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Objectives: The number of elderly head-and-neck squamous cell carcinoma (HNSCC) patients is increasing, and clinical trials defining the standard of care either excluded or underrepresented elderly patients. This leaves physicians with a challenging and highly individual treatment decision largely lacking clinical evidence. Methods: A tri-national patterns-of-care survey was sent to all members of the German (DEGRO), Austrian (ÖGRO), and Swiss (SRO/SSRO) national societies of radiation oncology. The online questionnaire consisted of 27 questions on the treatment of elderly HNSCC patients, including 6 case-based questions. Frequency distributions and subgroup comparisons were calculated using SPSS statistics software. Results: A total of 132 answers were collected, including 46(35%) form universities, 52(39%) from non-university-hospitals and 34(26%) from private practices. 83(63%) treat 1-5 and 42(32%) >5 elderly HNSCC patients per month. Target volumes are defined analog current guidelines by 65(50%) of responders and altered based on age/comorbidities or tumor stage by 36(28%) and 28(22%), respectively. Chemotherapy is routinely administered by 108(84%) if indicated, with weekly 40mg/m2 of cisplatin being the favored regimen by 68(53%) in the definitive situation and 60(47%) in the adjuvant setting. Hypofractionation and hyperfractionation/acceleration are used by 26(20%) and 11(9%), respectively. Only 7(5%) clinicians routinely recommend inpatient treatment for elderly HNSCC patients. In a typical definitive patient case, 73(63%) responders recommended chemoradiation with bilateral elective node irradiation analog current guidelines. In an adjuvant example case recommendations regarding elective volume and chemotherapy were heterogeneous. Differences between responders' institutions concern the frequency of PET-CT in staging, preventive port-catheter and PEG implantation, the choice of chemotherapy regimens and the use of alternative fractionations. Conclusion: Treatment of elderly HNSCC-patients in the German-speaking countries mainly follows guidelines established for younger patients. Algorithms for patient stratification and treatment de-escalation for "unfit" elderly patients are needed. [ABSTRACT FROM AUTHOR]

• Dose escalation ≥ 70 Gy improves local control of elderly salivary gland cancer patients. • Low-to-moderate acute and chronic toxicities with no grade 4/5 toxicities. • Performance status, T and N stage are prognosticators for local control and survival. • Concomitant chemotherapy does not improve local control or survival. • Resection with postoperative radiotherapy is superior to definitive radiotherapy. To evaluate oncological outcomes and treatment-related toxicities of elderly salivary gland cancer patients undergoing (chemo)radiotherapy. Local/locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) of elderly patients ≥ 65 years with primary salivary gland cancers undergoing (chemo)radiotherapy between 2005 and 2020 at three tertiary cancer centers were calculated. The impact of clinicopathological and treatment parameters on outcomes were analyzed, and acute and chronic toxicities were quantified. 288 elderly salivary gland cancer patients were included in this multicenter analysis, and their median LRC, PFS and OS amounted to 113, 39 and 75 months, respectively. Age, performance status, comorbidities, definitive vs. adjuvant (chemo)radiotherapy as well as locally/locoregionally advanced cancers and distant metastases correlated with reduced outcomes in elderly salivary gland patients. Patients receiving dose-escalated radiotherapy (total doses > 70 Gy EQD2) with carbon ion boost radiation resulted in improved LRC, but no improvements in PFS or OS. Concomitant chemoradiotherapy did not improve treatment outcomes in elderly salivary gland carcinoma patients. Radiotherapy of elderly salivary gland cancer patients resulted in moderate higher-grade toxicities despite dose escalation with 70 (24.3%) and 48 patients (16.7%) experiencing acute and chronic grade 3 toxicities, respectively. No grade 4/5 toxicities were observed in this patient cohort. Data from the largest multicenter analysis of elderly salivary gland cancer patients undergoing (chemo)radiotherapy demonstrate favorable LRC and tolerable toxicity rates. Decision-making for these vulnerable patients should be based on patient performance rather than chronological patient age. [ABSTRACT FROM AUTHOR]

Chemotherapeutic agents are part of the standard treatment algorithms for many malignancies; however, their application and dosage are limited by their toxic effects to normal tissues. Chemotherapy‐induced toxicities can be long‐lasting and may be incompletely reversible; therefore, causative therapies for chemotherapy‐dependent side effects are needed, especially considering the increasing survival rates of treated cancer patients. Mesenchymal stem cells (MSCs) have been shown to exhibit regenerative abilities for various forms of tissue damage. Preclinical data suggest that MSCs may also help to alleviate tissue lesions caused by chemotherapeutic agents, mainly by establishing a protective microenvironment for functional cells. Due to the systemic administration of most anticancer agents, the effects of these drugs on the MSCs themselves are of crucial importance to use stem cell‐based approaches for the treatment of chemotherapy‐induced tissue toxicities. Here, we present a concise review of the published data regarding the influence of various classes of chemotherapeutic agents on the survival, stem cell characteristics and physiological functions of MSCs. Molecular mechanisms underlying the effects are outlined, and resulting challenges of MSC‐based treatments for chemotherapy‐induced tissue injuries are discussed. [ABSTRACT FROM AUTHOR]

