Low-dose radiotherapy of osteoarthritis: from biological findings to clinical effects-challenges for future studies.

Osteoarthritis (OA) is one of the most common and socioeconomically relevant diseases, with rising incidence and prevalence especially with regard to an ageing population in the Western world. Over the decades, the scientific perception of OA has shifted from a simple degeneration of cartilage and bone to a multifactorial disease involving various cell types and immunomodulatory factors. Despite a wide range of conventional treatment modalities available, a significant proportion of patients remain treatment refractory. Low-dose radiotherapy (LDRT) has been used for decades in the treatment of patients with inflammatory and/or degenerative diseases and has proven a viable option even in cohorts of patients with a rather poor prognosis. While its justification mainly derives from a vast body of empirical evidence, prospective randomized trials have until now failed to prove the effectiveness of LDRT. Nevertheless, over the decades, adaptions of LDRT treatment modalities have evolved using lower dosages with establishment of different treatment schedules for which definitive clinical proof is still pending. Preclinical research has revealed that the immune system is modulated by LDRT and very recently osteoimmunological mechanisms have been described. Future studies and investigations further elucidating the underlying mechanisms are an essential key to clarify the optimal patient stratification and treatment procedure, considering the patients' inflammatory status, age, and sex. The present review aims not only to present clinical and preclinical knowledge about the mechanistic and beneficial effects of LDRT, but also to emphasize topics that will need to be addressed in future studies. Further, a concise overview of the current status of the underlying radiobiological knowledge of LDRT for clinicians is given, while seeking to stimulate further translational research.

Radio(chemo)therapy in anaplastic thyroid cancer-high locoregional but low distant control rates-a monocentric analysis of a tertiary referral center.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a lethal disease with highly aggressive disease progression. This study analyses the influence of radio(chemo)therapy, R(C)T, on disease control, survival rates and predictors for survival. PATIENTS AND METHODS: A total of 33 patients with ATC, treated at a tertiary referral center between May 2001 and April 2020 were included. Univariate and multivariate analysis were used to investigate correlates of R(C)T and predictors on disease control and survival rates. RESULTS: Median follow-up was 4 months. In UICC stage IVA and IVB median overall survival (OS) was 8 months, median progression-free survival (PFS) was 6 months. Patients with UICC stage IVA and IVB and patients being irradiated with a radiation dose of more than 60 Gy showed increased OS. Of these patients, 3 were alive and free from disease. All of them receiving cisplatin-based radiochemotherapy and a minimum radiation dose of 66 Gy. UICC stage IVC showed a median OS of 2.5 months and a median PFS of 1 month. Only 2 of 16 patients had local failure. CONCLUSION: Depending on UICC stage, RT with high radiation dose can lead to improved OS or at least higher locoregional control. A limiting factor is the high incidence of distant metastases; therefore modern systemic treatment options should be integrated into multimodal therapy concepts.

Detailed in vitro analyses of the impact of multimodal cancer therapy with hyperthermia and radiotherapy on the immune phenotype of human glioblastoma cells.

PURPOSE: Improvements of heat-delivery systems have led to hyperthermia (HT) being increasingly recognized as an adjunct treatment modality also for brain tumors. But how HT affects the immune phenotype of glioblastoma cells is only scarcely known. MATERIALS AND METHODS: We therefore investigated the effect of in vitro HT, radiotherapy (RT), and the combination of both (RHT) on cell death modalities, immune checkpoint molecule (ICM) expression and release of the danger signal HSP70 of two human glioblastoma cell lines (U87 and U251) by using multicolor flow cytometry and ELISA. Hyperthermia was performed once or twice for 60-minute sessions reaching temperatures of 39 °C, 41 °C, and 44 °C, respectively. RT was administered with 5 x 2 Gy. RESULTS: A hyperthermia chamber for cell culture t-flasks regulating the temperature via a contact sensor was developed. While the glioblastoma cells were rather radioresistant, particularly in U251 cells, the combination of RT with HT significantly increased the percentage of apoptotic and necrotic cells for all temperatures examined and for both, single and double HT application. In line with that, an increased release of HSP 70 was seen only in U251 cells, mainly following treatment with HT at temperatures of 44 °C alone or in combination with RT. In contrast, immune suppressive (PD-L1, PD-L2, HVEM) and immune stimulatory (ICOS-L, CD137-L and Ox40-L) ICMs were significantly increased mostly on U87 cells, and particularly after RHT with 41 °C. CONCLUSIONS: Individual assessment of the glioblastoma immune cell phenotype with regard to the planned treatment is mandatory to optimize multimodal radio-immunotherapy protocols including HT.

