Excellent long-term pain response and local control following postoperative radiotherapy in patients with multiple myeloma.

PURPOSE: Multiple myeloma is associated with osteolytic bone lesions, often requiring surgery of the spine and postoperative radiotherapy (RT). Although common, data for clinical and informed decision-making are sparse. In this monocentric retrospective study, we aim to report the outcome of patients who underwent spinal surgery and postoperative RT due to multiple myeloma. METHODS: A total of 54 patients with multiple myeloma who underwent prior spinal surgery and postoperative RT at our institution between 2009 and 2020 were analyzed. Spinal instability neoplastic score (SINS) and Bilsky score, posttherapeutic adverse events, clinical data, and outcomes were collected and analyzed. The primary endpoint of this study was overall survival (OS), secondary endpoints were progression-free survival (PFS), pain response, local control, and skeletal-related events (SRE). RESULTS: The 3­ and 5­year overall survival (OS) was 74.9% (95% confidence interval [CI]: 63.5-88.4%) and 58% (95% CI: 44.5-75.6%), respectively. Median survival was not reached and 75% survival was 34.3 months (95% CI: 28.7-95.4 months). Median follow-up was 63 months (95% CI: 49-94 months). The number of patients with good to adequate performance status (Karnofsky performance score [KPS] ≥ 70) significantly increased after surgery (p < 0.01). We observed no grade 3/4 toxicity and only 13 (24%) grade 1/2 adverse events. Two patients (4%) experienced SRE. Overall, 92% of patients reported reduced pain after radiotherapy, with 66% reporting complete pain response. There was no difference in pain response between patients with different Bilsky scores. Bisphosphonate therapy and lower Bilsky score at the start of RT were associated with improved OS in univariate analysis (all p < 0.05). Multivariate Cox regression confirmed a Bilsky score of 2 or 3 as an independent negative prognostic factor (HR 3.89; 95 CI 1.4-10.7; p < 0.01). We observed no in-field recurrences. CONCLUSION: In this study, we were able to show that the current standard of RT after spinal surgery of osteolytic lesions is safe. In addition, we observed a very low rate of SRE (4%) and no in-field recurrences, demonstrating the local efficacy of RT in multiple myeloma patients. Higher Bilsky scores were associated with worse OS in multivariate analysis, but had no effect on pain response.

Adjuvant chemoradiotherapy in elderly patients with head and neck cancer: a monoinstitutional, two-to-one pair-matching analysis.

PURPOSE: About one fifth of patients with head and neck cancer are aged 70 years and older at the time of diagnosis. In these patients, risk factors (R1 status or extracapsular extension of lymph node metastases, ECE) often lead to a need for combined chemoradiotherapy (CRT) in the postoperative setting. However, there is considerable concern about the toxicity of such therapy in this age group. METHODS: Retrospective evaluation of the data of 53 patients ≥ 70 years of age who underwent surgery in our hospital between 1999 and 2015 for tumors of the oral cavity, the oropharynx, the hypopharynx, or the larynx, who subsequently received adjuvant radiation therapy. Two younger patients (< 70 years) were assigned to each of the elderly patients in a matching procedure based on anatomic sublocalization and tumor stage. The total cohort was comprised of 154 patients. RESULTS: Univariate analyses revealed a statistically significant influence of many factors on overall survival (OS) and progression-free survival (PFS), including Karnofsky performance score (KPS), alcohol consumption, smoking, R status, ECE, chemotherapy, and discontinuation of RT. Younger patients had better OS and PFS compared to the elderly (p = 0.013 and 0.012, respectively). In a multivariate Cox regression, no independent influence of age on OS and PFS was found. Survival was primarily dependent on the addition of chemotherapy to radiotherapy (RT), application of the full course of RT, continued alcohol abuse, KPS, and the presence of ECE. Toxicity analysis showed a higher incidence of chronic renal failure but, generally, side effects for elderly patients were not substantially greater. CONCLUSION: Performance status and behavioral risk factors but not chronological age are crucial for the prognosis of patients who require adjuvant chemoradiation.

Towards a generalised development of synthetic CT images and assessment of their dosimetric accuracy.

