levels were included, leading to 3 distinct survival groups. The median OS for the 3 groups amounted to 107, 28 and 6 months, respectively (p < 0.001). The developed score was able to significantly differentiate between a favorable (median OS = 130 months), intermediate (29 months) and unfavorable prognosis (9 months) also in the external validation cohort (p = 0.005). CONCLUSION: We propose a novel, validated prognostic score based on easily accessible clinical data allowing stratification between prognostic groups of elderly HNSCC patients receiving (chemo)radiotherapy. The derived nomogram for the prediction of 2-year and 4-year OS may aid decision-making for this vulnerable population.

Radiation-induced toxicities and outcomes after radiotherapy are independent of patient age in elderly salivary gland cancer patients: results from a matched-pair analysis of a rare disease.

PURPOSE: This study analyzed survival and toxicity after (chemo)radiotherapy for primary salivary gland cancer patients aged ≥ 65 years and compared these results with younger patients using a matched-pair analysis. METHODS: Twenty-nine elderly patients with primary salivary gland carcinomas treated with (chemo)radiotherapy from 2008 to 2020 at University of Freiburg Medical Center were analyzed for oncological outcomes and therapy-associated toxicities. Local/locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and the influence of clinical parameters on patient outcomes was assessed. A matched-pair analysis was performed after matching with patients < 65 years. RESULTS: Nine patients (31.0%) received definitive (chemo)radiotherapy, and 20 patients (69.0%) were treated in the adjuvant setting. 2-year LRC, PFS and OS ranged at 82.4%, 53.7% and 71.8%, respectively. Smoking (HR 3.980, p = 0.020), reduced performance status (HR 3.735, p = 0.016) and higher comorbidity burden (HR 4.601, p = 0.005) correlated with inferior OS. Using a matched-pair analysis with younger patients, elderly patients exhibited a trend towards reduced OS (HR 3.015, p = 0.065), but not PFS (HR 1.474, p = 0.371) or LRC (HR 1.324, p = 0.633). Acute and chronic grade 3 toxicities occurred in 31.0% and 12.5% of elderly patients, respectively, and the matched-pair analysis revealed no significant differences between age groups regarding treatment-related toxicities. CONCLUSION: Treatment-related toxicities as well as LRC and PFS were comparable for salivary gland cancer patients undergoing radiotherapy. Therefore, concerns for more pronounced toxicities or reduced local/locoregional response rates should not guide treatment decisions in affected elderly patients.

App-Controlled Treatment Monitoring and Support for Head and Neck Cancer Patients (APCOT): Protocol for a Prospective Randomized Controlled Trial.