Background: Inhibition of cellular topoisomerases has been established as an effective way of treating certain cancers, albeit with often high levels of toxicity to the bone marrow. While the involvement of mesenchymal stem cells (MSCs) in bone marrow homeostasis and regeneration has been well established, the effects of topoisomerase-inhibiting anticancer agents remain largely unknown.Materials and Methods: Human bone marrow MSCs were treated with topoisomerase I inhibitor irinotecan or topoisomerase II inhibitor etoposide, and survival and apoptosis levels were measured. The influence of topoisomerase inhibition on cellular morphology, adhesion and migration potential and the ability to differentiate was assessed. Additionally, the role of individual DNA double-strand break repair pathways in MSCs was investigated as a potential cellular mechanism of resistance to topoisomerase inhibitors.Results: Human bone marrow MSCs were found relatively resistant to topoisomerase I and II inhibitors and show survival levels comparable to these of differentiated fibroblasts. Treatment with irinotecan or etoposide did not significantly influence cellular adhesion, migratory ability, surface marker expression or induction of apoptosis in human MSCs. The ability to differentiate was found preserved in MSCs after exposure to high doses of irinotecan or etoposide. MSCs were able to efficiently repair DNA double-strand breaks induced by topoisomerase inhibitors both by non-homologous end joining and homologous recombination pathways.Conclusion: Our data demonstrate a topoisomerase-resistant phenotype of human MSCs that may at least in part be due to the stem cells' ability to efficiently remove DNA damage caused by these anticancer agents. The observed resistance of MSCs warrants further investigation of these cells as a potential therapeutic option for treating topoisomerase inhibitor-induced bone marrow damage. [ABSTRACT FROM AUTHOR]

Simple Summary: HPV-related oropharyngeal squamous cell carcinoma patients have a very good prognosis but are often suffering from long-term treatment-induced toxicities. Therefore, a plethora of de-escalation trials is examining whether treatment for HPV-induced oropharyngeal carcinoma can be de-escalated without compromising the favorable outcomes. The purpose of this review was to present and critically discuss the published as well as the ongoing de-escalation trials in head-and-neck squamous cell carcinoma, in particular for HPV-related oropharyngeal carcinoma. De-escalation studies are using several approaches such as radiotherapy dose reduction, target volume reduction, omission of concomitant chemotherapy, replacement of cisplatin through less toxic systemic agents, omission of adjuvant (chemo)radiation after primary surgery and selection of suitable patients by induction chemotherapy or peritherapeutic hypoxia imaging. Although many promising results have been obtained from several Phase I and II trials, the two Phase III de-escalation trials failed to show the equivalence of the de-escalated treatment arm, so that so far, no treatment de-escalation can be recommended outside of clinical trials. Oncological outcomes for head-and-neck squamous cell carcinoma (HNSCC) patients are still unsatisfactory, especially for advanced tumor stages. Besides the moderate survival rates, the prevalence of severe treatment-induced normal tissue toxicities is high after multimodal cancer treatments, both causing significant morbidity and decreasing quality of life of surviving patients. Therefore, risk-adapted and individualized treatment approaches are urgently needed for HNSCC patients to optimize the therapeutic gain. It has been a well-known fact that especially HPV-positive oropharyngeal squamous cell carcinoma (OSCC) patients exhibit an excellent prognosis and may therefore be subject to overtreatment, resulting in long-term treatment-related toxicities. Regarding the superior prognosis of HPV-positive OSCC patients, treatment de-escalation strategies are currently investigated in several clinical trials, and HPV-positive OSCC may potentially serve as a model for treatment de-escalation also for other types of HNSCC. We performed a literature search for both published and ongoing clinical trials and critically discussed the presented concepts and results. Radiotherapy dose or volume reduction, omission or modification of concomitant chemotherapy, and usage of induction chemotherapy are common treatment de-escalation strategies that are pursued in clinical trials for biologically selected subgroups of HNSCC patients. While promising data have been reported from various Phase II trials, evidence from Phase III de-escalation trials is either lacking or has failed to demonstrate comparable outcomes for de-escalated treatments. Therefore, further data and a refinement of biological HNSCC stratification are required before deescalated radiation treatments can be recommended outside of clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: As the long-term effects of radiotherapy on the quality of life (QoL) of elderly (≥65 years) patients with head-and-neck squamous cell carcinoma (HNSCC) are not well understood, we examined the QoL of surviving elderly HNSCC patients who were treated with radiotherapy. In this cross-sectional study, long-term quality of life (QoL) at ≥1 year after radiotherapy completion was comparable to the general German population of the same age and gender. Patients whose HNSCC was induced by human papillomavirus (HPV) exhibited a superior long-term global QoL than elderly patients with HPV-negative tumors. Interestingly, concomitant chemotherapy administration did not deteriorate patients' global QoL in the long-term. We did not observe differences in patients' health-related QoL in dependence of the treatment (definitive versus adjuvant (chemo)radiotherapy). Our data are important for clinicians treating elderly HNSCC patients as well as for elderly HNSCC patients themselves. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]