Background: The interest in generating "synthetic computed tomography (CT) images" from magnetic resonance (MR) images has been increasing over the past years due to advances in MR guidance for radiotherapy. A variety of methods for synthetic CT creation have been developed, from simple bulk density assignment to complex machine learning algorithms.Material and methods: In this study, we present a general method to determine simplistic synthetic CTs and evaluate them according to their dosimetric accuracy. It separates the requirements on the MR image and the associated calculation effort to generate a synthetic CT. To evaluate the significance of the dosimetric accuracy under realistic conditions, clinically common uncertainties including position shifts and Hounsfield lookup table (HLUT) errors were simulated. To illustrate our approach, we first translated CT images from a test set of six pelvic cancer patients to relative electron density (ED) via a clinical HLUT. For each patient, seven simplified ED images (simED) were generated at different levels of complexity, ranging from one to four tissue classes. Then, dose distributions optimised on the reference ED image and the simEDs were compared to each other in terms of gamma pass rates (2 mm/2% criteria) and dose volume metrics.Results: For our test set, best results were obtained for simEDs with four tissue classes representing fat, soft tissue, air, and bone. For this simED, gamma pass rates of 99.95% (range: 99.72-100%) were achieved. The decrease in accuracy from ED simplification was smaller in this case than the influence of the uncertainty scenarios on the reference image, both for gamma pass rates and dose volume metrics.Conclusions: The presented workflow helps to determine the required complexity of synthetic CTs with respect to their dosimetric accuracy. The investigated cases showed potential simplifications, based on which the synthetic CT generation could be faster and more reproducible.

Stability and survival analysis of elderly patients with osteolytic spinal bone metastases after palliative radiotherapy : Results from a large multicenter cohort.

PURPOSE: This retrospective study aimed to evaluate the stability and fracture rates of osteolytic spinal bone metastases (SBM) in elderly patients following palliative radiotherapy (RT) and to derive prognostic factors for stability and survival. METHODS: A total of 322 patients aged at least 70 years received palliative RT at two major German academic medical centers or at the German Cancer Research Center. Stability assessment was based on the validated Taneichi score prior to RT and at 3 and 6 months after RT. The survival time following RT was assessed, and prognostic factors for stability and survival were analyzed. RESULTS: Prior to RT, 183 patients (57%) exhibited unstable SBM and 68 patients (21%) pathological fractures. At 3 and 6 months after RT, significant recalcification and stabilization were evident in 19% (23/118) and 40% (31/78) of surviving patients, respectively. Only 17 patients (5%) experienced new pathological fractures following RT. Tumor histology was found to significantly influence stabilization rates with only breast cancer patients exhibiting increased stabilization compared to patients with other histologies. The median survival time and 6­month survival rates following RT were 5.4 months (95% confidence interval 4.4-7.2 months) and 48%, respectively. The patients' performance status was found to be the strongest predictor for survival after RT in this patient cohort; further factors demonstrating a significant association with survival were the application of systemic treatment, the number of SBM and the primary tumor histology. To analyze the influence of age on survival after RT, study patients were stratified into 3 age groups (i.e., 70-74 years, 75-79 years, and ≥80 years). The subgroup of patients aged at least 80 years showed a strong trend towards a worse survival time following RT compared to younger patients (i.e., 6­month survival rate 39% vs. 51%; p = 0.06, log-rank test). CONCLUSIONS: Prognostic factors influencing overall survival such as performance status and histology should guide the choice for palliative RT for SBM. Strongly hypofractionated RT regimes may be advisable for most elderly patients considering the overall poor prognosis in order to reduce hospitalization times.

The impact of vaginal dilator use on vaginal stenosis and sexual quality of life in women treated with adjuvant radiotherapy for endometrial cancer.

BACKGROUND: Despite a lack of evidence and low compliance, current guidelines recommend the use of a vaginal dilator (VD) after pelvic radiotherapy (RT). We analyzed the effect of VD on vaginal stenosis (VS) and its influence on sexual quality of life (QoL) in women treated with adjuvant RT for endometrial cancer (EC). METHODS: Between 2014 and 2015, 56 consecutive patients were instructed to use a VD after completion of treatment. The maximum diameter of the comfortably introducible VD was measured before and at 1 year after treatment. The degree of VS was evaluated clinically, and sexual QoL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) sexual functioning items before RT, during RT, at 6 weeks, and at 1 year after RT. RESULTS: One year after RT, mean VD diameter had decreased by 2.7 ± 3.2 mm (p < 0.001) and 36 patients (64.3%) had clinical VS (grade I-III). A larger decrease in VD diameter correlated with a higher degree of clinical VS (p < 0.001). VD use (p = 0.81), RT modality (p = 0.68), and adjuvant ChT (p = 0.87) had no influence on VD diameter. Sexual activity decreased during RT and increased beyond pre-RT values 1 year after RT (p < 0.001). Sexual enjoyment decreased continuously during and after completion of RT (p = 0.013) and was influenced negatively by a higher degree of clinical VS (p = 0.01). CONCLUSION: Almost two thirds of patients developed clinical VS 1 year after adjuvant RT for EC, and sexual enjoyment was substantially reduced by VS. The use of a VD after RT may not serve to prevent sexual impairments and VS.

Radiation-induced acute toxicities after image-guided intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for patients with spinal metastases (IRON-1 trial) : First results of a randomized controlled trial.