High-grade salivary gland cancer: is surgery followed by radiotherapy an adequate treatment to reach tumor control? Results from a tertiary referral centre focussing on incidence and management of distant metastases.

PURPOSE: Salivary Gland cancer (SGC) is a rare and heterogenous group of tumors. Standard therapeutic options achieve high local but poor distant control rates, especially in high-grade SGC. The aim of this monocentric study was to evaluate patterns of recurrence and its treatment options (local ablative vs. systemic) in a homogenously treated patient population with high-grade SGC after surgery and radio(chemo)therapy. METHODS: Monocentric, retrospective study of patients with newly diagnosed high-grade salivary gland cancer. We retrospectively reviewed clinical reports from 69 patients with high-grade salivary gland cancer in a single-center audit. Survival rates were calculated using the Kaplan-Meier method and prognostic variables were analyzed (univariate analysis: log-rank test; multivariate analysis: Cox regression analysis). RESULTS: The median time of follow-up was 31 months. After 5 years, the cumulative overall survival was 65.2%, cumulative incidence of local recurrence was 7.2%, whereas the cumulative incidence of distant metastases was 43.5% after 5 years. 30 of 69 patients developed distant metastases during the time of follow-up, especially patients with adenoid cystic carcinoma, salivary duct carcinoma, adenocarcinoma NOS and acinic cell carcinoma with high-grade transformation. The most common type of therapy therefore was chemotherapy (50%). 85.7% of patients with local ablative therapy of distant metastases show disease progression during follow-up afterwards. CONCLUSION: With surgery and radio-chemotherapy, a high rate of loco-regional control is reached, but over 40% of patients develop distant metastases in the further follow-up which usually present a diffuse pattern involving in a diffuse metastases. Therefore, in the future, intensified interdisciplinary combination therapies even in the first-line treatment in certain subtypes of high-grade SGC should be investigated.

Low- vs. high-dose radiotherapy in Graves' ophthalmopathy: a retrospective comparison of long-term results.

PURPOSE: Radiotherapy represents an effective treatment option in Graves' ophthalmopathy (GO), leading to palliation of clinical symptoms. However, there are only a limited number of trials comparing the effectiveness of low- vs. high-dose radiotherapy. METHODS: We analyzed 127 patients treated with radiotherapy for stage 3/4 GO (NOSPECS classification). Patients were treated with single doses of 2.0 Gy (cumulative dose 20 Gy) until 2007, afterwards a single dose of 0.8 Gy (cumulative dose 4.8 Gy) was applied. With a median follow-up-time of 9.0 years, the treatment efficacy (overall improvement, sense of eye pressure, lid edema, ocular motility, exophthalmos, subjective vision, and diplopia) and adverse effects were analyzed by a standardized survey. RESULTS: Overall, 63.8% described improvement of symptoms after radiotherapy. No significant differences in overall treatment response and improvement of main outcome measures between low- or high-dose radiotherapy treatments are detectable, while low-dose radiotherapy leads significantly more often to retreatment (13.1% vs. 1.7%, p = 0.016). The main independent predictor of treatment response is the presence of lid edema (odds ratio, OR, 3.53; p = 0.006). CONCLUSION: At long-term follow-up, the majority of patients reported palliation of symptoms with limited adverse effects, suggesting clinical effectiveness of radiotherapy for amelioration of GO symptoms independent of low- or high-dose radiotherapy.

Adaptive radiotherapy and the dosimetric impact of inter- and intrafractional motion on the planning target volume for prostate cancer patients.