BACKGROUND: Head and neck cancers (HNCs) are among the most common malignancies, which often require multimodal treatment that includes radiation therapy and chemotherapy. Patients with HNC have a high burden of symptoms due to both the damaging effects of the tumor and the aggressive multimodal treatment. Close symptom monitoring over the course of the disease may help to identify patients in need of medical interventions. OBJECTIVE: This APCOT (App-Controlled Treatment Monitoring and Support for Head and Neck Cancer Patients) trial is designed to assess the feasibility of monitoring HNC patients during the course of (chemo)radiation therapy daily using a mobile app. Additionally, symptom patterns, patient satisfaction, and quality of life will be measured in app-monitored patients in comparison to a patient cohort receiving standard-of-care physician appointments, and health economy aspects of app monitoring will be analyzed. METHODS: This prospective randomized single-center trial will evaluate the feasibility of integrating electronic patient-reported outcome measures (ePROMs) into the treatment workflow of HNC patients. Patients undergoing definitive or adjuvant (chemo)radiation therapy as part of their HNC treatment at the Department of Radiation Oncology, University Medical Center Freiburg (Freiburg, Germany) will receive weekly physician appointments and additional appointments as requested to monitor and potentially treat symptoms during the course of treatment. Patients in the experimental arm will additionally be monitored daily using a dedicated app regarding their disease- and treatment-related symptoms, quality of life, and need for personal physician appointments. The feasibility of ePROM monitoring will be tested as the primary endpoint and will be defined if ≥80% of enrolled patients have answered ≥80% of their daily app-based questions. Quality of life will be assessed using the validated European Organisation for Research and Treatment of Cancer questionnaires, and patient satisfaction will be measured by the validated Patient Satisfaction Questionnaire Short Form at the initiation, in the middle, and at completion of radiation therapy, as well as at follow-up examinations. Additionally, the number and duration of physician appointments during the course of radiation therapy will be quantified for both ePROM-monitored and standard-of-care patients. RESULTS: This trial will enroll 100 patients who will be randomized (1:1) between the experimental arm with ePROM monitoring and the control arm with standard patient care. Recruitment will take 18 months, and trial completion is planned at 24 months after enrollment of the last patient. CONCLUSIONS: This trial will establish the feasibility of close ePROM monitoring of HNC patients undergoing (chemo)radiation therapy. The results can form the basis for further trials investigating potential clinical benefits of detailed symptom monitoring and patient-centered care in HNC patients regarding oncologic outcomes and quality of life. TRIAL REGISTRATION: German Clinical Trials Register DRKS00020491; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00020491. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/21693.

Hypoxia dynamics on FMISO-PET in combination with PD-1/PD-L1 expression has an impact on the clinical outcome of patients with Head-and-neck Squamous Cell Carcinoma undergoing Chemoradiation.

Tumor-associated hypoxia influences the radiation response of head-and-neck cancer (HNSCC) patients, and a lack of early hypoxia resolution during treatment considerably deteriorates outcomes. As the detrimental effects of hypoxia are partly related to the induction of an immunosuppressive microenvironment, we investigated the interaction between tumor hypoxia dynamics and the PD-1/PD-L1 axis in HNSCC patients undergoing chemoradiation and its relevance for patient outcomes in a prospective trial. Methods: 49 patients treated with definitive chemoradiation for locally advanced HNSCC were enrolled in this trial and received longitudinal hypoxia PET imaging using fluorine-18 misonidazole ([18F]FMISO) at weeks 0, 2 and 5 during treatment. Pre-therapeutic tumor biopsies were immunohistochemically analyzed regarding the PD-1/PD-L1 expression both on immune cells and on tumor cells, and potential correlations between the PD-1/PD-L1 axis and tumor hypoxia dynamics during chemoradiation were assessed using Spearman's rank correlations. Hypoxia dynamics during treatment were quantified by subtracting the standardized uptake value (SUV) index at baseline from the SUV values at weeks 2 or 5, whereby SUV index was defined as ratio of maximum tumor [18F]FMISO SUV to mean SUV in the contralateral sternocleidomastoid muscle (i.e. tumor-to-muscle ratio). The impact of the PD-1/PD-L1 expression alone and in combination with persistent tumor hypoxia on locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) was examined using log-rank tests and Cox proportional hazards models. Results: Neither PD-L1 nor PD-1 expression levels on tumor-infiltrating immune cells influenced LRC (HR = 0.734; p = 0.480 for PD-L1, HR = 0.991; p = 0.989 for PD-1), PFS (HR = 0.813; p = 0.597 for PD-L1, HR = 0.796; p = 0.713 for PD-1) or OS (HR = 0.698; p = 0.405 for PD-L1, HR = 0.315; p = 0.265 for PD-1). However, patients with no hypoxia resolution between weeks 0 and 2 and PD-L1 expression on tumor cells, quantified by a tumor proportional score (TPS) of at least 1%, showed significantly worse LRC (HR = 3.374, p = 0.022) and a trend towards reduced PFS (HR = 2.752, p = 0.052). In the multivariate Cox regression analysis, the combination of absent tumor hypoxia resolution and high tumoral PD-L1 expression remained a significant prognosticator for impaired LRC (HR = 3.374, p = 0.022). On the other side, tumoral PD-L1 expression did not compromise the outcomes of patients whose tumor-associated hypoxia declined between week 0 and 2 during chemoradiation (LRC: HR = 1.186, p = 0.772, PFS: HR = 0.846, p = 0.766). Conclusion: In this exploratory analysis, we showed for the first time that patients with both persistent tumor-associated hypoxia during treatment and PD-L1 expression on tumor cells exhibited a worse outcome, while the tumor cells' PD-L1 expression did not influence the outcomes of patients with early tumor hypoxia resolution. While the results have to be validated in an independent cohort, these findings form a foundation to investigate the combination of hypoxic modification and immune checkpoint inhibitors for the unfavorable subgroup, moving forward towards personalized radiation oncology treatment.