PURPOSE: Radiation therapy (RT) provides an important treatment approach in the palliative care of vertebral metastases, but radiation-induced toxicities in patients with advanced disease and low performance status can have substantial implications for quality of life. Herein, we prospectively compared toxicity profiles of intensity-modulated radiotherapy (IMRT) vs. conventional three-dimensional conformal radiotherapy (3DCRT). METHODS: This was a prospective randomized monocentric explorative pilot trial to compare radiation-induced toxicity between IMRT and 3DCRT for patients with spinal metastases. A total of 60 patients were randomized between November 2016 and May 2017. In both cohorts, RT was delivered in 10 fractions of 3 Gy each. The primary endpoint was radiation-induced toxicity at 3 months. RESULTS: Median follow-up was 4.3 months. Two patients suffered from grade 3 acute toxicities in the IMRT arm, along with 1 patient in the 3DCRT group. At 12 weeks after treatment (t2), 1 patient reported grade 3 toxicity in the IMRT arm vs. 4 patients in the 3DCRT group. No grade 4 or 5 adverse events occurred in either group. In the IMRT arm, the most common side effects by the end of irradiation (t1) were grade 1-2 xerostomia and nausea in 8 patients each (29.6%), and dyspnea in 7 patients (25.9%). In the 3DCRT group, the most frequent adverse events (t1) were similar: grade 1-2 xerostomia (n = 10, 35.7%), esophagitis (n = 10, 35.8%), nausea (n = 10, 35.8%), and dyspnea (n = 5, 17.9%). CONCLUSION: This is the first randomized trial to evaluate radiation-induced toxicities after IMRT versus 3DCRT in patients with vertebral metastases. This trial demonstrated an additional improvement for IMRT in terms of acute side effects, although longer follow-up is required to further ascertain other endpoints.

Prospective feasibility analysis of a novel off-line approach for MR-guided radiotherapy.

BACKGROUND: The present work aimed to analyze the feasibility of a shuttle-based MRI-guided radiation therapy (MRgRT) in the treatment of pelvic malignancies. PATIENTS AND METHODS: 20 patients with pelvic malignancies were included in this prospective feasibility analysis. Patients underwent daily MRI in treatment position prior to radiotherapy at the German Cancer Research Center. Positional inaccuracies, time and patient compliance were assessed for the application of off-line MRgRT. RESULTS: In 78% of applied radiation fractions, MR imaging for position verification could be performed without problems. Additionally, treatment-related side effects and reduced patient compliance were only responsible for omission of MRI in 9% of radiation fractions. The study workflow took a median time of 61 min (range 47-99 min); duration for radiotherapy alone was 13 min (range 7-26 min). Patient positioning, MR imaging and CT imaging including patient repositioning and the shuttle transfer required median times of 10 min (range 7-14 min), 26 min (range 15-60 min), 5 min (range 3-8 min) and 8 min (range 2-36 min), respectively. To assess feasibility of shuttle-based MRgRT, the reference point coordinates for the x, y and z axis were determined for the MR images and CT obtained prior to the first treatment fraction and correlated with the coordinates of the planning CT. In our dataset, the median positional difference between MR imaging and CT-based imaging based on fiducial matching between MR and CT imaging was equal to or less than 2 mm in all spatial directions. The limited space in the MR scanner influenced patient selection, as the bore of the scanner had to accommodate the immobilization device and the constructed stereotactic frame. Therefore, obese, extremely muscular or very tall patients could not be included in this trial in addition to patients for whom exposure to MRI was generally judged inappropriate. CONCLUSION: This trial demonstrated for the first time the feasibility and patient compliance of a shuttle-based off-line approach to MRgRT of pelvic malignancies.

Local response and pathologic fractures following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy for spinal metastases - a randomized controlled trial.

BACKGROUND: This was a prespecified secondary analysis of a randomized trial, which analyzed bone density following stereotactic body radiotherapy (SBRT) versus conventional three-dimensional conformal radiotherapy (3DCRT) as part of palliative management of painful spinal metastases. METHODS: Fifty-five patients were enrolled in this single-institutional randomized exploratory trial (NCT02358720). Participants were randomly assigned to receive SBRT (single-fraction 24 Gy) or 3DCRT (30 Gy/10 fractions). Quantitative bone density was evaluated at baseline, 3 and 6 months in both irradiated and unirradiated spinal bodies, along with rates of pathologic fractures and vertebral compression fractures. RESULTS: As compared to baseline, bone density became significantly higher at 3 and 6 months following SBRT by a median of 33.8% and 72.1%, respectively (p < 0.01 for both). These figures in the 3DCRT cohort were 32.9% and 41.2%, respectively (p < 0.01 for both). There were no statistical differences in bone density between SBRT and 3DCRT at 3 (p = 0.629) or 6 months (p = 0.327). Subgroup analysis of osteolytic metastases showed an increase in bone density relative to baseline in the SBRT (but not 3DCRT) arm. Bone density in unaffected vertebrae did not show substantial changes in either group. The 3-month incidence of new pathological fractures was 8.7% in the SBRT arm vs. 4.3% in the 3DCRT arm. CONCLUSIONS: Despite high ablative doses in the SBRT arm, the significant increase in bone density after 3 and 6 months was similar to that of 3DCRT. Our trial demonstrated a moderate rate of subsequent pathological fracture after SBRT. Future randomized investigations with larger sample sizes are recommended. TRIAL REGISTRATION: www.clinicaltrials.gov : NCT02358720 on 9nd of February 2015.