PURPOSE: To investigate the dosimetric influence of daily interfractional (inter) setup errors and intrafractional (intra) target motion on the planning target volume (PTV) and the possibility of an offline adaptive radiotherapy (ART) method to correct larger patient positioning uncertainties in image-guided radiotherapy for prostate cancer (PCa). MATERIALS AND METHODS: A CTV (clinical target volume)-to-PTV margin ranging from 15 mm in LR (left-right) and SI (superior-inferior) and 5-10 mm in AP (anterior-posterior) direction was applied to all patients. The dosimetric influence of this margin was retrospectively calculated by analysing systematic and random components of inter and intra errors of 31 consecutive intermediate- and high-risk localized PCa patients using daily cone beam computed tomography and kV/kV (kilo-Voltage) imaging. For each patient inter variation was assessed by observing the first 4 treatment days, which led to an offline ART-based treatment plan in case of larger variations. RESULTS: Systematic inter uncertainties were larger (1.12 in LR, 2.28 in SI and 1.48 mm in AP) than intra systematic errors (0.44 in LR, 0.69 in SI and 0.80 mm in AP). Same findings for the random error in SI direction with 3.19 (inter) and 2.30 mm (intra), whereas in LR and AP results were alike with 1.89 (inter) and 1.91 mm (intra) and 2.10 (inter) and 2.27 mm (intra), respectively. The calculated margin revealed dimensions of 4-5 mm in LR, 8-9 mm in SI and 6-7 mm in AP direction. Treatment plans which had to be adapted showed smaller variations with 1.12 (LR) and 1.72 mm (SI) for Σ and 4.17 (LR) and 3.75 mm (SI) for σ compared to initial plans with 1.77 and 2.62 mm for Σ and 4.46 and 5.39 mm for σ in LR and SI, respectively. CONCLUSION: The currently clinically used margin of 15 mm in LR and SI and 5-10 mm in AP direction includes inter and intra uncertainties. The results show that offline ART is feasible which becomes a necessity with further reductions in PTV margins.

Magnetic resonance imaging for brain stereotactic radiotherapy : A review of requirements and pitfalls.

Due to its superior soft tissue contrast, magnetic resonance imaging (MRI) is essential for many radiotherapy treatment indications. This is especially true for treatment planning in intracranial tumors, where MRI has a long-standing history for target delineation in clinical practice. Despite its routine use, care has to be taken when selecting and acquiring MRI studies for the purpose of radiotherapy treatment planning. Requirements on MRI are particularly demanding for intracranial stereotactic radiotherapy, where accurate imaging has a critical role in treatment success. However, MR images acquired for routine radiological assessment are frequently unsuitable for high-precision stereotactic radiotherapy as the requirements for imaging are significantly different for radiotherapy planning and diagnostic radiology. To assure that optimal imaging is used for treatment planning, the radiation oncologist needs proper knowledge of the most important requirements concerning the use of MRI in brain stereotactic radiotherapy. In the present review, we summarize and discuss the most relevant issues when using MR images for target volume delineation in intracranial stereotactic radiotherapy.

Evidence for improved survival with bevacizumab treatment in recurrent high-grade gliomas: a retrospective study with ("pseudo-randomized") treatment allocation by the health insurance provider.