The Value of Laboratory Parameters for Anemia, Renal Function, Systemic Inflammation and Nutritional Status as Predictors for Outcome in Elderly Patients with Head-and-Neck Cancers.

The purpose of this study was to evaluate the value of routine blood markers regarding their predictive potential for treatment outcomes of elderly head-and-neck squamous cell carcinoma (HNSCC) patients. In total, 246 elderly HNSCC patients (≥65 years) undergoing (chemo)radiotherapy from 2010 to 2018 were analyzed for treatment outcomes, depending on their hemoglobin, glomerular filtration rate (GFR), C-reactive protein (CRP) and albumin values, representing anemia, kidney function, inflammation and nutrition status, respectively. Local/locoregional control, progression-free and overall survival (OS) were calculated using the Kaplan-Meier method. Cox analyses were performed to examine the influence of blood parameters on oncological outcomes. In the univariate Cox regression analysis, hemoglobin ≤ 12 g/dL (HR = 1.536, p < 0.05), a GFR ≤ 60 mL/min/1.73 m2 (HR = 1.537, p < 0.05), a CRP concentration > 5 mg/L (HR = 1.991, p < 0.001) and albumin levels ≤ 4.2 g/dL (HR = 2.916, p < 0.001) were significant risk factors for OS. In the multivariate analysis including clinical risk factors, only performance status (HR = 2.460, p < 0.05) and baseline albumin (HR = 2.305, p < 0.05) remained significant prognosticators. Additionally, baseline anemia correlated with the prevalence of higher-grade chronic toxicities. We could show for the first time that laboratory parameters for anemia (and at least partly, tumor oxygenation), decreased renal function, inflammation and reduced nutrition status are associated with impaired survival in elderly HNSCC patients undergoing (chemo)radiotherapy.

Radiotherapy for nonagenarians: the value of biological versus chronological age.

BACKGROUND: The number of nonagenarian cancer patients (≥ 90 years) is continuously increasing, and radiotherapy is performed in a relevant proportion of patients, as surgery and chemotherapy are often not feasible for these patients. However, the evidence regarding the feasibility and treatment outcomes after radiotherapy for this patient group is very limited. METHODS: All nonagenarian patients receiving (chemo) radiotherapy between 2009 and 2019 at the University of Freiburg - Medical Center were analyzed for patterns of care, overall survival (OS) and therapy-associated toxicities according to the Common Terminology Criteria for Adverse Events. Uni- and multivariate Cox regression analyses were conducted to assess the influence of patient- and treatment-related factors on patient outcomes. RESULTS: One hundred nineteen patients with a total of 137 irradiated lesions were included in this analysis. After a median follow-up of 27 months, median OS was 10 months with a 3-year OS amounting to 11.1%. Univariate analyses demonstrated that a reduced performance status (HR = 1.56, 95% CI 1.00-2.45, p < 0.05), a higher burden of comorbidities (HR = 2.00, 95% CI 1.00-4.10, p < 0.05) and higher UICC tumor stages (HR = 2.21, 95% CI 1.14-4.26, p < 0.05) were associated with impaired survival rates. Split-course treatments (HR = 2.05, 95% CI 1.07-3.94, p < 0.05), non-completion of radiotherapy (HR = 7.17, 95% CI 3.88-13.26, p < 0.001) and palliative treatments (HR = 2.84, 95% CI 1.68-4.81, p < 0.05) were found to result in significantly reduced OS. In the multivariate analysis, split-course concepts (HR = 2.21, 95% CI 1.10-4.37, p < 0.05) and palliative treatments (HR = 3.19, 95% CI 1.77-5.75, p < 0.001) significantly deteriorated outcomes, while impaired ECOG status (HR = 1.49, 95% CI 0.91-2.43, p = 0.11) did not. The vast majority of patients reported either no (n = 40; 33.6%) or grade 1-2 acute toxicities (n = 66; 55.5%), and only very few higher-grade toxicities were observed in our study. CONCLUSION: Radiotherapy for nonagenarian patients is generally feasible and associated with a low toxicity profile. Given the relatively poor OS rates and the importance of the quality of life for this patient group, individualized treatment regimens including hypofractionation concepts should be considered.