Survival and Stability of Patients with Urothelial Cancer and Spinal Bone Metastases after Palliative Radiotherapy.

BACKGROUND: The aim of the study was to analyze survival and stability of patients with urothelial cell cancer and spinal bone metastases (SBM) after radiotherapy (RT). Furthermore, to assess the effects of RT on bone mineral density (BMD) as a local response in SBM after RT. PATIENTS AND METHODS: Survival of 38 patients with 132 SBM from urothelial cancer, treated from January 2000 to January 2012, was calculated. Stability of irradiated thoracic and lumbar SBM was retrospectively evaluated in computed tomography (CT) scans using the validated Taneichi et al. score. Difference in BMD, measured in Hounsfield units (HU), of the SBM before and at 3 and 6 months after RT was analyzed. RESULTS: All patients died during follow-up. Overall survival (OS) after 6 months, 1 year and 2 years was 90%, 80% and 40%, respectively. Bone survival (BS) was 85%, 64% and 23% after 6 months, 1 year and 2 years, respectively. Survival from start of RT (RTS) was 42% after 6 months, 18% after 1 year and 5% after 2 years. Only 11% received bisphosphonates. Stability did not improve at 3 or 6 months after RT. BMD increased by 25.0 HU ± 49.7 SD after 3 months (p = 0.001) and by 24.2 HU ± 52.2 SD after 6 months (p = 0.037). Pain relief (> 2 points on the visual analogue scale) was achieved in only 27% of patients. CONCLUSIONS: Benefit from palliative RT of painful or unstable SBM is limited in these patients and they should be carefully selected for RT. Shorter fractionation schedules may be preferred and outcome may improve with concomitant bisphosphonates.

Survival and prognostic factors in patients with stable and unstable spinal bone metastases from solid tumors: a retrospective analysis of 915 cases.

BACKGROUND: Adequate prediction of survival plays an important role in treatment decisions for patients with spinal bone metastases (SBM). Several prognostic factors are already used in daily clinical practice, but factors related to stability of SBM are still unknown. Therefore, we designed this study to identify these prognostic factors. METHODS: We retrospectively assessed 915 patients from solid tumors with commonly metastased into the bone treated at our department between January 2000 and January 2012. Lung cancer (NSCLC), breast and renal cancer listed in Table 1 are the most common solid tumors with bone metastasis in this study. Prostate carcinoma was excluded due to osteoblastic SBM with no influence for stability. We calculated overall survival (OS) and bone survival (BS; time between first diagnosis of bone metastases until death) with the Kaplan-Meier method and assessed prognostic factors for BS with the log-rank test and a Cox regression model separately for patients with stable and unstable SBM. RESULTS: Median follow-up was 9.3 months. OS after 6 months, 1, 2, and 5 years was 81, 62, 42, and 25 % in patients with stable SBM and 78, 57, 38, and 22 % in patients with unstable SBM (p = 0.851). BS was 57, 38, 22, and 5 % in the group of stable SBM after 6 months, 1, 2, and 5 years. For patients with unstable SBM BS after 6 months, 1, 2, and 5 years was 59, 39, 19, and 8 % (p = 0.755). In multivariate analysis we found male gender (HR = 1.27 [95 % CI 1.01-1.60], p = 0.04), Karnofsky performance status (KPS) <80 % (HR = 1.27 [95%CI 1.04-1.55], p = 0.02) and non-small cell lung cancer (NSCLC; HR = 2.77 [95%CI 1.99-3.86], p < 0.0001) to be independent prognostic factors for shortened survival in patients with stable SBM. Independent prognostic factors for unstable SBM were age per year (HR = 1.01 [95 % CI 1.0-1.02], p = 0.025), multiple SBM (HR = 1.35 [95 % CI 1.1-1.65], p = 0.003), and NSCLC (HR = 2.0 [95 % CI 1.43-2.80], p < 0.0001). Additionally, not wearing an orthopedic corset (HR = 0.77 [95 % CI 0.62-0.96], p = 0.02) was associated with prolonged BS in patients with unstable SBM and in both groups BS was significantly longer in patients without liver metastases (stable SBM: HR = 0.72 [95 % CI 0.56-0.92], p = 0.008; unstable SBM: HR = 0.71 [95 % CI 0.54-0.92], p = 0.01). CONCLUSIONS: Survival was equal for patients with stable and unstable SBM. However, prognostic factors differed in both groups and stability should therefore be considered in treatment decision-making.