INTRODUCTION: Despite a large number of trials, the role of bevacizumab (BEV) in the treatment of recurrent high-grade gliomas is still controversial. Evidence regarding an effect on overall survival in this context is ultimately inconclusive. At the Department of Radiation Oncology at Erlangen, Germany we treated a large cohort of patients with recurrent gliomas where bevacizumab use was determined exclusively by the health care provider's approval of reimbursement. METHODS: 61 patients (between 06/2008 and 01/2014) with recurrent high-grade gliomas had reimbursement requests for BEV sent to their health insurance. 37 patients out of 61 (60.7%) had their requests approved and therefore received bevacizumab (BEV-arm) as part of their treatment. The remaining 24 (39.3%) patients received standard therapy without bevacizumab (non-BEV-arm). Survival endpoints were defined with reference to the first BEV request to the health insurance provider. RESULTS: Median overall survival (OS) for the whole cohort was 7.0 months. OS was significantly better for BEV vs. Non-BEV patients (median, 10.3 vs. 4.2 months, logrank p = 0.023). There was an increased BEV benefit in cases of higher-order recurrences (first order recurrence BEV vs. Non-BEV, 12.5 vs. 10.2 months, p = 0.578) (second or higher order of recurrence, 9.9 vs. 2.6 months, p = 0.010). On multivariate analysis for overall survival the prognostic impact of bevacizumab (HR = 0.43, p = 0.034) remained significant. CONCLUSION: Our results suggest an influence of BEV on overall survival in a heavily pretreated patient population suffering from high-grade gliomas with BEV benefit being greatest in case of second or later recurrence.

Major Pathologic Response after Induction Therapy Has a Long-Term Impact on Survival and Tumor Recurrence in Stage IIIA/B Locally Advanced NSCLC.

BACKGROUND: Major pathologic response (MPR) determines favorable outcome in locally advanced non-small cell lung cancer after induction therapy (IT) followed by lung resection. The aim of this retrospective study was to identify the prognostic relevance of MPR in long-term interval. METHODS: In 55 patients, the survival rate according to MPR and non-MPR was estimated by Kaplan-Meier method and compared using log-rank, Breslow, and Tarone-Ware tests. RESULTS: The IT included chemoradiation with 50.4 Gy (range: 45-56.4 Gy) combined with platinum-based chemotherapy in 52 patients (94.5%) and platinum-based chemotherapy in 3 patients (5.5%). Perioperative morbidity and 30-day mortality were 36 and 3.6%, respectively. The estimated 5-year postoperative and progressive-free survivals were statistically significantly improved in MPR versus non-MPR with 53.5 versus 18% and 49.4 versus 18.5%, respectively. According to the log-rank, Breslow, and Tarone-Ware tests, the MPR demonstrates prognostic significance in early, long-term, and whole postoperative interval. CONCLUSION: MPR is associated with a robust correlation to long-term postoperative and recurrence-free survival improvement, and can potentially simplify the multidisciplinary debate and allow further stratification of adjuvant treatment in multimodality therapy.

Fractionated stereotactic radiation therapy for adrenal metastases: contributing to local tumor control with low toxicity.

PURPOSE: To report on the Erlangen (UK-Er) experience with linear accelerator stereotactic body radiation therapy (LINAC SBRT) for adrenal metastasis from various primary tumors. MATERIALS AND METHODS: 33 patients were treated. Primary sites included lung (n = 19), melanoma (n = 8), colorectal (n = 2), hepatocellular (n = 1), esophageal (n = 2), and breast cancer (n = 1). 14 patients were treated palliatively, 19 patients were treated with local curative intent. RADIATION TREATMENT: Treatment planning was done based on an exhale, mid-ventilation, and inspiration CT series. Further planning CTs were done to check for the correctness of the breathing pattern. Irradiation was performed using a NOVALIS (Varian, Palo Alto, CA, USA; Brainlab AG, München, Germany) linear accelerator. The isocenter was verified before each treatment session using the BrainLab ExacTrac® (Brainlab AG, München, Germany) system to minimize setup errors. Dose was prescribed to the planning target volume (PTV) surrounding 90% isodose. FOLLOW-UP: Depending on their overall performance status and prognosis, patients received clinical check-ups and radiological imaging. Median follow-up was 11 months. STATISTICAL ANALYSIS: IBM SPSS v. 24 was used for univariate analysis using Kaplan-Meier curves, nonparametric Kruskal-Wallis test, and the chi-square test for frequency distributions. Toxicity was graded according to NCI CTCAE v4.0. Depending on radiologic imaging, patients were classified as stable, regression, and progression. RESULTS: Median survival was 11 months, median PFS was 5 months. Median local failure-free survival was 21 months. Patients who were treated with curative intent showed a better survival curve (p < 0.0001) and PFS (p = 0.004). BED ranged from 42 to 108.8 Gy, median BED was 67.2 Gy. Three BED groups were formed. Overall survival curves differed significantly (p = 0.046), favoring the high-dose group. 21 patients were free from any adverse events or discomfort. In 7 cases, a grade I toxicity was noted.