The value of moderate dose escalation for re-irradiation of recurrent or second primary head-and-neck cancer.

BACKGROUND: Treatment for local and locoregional recurrence or second head-and-neck (H&N) cancers after previous radiotherapy is challenging, and re-irradiation carries a significantly increased risk for radiotherapy-related normal tissue toxicities and treatment failure due to a radioresistant tumor phenotype. Here, we analyzed re-irradiation management and outcomes in patients with recurrent or second primary H&N carcinoma using state-of-the-art diagnostic procedures and radiotherapy techniques. METHODS: Between 2010 and 2019, 48 patients with recurrent or second primary H&N carcinoma received re-radiotherapy at the University of Freiburg Medical Center and were included in this study. Overall survival (OS) and progression-free survival (PFS) were calculated with the Kaplan-Meier method, and univariate Cox-regression analyses were performed to assess the effects of clinico-pathological factors on treatment outcomes. Acute and chronic treatment-related toxicities were quantified using the Common Terminology Criteria for Adverse Events (CTCAE v4.03). RESULTS: Thirty-one patients (64.6%) received definitive and 17 (35.4%) adjuvant radiotherapy. Simultaneous chemotherapy was administered in 28 patients (58.3%) with cetuximab as the most commonly used systemic agent (n = 17, 60.7%). After a median time of 17 months (range 4 months to 176 months) between first and second radiotherapy, patients were re-irradiated with a median of 58.4 Gy and a treatment completion rate of 87.5% (n = 42). Median OS was 25 months with a 1-year OS amounting to 62.4%, and median PFS was 9 months with a 1-year PFS of 37.6%. Univariate analyses demonstrated that both a lower rT-status and a radiotherapy boost were associated with improved OS (p < 0.05). There was a trend towards superior OS for patients who received > 50 Gy (p = 0.091) and who completed the prescribed radiotherapy (p = 0.055). Five patients (10.4%) suffered from at least one grade 3 toxicities, while 9 patients (27.3%) experienced chronic higher-grade toxicities (≥ grade 3) with one (3.0%) grade 4 carotid blowout and one (3.0%) grade 4 osteoradionecrosis. CONCLUSION: Re-irradiation of recurrent or second primary H&N cancer with modern radiation techniques such as intensity-modulated radiotherapy resulted in promising survival rates with acceptable toxicities compared to historical cohorts. Increased re-irradiation doses, utilization of a radiotherapy boost and completion of the re-irradiation treatment were found to result in improved survival.

Radiotherapeutic management of cervical lymph node metastases from an unknown primary site - experiences from a large cohort treated with modern radiation techniques.