Biochemical markers of bone turnover in patients with spinal metastases after resistance training under radiotherapy--a randomized trial.

BACKGROUND: To compare the effects of resistance training versus passive physical therapy on bone turnover markers (BTM) in the metastatic bone during radiation therapy (RT) in patients with spinal bone metastases. Secondly, to evaluate an association of BTM to local response, skeletal-related events (SRE), and number of metastases. METHODS: In this randomized trial, 60 patients were allocated from September 2011 to March 2013 into one of the two arms: resistance training (Arm A) or passive physical therapy (Arm B) with thirty patients in each arm during RT. Biochemical markers such as pyridinoline (PYD), desoxy-pyridinoline (DPD), bone alkaline phosphatase (BAP), total amino-terminal propeptide of type I collagen (PINP), beta-isomer of carboxy-terminal telopeptide of type I collagen (CTX-I), and cross-linked N-telopeptide of type I collagen (NTX) were analyzed at baseline, and three months after RT. RESULTS: Mean change values of PYD and CTX-I were significantly lower at 3 months after RT (p = 0.035 and p = 0.043) in Arm A. Importantly, all markers decreased in both arms, except of PYD and CTX-I in arm B, although significance was not reached for some biomarkers. In arm A, the local response was significantly higher (p = 0.003) and PINP could be identified as a predictor for survivors (OR 0.968, 95%CI 0.938-0.999, p = 0.043). BAP (OR 0.974, 95%CI 0.950-0.998, p = 0.034) and PINP (OR 1.025, 95%CI 1.001-1.049, p = 0.044) were related with an avoidance of SRE. CONCLUSIONS: In this group of patients with spinal bone metastases, we were able to show that patients with guided resistance training of the paravertebral muscles can influence BTM. PYD and CTX-I decreased significantly in arm A. PINP can be considered as a complementary tool for prediction of local response, and PINP as well as BAP for avoidance of SRE. TRIAL REGISTRATION: Clinical trial identifier NCT 01409720. August 2, 2011.

The influence of hyperglycemia during radiotherapy on survival in patients with primary glioblastoma.

BACKGROUND AND PURPOSE: Metabolism in tumor cells depends mainly on glycolysis and thus hyperglycemia has been shown to influence tumor properties in various tumor entities. In this retrospective study we set out to determine if hyperglycemic serum levels during radiation therapy impact patient survival and progression patterns in primary glioblastoma (GBM). MATERIAL AND METHODS: We retrospectively analyzed glucose serum levels, survival and progression patterns on magnetic resonance imaging (MRI) in 262 GBM patients receiving radiation therapy. Hyperglycemia was classified as mild (> 180 mg/dL) or excessive (≥ 300 mg/dL), and isolated (one hyperglycemic event) or persistent (≥ 3 hyperglycemic events). The multivariate Cox proportional hazards ratio was used to assess the influence of cofactors on survival. RESULTS: Persistent mild (HR = 2.23; p < 0.001) and excessive hyperglycemia (HR = 2.51; p < 0.001) were associated with a decrease in overall survival rates, even when considering the covariate corticosteroid therapy. Here metabolic imbalances did not affect the progression-free interval (p = 0.402), the occurrence of distant (p = 0.587) and multifocal progression (p = 0.445). CONCLUSION: Our findings support the theory that hyperglycemia during radiation therapy in GBM patients is an unfavorable prognostic cofactor for survival and is detrimental to the survival rates independent of corticosteroid therapy. However, no significant effects of hyperglycemic metabolism on the progression-free interval and recurrence patterns were found.

Metformin influences progression in diabetic glioblastoma patients.