Is there a patient population with squamous cell carcinoma of the head and neck region who might benefit from de-intensification of postoperative radiotherapy? : A monocentric retrospective analysis of a previously defined low-risk patient population treated with standard-of-care radiotherapy.

PURPOSE: The aim of this retrospective study was to evaluate the clinical outcome of a previously defined low-risk patient population with completely resected (R0) squamous cell carcinoma of the oral cavity, oropharynx, larynx (pT1-3, pN0-pN2b), hypopharynx (pT1-2, pN0-pN1), and the indication for postoperative radio(chemo)therapy. PATIENTS AND METHODS: According to predefined criteria, 99 patients with head and neck squamous cell carcinoma (SCC) who were treated at our institution from January 1, 2005 to December 31, 2014, were available for analysis. The Kaplan-Meier method was used for calculating survival and incidence rates. For univariate comparative analysis, the log-rank test was used for analyzing prognostic clinicopathologic parameters. RESULTS: Median follow-up was 67 months. Cumulative overall (OS) and disease-free survival (DFS) were 97.9%/94.7%/88.0% and 96.9%/92.6%/84.7% after 1, 2, and 5 years, respectively. Cumulative incidence of loco-regional recurrence (LRR), distant metastases (DM), and second cancer (SC) were 1.0%/1.0%/4.9%, 0.0%/3.4%/5.8%, and 2.1%/4.2%/13.1%, respectively. In univariate comparative analysis, location of the primary tumor in the oropharynx was a significant predictor for increased OS (p = 0.043) and DFS (p = 0.048). CONCLUSION: Considering the low disease relapse rates and high rates of therapy-induced late side effects, as well as the increased risk of developing SC, a prospective multicentric trial investigating de-escalation of radiotherapy in this clearly defined low-risk patient population was started and is still recruiting patients (DIREKHT-Trial, NCT02528955).

Time course of pain response and toxicity after whole-nerve-encompassing LINAC-based stereotactic radiosurgery for trigeminal neuralgia-a prospective observational study.

PURPOSE: To prospectively evaluate the time course of pain response and toxicity after linear accelerator-based whole-nerve-encompassing radiosurgery (LINAC-SRS) using a uniform treatment schedule for dosing and target volume definition in patients with refractory trigeminal neuralgia. METHODS: From December 2012 to December 2016, 21 patients were treated using a standardized protocol. Patients received LINAC-SRS with 70 Gy to the cisternal portion while aiming for the 90% isodose to fully envelope the nerve in one cross-sectional plane. Data on pain, analgesics, and toxicity were gathered prospectively. Four time intervals (1-6, 6-12, 12-18, and 18-24 months) were defined and compared to baseline and each other. RESULTS: The median follow-up from radiotherapy was 16 months. Freedom from pain was achieved at least once in 90.5, 81.0, and 85.7% of patients for everyday pain, rest pain, and pain peaks, respectively. At 1-6 months, pain was significantly reduced in everyday routine (mean VAS, 2.0/10 vs. 5.8/10; P = 0.004), at rest (1.5/10 vs. 4.0/10; P = 0.002), and for pain peaks (2.9/10 vs. 10/10; P < 0.001), as was the number of analgesics (mean 1.5 vs. 2.9; P < 0.001). No significant increase in pain or analgesics was observed for subsequent time intervals. At last follow-up, reduction in pain compared to baseline for everyday routine (2.1/10 vs. 5.8/10; P = 0.010) and for pain peaks (3.3/10 vs. 10/10; P < 0.001) was significant, whereas it was not for rest pain (1.8/10 vs. 3.9/10; P = 0.073). Most toxicities were related to trigeminal nerve impairment, with 42.9% reporting new-onset hypoesthesia at last follow-up. CONCLUSION: This study provides prospective data after whole nerve encompassing LINAC-SRS for trigeminal neuralgia. No significant pain relapse was observed.