PURPOSE: To analyze management and outcomes following (chemo)radiation therapy in patients with cervical lymph node metastases from an unknown primary site (CCUP) in a large single-center cohort. METHODS: Between 2008 and 2019, 58 patients with CCUP were treated with (chemo)radiation therapy at the University of Freiburg Medical Center and were included in this analysis. Overall survival (OS), locoregional progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method. The use of diagnostic procedures and their impact on oncological outcomes was analyzed by Cox regression, and treatment-related toxicities were quantified. RESULTS: Median follow-up was 29.9 months (range 4.6-121.9). Twenty-one patients (36.2%) received definitive RT, 35 (60.3%) underwent adjuvant RT, and 2 (3.4%) were treated for oligometastatic disease. Concurrent chemotherapy was prescribed in 40 patients (69.0%). 89.6% of patients completed the prescribed RT, and 65.0% completed the prescribed simultaneous chemotherapy. Locoregional recurrence was observed in 7 patients (12.1%) and distant metastases in 13 cases (22.4%). OS was 81,1, 64.9% and 56,6% after 1, 3 and 5 years, respectively. Univariate analysis of age, gender, extracapsular spread, tumor grading, neck dissection, diagnostic utilization of 18F-fluorodeoxyglucose positron-emission tomography and concomitant chemotherapy showed no effect on OS (p > 0.05 for all), while smoking was significantly associated with decreased survival (p < 0.05). There was a trend towards impaired OS for patients with advanced nodal status (pN3) (p = 0.07). Three patients (5.2%) experienced grade 3 radiation dermatitis, and 12 (22.4%) developed grade 3 and 1 (1.7%) grade 4 mucositis. CONCLUSIONS: RT of the panpharynx and cervical lymph nodes with concurrent chemotherapy in case of risk factors demonstrated good locoregional control, but the metachronous occurrence of distant metastases limited survival and must be further addressed.

Radiotherapy for geriatric head-and-neck cancer patients: what is the value of standard treatment in the elderly?

BACKGROUND: Head-and-neck squamous cell carcinoma (HNSCC) is one of the most common malignancies globally, and the number of elderly patients diagnosed with HNSCC is increasing. However, as elderly HNSCC patients are underrepresented in clinical trials, current clinical decision making for this cohort largely lacks clinical evidence. METHODS: Elderly patients (≥65 years) with HNSCC undergoing (chemo)radiotherapy from 2010 to 2018 at Freiburg University Medical Center were assessed for patterns of care, locoregional control (LRC), progression-free (PFS) and overall survival (OS) regarding definitive and adjuvant treatments. Acute and late therapy-associated toxicities were quantified according to CTCAE v5.0. RESULTS: Two hundred forty-six patients were included in this analysis, of whom 166 received definitive and 80 adjuvant treatment. Two-year rates for OS, PFS and LRC were 56.9, 44.9 and 75.5%, respectively. Survival differed significantly between age groups with an OS of 40 and 22 months and a PFS of 23 and 12 months for patients aged 65-74 or ≥ 75 years, respectively (p < 0.05). Concomitant chemotherapy resulted in improved OS in patients aged 65-74 years compared to radiotherapy alone (p < 0.05) for definitive treatments, while patients ≥75 years did not benefit (p = 0.904). For adjuvant chemoradiotherapy, a trend towards superior OS rates was observed for patients aged 65-74 years (p = 0.151). Low performance status (HR = 2.584, 95% CI 1.561-4.274; p < 0.001) and smoking (HR = 1.960, 95% CI 1.109-3.464, p < 0.05) were the strongest independent prognostic factor in the multivariate analysis for decreased OS. One hundred thirty-eight patients (56.1%) experienced acute grade 3/4 and 45 patients (19.9%) chronic grade 3 toxicities. CONCLUSION: Radiotherapy is a feasible treatment modality for elderly HNSCC patients. The relatively low OS compared to high LRC may reflect age and comorbidities. Concomitant chemotherapy should be critically discussed in elderly HNSCC patients.