PURPOSE: Changes in metabolism, including high glucose serum levels, seem to influence the initiation of malignancy as well as recurrence. Therefore, limiting the energy supply in tumor cells with the antidiabetic drug metformin might be a useful approach to inhibit glioma cell progression. However, little is known about the effects of endocrine disorders (e.g., diabetes mellitus, corticosteroid therapy, and metformin therapy) on progression and survival in primary glioblastoma patients. PATIENTS AND METHODS: Between 2006 and 2013, 276 patients with primary glioblastoma underwent radiation therapy at Heidelberg University Hospital and German Cancer Research Center. Clinical records as well as pretherapeutic and follow-up magnetic resonance (MR) images were assessed. Forty patients (14.5 %) were identified with a pretherapeutic history of diabetes, and 20 (50 %) of them were treated with metformin. Survival and correlations were calculated using t-test and log-rank, univariate and multivariate Cox proportional hazards ratio analyses. RESULTS: Persistent mild and excessive hyperglycemia were correlated with decreased survival. Corticosteroid therapy was associated with decreased progression-free and overall survival in the multivariate analysis. No negative influence of diabetes on progression and survival could be detected. Interestingly, diabetic patients with metformin therapy demonstrated prolonged progression-free intervals. CONCLUSION: Corticosteroid therapy and hyperglycemia were strongly associated with impaired survival rates and serves as negative prognostic factors. Diabetes did not influence survival. Interestingly, our findings showed an association of metformin therapy and prolonged progression-free survival in glioblastoma patients with diabetes and therefore serve as a foundation for further preclinical and clinical investigations.

Impact of delays in initiating postoperative chemoradiation while determining the MGMT promoter-methylation statuses of patients with primary glioblastoma.

BACKGROUND: The benefits of new innovations in glioblastoma therapies should not be curtailed as a result of delays in commencement of radiation therapy, caused by clinical circumstances as well as diagnostic procedures. This study evaluates whether delays in chemo-radiotherapy after surgery, while determining O6-methylguanine-DNA-methyltransferase (MGMT) promoter status, affect the survival rates of patients with glioblastoma (GBM). METHODS: Our sample comprised 50 GBM patients in a retrospective analysis of three prospective studies that focused on combined radiotherapy and required MGMT promoter-status testing as inclusion criteria. Results were compared with a reference group of 127 favourable GBM cases (Karnofsky performance-status scale ≥ 70), in which the patients underwent standard postoperative chemo-radiotherapy with temozolomide. Survival time was calculated using the Kaplan-Meier method, and a multivariate analysis of the delays between surgical and radiotherapy procedures was performed using the Cox regression model. RESULTS: The study group's median overall survival time was 16.2 months (with a range of 2 to 56 months), versus the reference group's survival time of 18.2 months (with a range of 1 to 92 months) (p = 0.64). The delay between surgery and radiotherapy was increased by 8 days in the study patients (p < 0.001), with a median delay of 35 days (range: 18-49 days) corresponding to the typical 27-day delay (range: 5-98 days) for those in the reference group. Univariate and multivariate analyses did not show any negative association between survival time and delaying radiation therapy to determine MGMT-promoter status; commencement of radiation therapy sooner than 24 days after surgery was the threshold for significantly decreased overall survival (p = 0.01) and progression-free (p = 0.03) survival. CONCLUSION: Delaying postoperative chemoradiation for GBM patients--carried out in order to determine MGMT-promoter status-did not have a negative impact on survival time. Indeed, the data of the present study shows that initiating radiation therapy sooner than 24 days after surgery has a negative impact on progression and survival.

The influence of orthopedic corsets on the incidence of pathological fractures in patients with spinal bone metastases after radiotherapy.

BACKGROUND: Clinical care of unstable spinal bone metastases in many centers often includes patient immobilization by means of an orthopedic corset in order to prevent pathological fractures. The aim of this retrospective analysis was to evaluate the incidence of pathological fractures after radiotherapy (RT) in patients with and without orthopedic corsets and to assess prognostic factors for pathological fractures in patients with spinal bone metastases. METHODS: The incidence of pathological fractures in 915 patients with 2.195 osteolytic metastases in the thoracic and lumbar spine was evaluated retrospectively on the basis of computed tomography (CT) scans between January 2000 and January 2012 depending on prescription and wearing of patient-customized orthopedic corsets. RESULTS: In the corset group, 6.8 and 8.0 % in no-corset group showed pathological fractures prior to RT, no significant difference between groups was detected (p = 0.473). After 6 months, patients in the corset group showed pathological fractures in 8.6 % and in no-corset group in 9.3 % (p = 0.709). The univariate and bivariate analyses demonstrated no significant prognostic factor for incidence of pathological fractures in both groups. CONCLUSIONS: In this analysis, we could show for the first time in more than 900 patients, that abandoning a general corset supply in patients with spinal metastases does not significantly cause increased rates of pathological fractures. Importantly, the incidence of pathological fracture after RT was small.

Intensity-modulated radiotherapy versus proton radiotherapy versus carbon ion radiotherapy for spinal bone metastases: a treatment planning study.