Repeating of local therapy of distant metastases increases overall survival in patients with synchronous metastasized rectal cancer-a monocentric analysis.

PURPOSE: The aim was to evaluate the outcome of treatment-naive patients with synchronous metastatic rectal cancer after chemotherapy with FOLFOXIRI followed by local therapeutic procedures of all tumor lesions as complete as possible. METHODS: We reviewed data of 30 patients with synchronous distant metastatic rectal cancer who underwent chemotherapy with FOLFOXIRI and subsequent local therapy in our institution. RESULTS: Median follow-up was 28 months (range: 8; 74). Cumulative overall survival (OS) and progression-free survival (PFS) was 93.3, 76.9, 55.6% and 46.2, 29.7, 29.7% after 1, 2, 4 years. Non-response to chemotherapy with FOLFOXIRI was associated with a highly significant decreased OS (p < 0.0001). The consistent use of local ablative procedures led to a statistically significant increase in OS (p < 0.0001), but not in PFS (p = 0.635). Patients with ≤ 4 distant metastases showed a better OS (p = 0.033). CONCLUSIONS: Response to intensified first-line chemotherapy with FOLFOXIRI, treatment of the primary rectal tumor, and repeated thorough local ablative procedures in patients with synchronous metastasized rectal cancer may lead to long-term survival, even in a subset of patients with unresectable disease at initial diagnosis.

Long-Term Survival after Salvage Surgery for Local Failure after Definitive Chemoradiation Therapy for Locally Advanced Non-small Cell Lung Cancer.

BACKGROUND: The incidence of local failure and residual tumor after definitive chemoradiation therapy (dCRT) for locally advanced non-small-cell lung cancer remains high, irrespective of applied radiation dose (>59 Gy). So-called salvage surgery has been suggested as a feasible treatment option after failure of definitive chemoradiation for locally advanced non-small cell lung cancer (NSCLC). Experience with salvage lung surgery (SLS) is limited, and long-term survival is rarely reported. Patient selection criteria for surgical lung salvage are not defined. The aim of this study was to assess postoperative survival and perioperative morbidity/mortality to identify prognostic factors and to define patient selection criteria. PATIENTS AND METHODS: Records of 13 consecutive patients with locally advanced NSCLC, who underwent SLS at a single institution between March 2011 and November 2016, were reviewed. Descriptive statistics were applied for patient characteristics and surgical and oncological outcome. Survival rates were calculated using the Kaplan-Meier method and were compared with the long-rank test. RESULTS: All patients initially received curative-intent definitive chemoradiation with median radiation doses of 66 Gy (range 59.4-72) and concurrent platinum-based chemotherapy. Clinical tumor stage before definitive chemoradiation was IIIA in 9, IIIB in 3, IV in 1 patients. Median interval between definitive chemoradiation and salvage surgery was 6.7 months. Perioperative morbidity and 30-days-mortality was 38% and 7.7%, respectively. The median postoperative survival and estimated 5-year survival rate were 29.7 months and 46%, respectively. CONCLUSION: SLS in patients with locally advanced non-small cell lung surgery following dCRT is feasible, prolongs long-term survival and allows local tumor control. Selection criteria remain undefined and patients should be considered surgical candidates during multidisciplinary team conference.

[Lung Resection after Definitive and Neo-Adjuvant Chemoradiation for Stage IIIA/B Locally Advanced Non-Small Cell Lung Cancer: a Retrospective Analysis]. / Lungenresektion nach definitiver und neoadjuvanter Radiochemotherapie im Stadium IIIA/B des lokal fortgeschrittenen nicht kleinzelligen Lungenkarzinoms: eine retrospektive Analyse.

BACKGROUND: The outcomes of so called "salvage" resections after definitive chemoradiation vs. curative resections after neoadjuvant chemoradiation therapy (IT-resection) in patients with stage IIIA/B locally advanced non-small cell lung cancer have rarely been compared. The aim of our study was to compare perioperative results, postoperative and recurrence-free survival and to identify relevant prognostic survival factors for both therapy strategies. PATIENTS AND METHODS: Between June 2008 and May 2017, 43 patients underwent pulmonary resection following induction therapy (group 1) and 14 patients underwent salvage resection after definitive chemoradiation (group 2). Retrospective analysis was performed of demographic factors, tumour stage and location, initial therapy, preoperative regression status, perioperative morbidity and mortality, postoperative and recurrence-free survival. RESULTS: In group 2, significantly higher radiation dose was applied (p < 0.001) and the interval between chemoradiation and lung resection was significantly longer (p = 0.02). In addition, significantly higher perioperative blood loss and more frequent blood transfusions were noted (p = 0.003 and 0.005, respectively). Perioperative morbidity and mortality were statistically comparable in the two groups (p = 0.72 and 0.395, respectively). Postoperative 5 year survival in group 1 was 55%, in group 2 48% (log-rank p = 0.353). Five year recurrence-free survival in group 1 was 53%, in group 2 42% (log-rank p = 0.180). Diffuse metastasis occurred mostly in group 2, whereas in group 1 oligometastasis was more frequently noted. CONCLUSION: Postoperative outcome after salvage resection seems statistically comparable to results following curative resection after induction therapy. Diffuse distant metastasis is frequently noted. Careful patient selection is required.

Impact of postoperative radiotherapy and HER2/new overexpression in salivary duct carcinoma : A monocentric clinicopathologic analysis.

AIM: Retrospective Investigation of the prognostic relevance of clinicopathologic parameters in patients with salivary duct carcinoma (SDC). METHODS: An experienced pathologist reviewed 67 patients with de novo SDC or SDC ex pleomorphic adenoma. Paraffin-embedded tumor samples were examined by immunohistochemistry for expression of HER2/neu, androgen (AR), progesterone (PR), estrogen (ER), epidermal growth factor (EGFR) and programmed death ligand 1 (PD-L1-R) receptor. In 45 patients who had cM0 and follow-up data available, survival rates were calculated (Kaplan-Meier method) and prognostic variables were analyzed (univariate analysis: log-rank test; multivariate analysis: Cox-regression analysis). RESULTS: Overexpression of HER2/neu, AR, ER, PR, EGFR, PD-L1-R was found in 25.4%, 84%, 0%, 0%, 17.9%, 16.4% of patients. Overall (OS), disease-free (DFS), distant-metastases-free survival (DMFS) and locoregional control (LRC) were 92.3/72.4/56.9%, 78.2/58.1/58.1%, 85.4/65.2/65.2% and 89.7/81.9/81.9% after 1/3/5 years (medial follow-up 26 months). In univariate analysis a positive resection margin (p = 0.008) and no postoperative radiotherapy (p = 0.001) predict an increased locoregional recurrence rate. In multivariate analysis only postoperative radiotherapy is statistically significant (p = 0.004). Presence of lymph node metastases, a lymph node density >4 and HER2/neu overexpression predict decreased DFS and DMFS. In multivariate HER2/neu overexpression was the only significant predictor for reduced DFS (p = 0.04) and DMFS (p = 0.02). CONCLUSION: Postoperative radiotherapy is the only significant predictor for LRC. HER2/neu receptor expression is an independent prognostic factor for decreased DFS and DMFS in patients with SDC. In addition to radio(chemo)therapy, intensified first-line treatment regimens should also be evaluated in the future.

Stereotactic radiotherapy of vestibular schwannoma : Hearing preservation, vestibular function, and local control following primary and salvage radiotherapy.