Outcomes for selected patients with spinal metastases may be improved by dose escalation using stereotactic body radiotherapy (SBRT). As target geometry is complex, we compared SBRT plans using step-and-shoot intensity-modulated radiotherapy (IMRT), carbon ion RT, and proton RT. We prepared plans treating cervical, thoracic, and lumbar metastases for three different techniques--IMRT, carbon ion, and proton plans--to deliver a median single 24 Gy fraction such that at least 90% of the planning target volume (PTV) received more than 18 Gy and were compared for PTV coverage, normal organ sparing, and estimated delivery time. PTV coverage did not show significant differences for the techniques, spinal cord dose sparing was lowered with the particle techniques. For the cervical lesion spinal cord maximum dose, dose of 1% (D1), and percent volume receiving 10 Gy (V10Gy) were 11.9 Gy, 9.1 Gy, and 0.5% in IMRT. This could be lowered to 4.3 Gy, 2.5 Gy, and 0% in carbon ion planning and to 8.1 Gy, 6.1 Gy, and 0% in proton planning. Regarding the thoracic lesion no difference was found for the spinal cord. For the lumbar lesion maximum dose, D1 and percent volume receiving 5Gy (V5Gy) were 13.4 Gy, 8.9 Gy, and 8.9% for IMRT; 1.8 Gy, 0.7 Gy, and 0% for carbon ions; and 0 Gy, < 0.01 Gy, and 0% for protons. Estimated mean treatment times were shorter in particle techniques (6-7 min vs. 12-14 min with IMRT). This planning study indicates that carbon ion and proton RT can deliver high-quality PTV coverage for complex treatment volumes that surround the spinal cord.

Mesenchymal stem cells are sensitive to treatment with kinase inhibitors and ionizing radiation.

INTRODUCTION: Mesenchymal stem cells (MSCs) can regenerate damaged tissues and may therefore be of importance for normal tissue repair after cancer treatment. Small molecule receptor kinase inhibitors (RKIs) have recently been introduced into cancer treatment. However, the influence of these drugs-particularly in combination with radiotherapy-on the survival of MSCs is largely unknown. METHODS: The sensitivity of human primary MSCs from healthy volunteers and primary human fibroblast cells to small molecule kinase inhibitors of the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and transforming growth factor ß (TGFß) receptors, as well to inhibitors of c-Kit, was examined in combination with ionizing radiation (IR); cell survival and proliferation were assessed. Expression patterns of different kinase receptors and ligands were investigated using gene arrays. RESULTS: MSCs were highly sensitive to the tyrosine kinase inhibitors SU14816 (imatinib) and SU11657 (sunitinib), but showed only moderate sensitivity to the selective TGFß receptor 1 inhibitor LY2109761. Primary adult human fibroblasts were comparably resistant to all three inhibitors. The addition of IR had an additive or supra-additive effect in the MSCs, but this was not the case for differentiated fibroblasts. Proliferation was markedly reduced in MSCs following kinase inhibition, both with and without IR. Gene expression analysis revealed high levels of the PDGF α and ß receptors, and lower levels of the TGFß receptor 2 and Abl kinase. IR did not alter the expression of kinase receptors or their respective ligands in either MSCs or adult fibroblasts. CONCLUSION: These data show that MSCs are highly sensitive to RKIs and combination treatments incorporating IR. Expression analyses suggest that high levels of PDGF receptors may contribute to this effect.

Multicenter analysis on the value of standard (chemo)radiotherapy in elderly patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction.

BACKGROUND: To assess the tolerability and oncological results of chemoradiation in elderly patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction. METHODS: This multi-center retrospective analysis included 86 elderly patients (≥ 65 years) with esophageal or gastroesophageal junction adenocarcinoma (median age 73 years; range 65-92 years) treated with definitive or neoadjuvant (chemo)radiotherapy. The treatment was performed at 3 large comprehensive cancer centers in Germany from 2006 to 2020. Locoregional control (LRC), progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), and treatment-associated toxicities according to CTCAE criteria v5.0 were analyzed, and parameters potentially relevant to patient outcomes were evaluated. RESULTS: Thirty-three patients (38%) were treated with neoadjuvant chemoradiation followed by surgery, while the remaining patients received definitive (chemo)radiation. The delivery of radiotherapy without dose reduction was possible in 80 patients (93%). In 66 patients (77%), concomitant chemotherapy was initially prescribed; however, during the course of therapy, 48% of patients (n = 32) required chemotherapy de-escalation due to treatment-related toxicities and comorbidities. Twenty-nine patients (34%) experienced higher-grade acute toxicities and 14 patients (16%) higher-grade late toxicities. The 2-year LRC, DMFS, PFS, and OS amounted to 72%, 49%, 46%, and 52%, respectively. In multivariate analysis, neoadjuvant chemoradiation followed by surgery was shown to be associated with significantly better PFS (p = 0.006), DMFS (p = 0.006), and OS (p = 0.004) compared with all non-surgical treatments (pooled definitive radiotherapy and chemoradiation). No such advantage was seen over definitive chemoradiation. The majority of patients with neoadjuvant therapy received standard chemoradiotherapy without dose reduction (n = 24/33, 73%). In contrast, concurrent chemotherapy was only possible in 62% of patients undergoing definitive radiotherapy (n = 33/53), and most of these patients required dose-reduction or modification of chemotherapy (n = 23/33, 70%). CONCLUSIONS: In our analysis, omission of chemotherapy or adjustment of chemotherapy dose during definitive radiotherapy was necessary for the overwhelming majority of elderly esophageal cancer patients not eligible for surgery, and hence resulted in reduced PFS and OS. Therefore, optimization of non-surgical approaches and the identification of potential predictive factors for safe administration of concurrent chemotherapy in elderly patients with (gastro)esophageal adenocarcinoma is required.

Chemoradiotherapy in geriatric patients with squamous cell carcinoma of the esophagus: Multi-center analysis on the value of standard treatment in the elderly.

Background and purpose: To evaluate the tolerability and outcomes of chemoradiation in elderly patients with locally advanced esophageal squamous cell carcinoma (ESCC). Materials and methods: This multi-center retrospective analysis included 161 patients with SCC of the esophagus with a median age of 73 years (range 65-89 years) treated with definitive or neoadjuvant (chemo)radiotherapy between 2010 and 2019 at 3 large comprehensive cancer centers in Germany. Locoregional control (LRC), progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), and treatment-associated toxicities were analyzed, and parameters determining patient outcomes and treatment tolerance were assessed. Results: The delivery of radiotherapy without dose reduction was possible in 149 patients (93%). In 134 patients (83%), concomitant chemotherapy was initially prescribed; however, during the course of therapy, 41% of these patients (n = 55) required chemotherapy de-escalation due to treatment-related toxicities. Fifty-two patients (32%) experienced higher-grade acute toxicities, and 22 patients (14%) higher-grade late toxicities. The 2-year LRC, DMFS, PFS, and OS rates amounted to 67.5%, 33.8%, 31.4%, and 40.4%, respectively. Upon multivariate analysis, full-dose concomitant chemotherapy (vs. no or modified chemotherapy) was associated with significantly better DMFS (p=0.005), PFS (p=0.005) and OS (p=0.001). Furthermore, neoadjuvant chemoradiotherapy followed by tumor resection (vs. definitive chemoradiotherapy or definitive radiotherapy alone) significantly improved PFS (p=0.043) and OS (p=0.049). We could not identify any clinico-pathological factor that was significantly associated with LRC. Furthermore, definitive (chemo)radiotherapy, brachytherapy boost and stent implantation were significantly associated with higher-grade acute toxicities (p<0.001, p=0.002 and p=0.04, respectively). The incidence of higher-grade late toxicities was also significantly associated with the choice of therapy, with a higher risk for late toxicities when treatment was switched from neoadjuvant to definitive (chemo)radiotherapy compared to primary definitive (chemo)radiotherapy (p<0.001). Conclusions: Chemoradiation with full-dose and unmodified concurrent chemotherapy has a favorable prognostic impact in elderly ESCC patients; however, about half of the analyzed patients required omission or adjustment of chemotherapy due to comorbidities or toxicities. Therefore, the identification of potential predictive factors for safe administration of concurrent chemotherapy in elderly ESCC patients requires further exploration to optimize treatment in this vulnerable patient cohort.

Stereotactic Radiotherapy after Radical Prostatectomy in Patients with Prostate Cancer in the Adjuvant or Salvage Setting: A Systematic Review.

(1) Background: Prostate cancer is the most common cancer in men and can be treated with radical prostatectomy (RPE) or radiotherapy in the primary setting. Stereotactic radiotherapy (SBRT) has proven to be effective and well tolerated in this setting. However, if SBRT is an equally promising treatment option if applied in the adjuvant or salvage setting after RPE remains unknown. (2) Methods: We searched the PubMed and Embase databases with the following full-text queries in August 2021 for any combination of the terms "SBRT", "prostate", "adjuvant", "postoperative", "salvage", "stereotactic radiotherapy", "prostate bed". There were no limitations regarding publication date or language. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. (3) Results: We identified 11 individual studies that were included in this systematic review. Three publications included patients without prior radiotherapy and the remaining eight patients with prior radiotherapy. In all but two publications the radiation target was the macroscopic recurrence. SBRT was overall well tolerated with acceptable rates of acute and late gastrointestinal or genitourinary toxicity. Quality of life was published for two phase I trials with good results. There was a very heterogeneous reporting on biochemical control after SBRT. (4) Conclusions: At this point, ultra-hypofractionated RT using SBRT to the prostate bed remains experimental and its use should be restricted to clinical trials. Given the biological rationale for extreme hypofractionation in patients with prostate cancer and the acceptable toxicity rates that have been reported, further exploration of this field is warranted.