OBJECTIVE: The aim of this publication is to present long-term data on functional outcomes and tumor control in a cohort of 107 patients treated with stereotactic radiotherapy (RT) for vestibular schwannoma. PATIENTS AND METHODS: Included were 107 patients with vestibular schwannoma (primary or recurrent following resection) treated with stereotactic RT (either fractioned or single-dose radiosurgery) between October 2002 and December 2013. Local control and functional outcomes were determined. Analysis of hearing preservation was limited to a subgroup of patients with complete audiometric data collected before treatment and during follow-up. Vestibular function test (FVT) results could be analyzed in a subset of patients and were compared to patient-reported dizziness. RESULTS: After a mean follow-up of 46.3 months, actuarial local control for the whole cohort was 100% after 2, 97.6% after 5, and 94.1% after 10 years. In patients with primary RT, serviceable hearing was preserved in 72%. Predictors for preservation of serviceable hearing in multivariate analysis were time of follow-up (odds ratio, OR = 0.93 per month; p = 0.021) and pre-RT tumor size (Koos stage I-IIa vs. IIb-IV; OR = 0.15; p = 0.031). Worsening of FVT results was recorded in 17.6% (N = 3). Profound discrepancy of patient-reported dizziness and FVT results was observed after RT. In patients with primary RT, worsening of facial nerve function occurred in 1.7% (N = 1). CONCLUSION: Stereotactic RT of vestibular schwannoma provides good functional outcomes and high control rates. Dependence of hearing preservation on time of follow-up and initial tumor stage has to be considered.

Improved survival for elderly married glioblastoma patients : Better treatment delivery, less toxicity, and fewer disease complications.

OBJECTIVES: Marital status is a well-described prognostic factor in patients with gliomas but the observed survival difference is unexplained in the available population-based studies. METHODS: A series of 57 elderly glioblastoma patients (≥70 years) were analyzed retrospectively. Patients received radiotherapy or chemoradiation with temozolomide. The prognostic significance of marital status was assessed. Disease complications, toxicity, and treatment delivery were evaluated in detail. RESULTS: Overall survival was significantly higher in married than in unmarried patients (median, 7.9 vs. 4.0 months; p = 0.006). The prognostic significance of marital status was preserved in the multivariate analysis (HR, 0.41; p = 0.011). Married patients could receive significantly higher daily temozolomide doses (mean, 53.7 mg/m² vs. 33.1 mg/m²; p = 0.020), were more likely to receive maintenance temozolomide (45.7 % vs. 11.8 %; p = 0.016), and had to be hospitalized less frequently during radiotherapy (55.0 % vs. 88.2 %; p = 0.016). Of the patients receiving temozolomide, married patients showed significantly lower rates of hematologic and liver toxicity. Most complications were infectious or neurologic in nature. Complications of any grade were more frequent in unmarried patients (58.8 % vs. 30.0 %; p = 0.041) with the incidence of grade 3-5 complications being particularly elevated (47.1 % vs. 15.0 %; p = 0.004). CONCLUSION: We found poorer treatment delivery as well as an unexpected severe increase in toxicity and disease complications in elderly unmarried glioblastoma patients. Marital status may be an important predictive factor for clinical decision-making and should be addressed in further studies.

Recurrent glioblastoma: who receives tumor specific treatment and how often?

The recurrence of glioblastoma (rGBM) is inevitable and often short-term. Therefore, information on the prognosis and effectiveness of tumor-specific versus purely palliative approaches should be more in-depth than a mere list of available treatment options for patients in this situation. However, follow-up data on the course of the disease in unselected patient populations after completion of primary treatment are scarce. This single-center analysis investigated the rate and number of glioblastoma recurrences after initial radiotherapy in 189 consecutive GM patients, focusing on the incidence of early death and the frequency of tumor-specific treatment (TST) versus best-supportive care (BSC) as well as the outcomes for the different approaches. In 61 % of initial population first recurrence (rGBM) could be determined by histology or imaging. 47 % received TST. 58 % of the patients with rGBM and TST were diagnosed with a second recurrence. Up to five recurrences were treated. 35-45 % of patients died before undergoing imaging studies to confirm the next recurrence. Multivariate analysis identified male sex and KPS score as independent factors (p < 0.01) for the choice of TST over BSC. Median overall survival from the diagnosis of first recurrence was 267 days in the TST group versus 65 days in patients receiving BSC (p < 0.0001). Nearly half of all rGBM patients received second-line TST, but a remarkably high proportion died early. Gender and KPS played a role in the choice of TST over BSC for recurrence treatment.