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Introduction Turoctocog alfa (NovoEight® ) is a B-domain-truncated recombinant factor VIII (FVIII) approved for patients with haemophilia A. Aim To investigate the long-term safety and efficacy of turoctocog alfa in routine clinical practice. Methods Guardian 5 was a prospective, multinational, non-interventional, post-authorisation safety study. Male previously treated patients (> 150 exposure days [EDs]) of any age with severe/moderately severe haemophilia A (FVIII ≤ 2%) and a negative inhibitor test prior to first dosing (independent of FVIII-inhibitor history) were included to receive prophylaxis or on-demand treatment. The primary endpoint was the proportion of patients developing FVIII inhibitors (≥.6 Bethesda Units [BU]) after baseline visit, measured as per routine practice of each study site during clinic visits. Secondary endpoints included haemostatic effect, annualised bleeding rate (ABR), and adverse reactions assessment. The study concluded when 50 patients reached 100 EDs/patient minimum. Results Seventy patients were screened and 68 exposed to turoctocog alfa; 63 (92.6%) were on prophylaxis and five received on-demand treatment. Six (8.8%) patients reported a history of positive inhibitors. During the study, patients were exposed to turoctocog alfa for a mean (standard deviation) of 131.9 (99.0) days/patient. Fifty-five of 58 patients who completed the study were tested for FVIII inhibitors; no positive tests were reported. Overall success rate of turoctocog alfa for treatment of bleeds was 87.3%. Among patients receiving prophylaxis, median (range) ABR was 1.97 (.0-25.5) bleeds/year; estimated ABR (negative binomial model) was 3.65 (95% confidence interval: 2.53-5.25). Conclusion Turoctocog alfa was safe and efficacious for haemophilia A treatment in routine clinical practice.

OA Förderung 2022 Background: Despite an intensive multimodal treatment approach, approximately 50% of high-risk (HR) neuroblastoma (NB) patients experience progression. Despite the advances in targeted therapy, high-dose chemotherapy, and other systemic treatment options, radiation therapy (RT) to sites of relapsed disease can be an option to reduce tumor burden and improve chance for disease control. Methods: Patients who received salvage irradiation with proton beam therapy (PBT) for local or metastatic relapse of HR NB within the prospective registry trials KiProReg and ProReg were eligible for this retrospective analysis. Data on patient characteristics, multimodality therapy, adverse events, and oncologic endpoints were evaluated. Adverse events were assessed before, during, and after PBT according to common terminology criteria for adverse events (CTCAE) V4.0. Results: Between September 2013 and September 2020, twenty (11 male; 9 female) consecutive patients experiencing local (N = 9) or distant recurrence (N = 25) were identified for this analysis. Distant recurrences included osteomedullary (N = 11) or CNS lesions (N = 14). Salvage therapy consisted of re-induction chemo- or chemo-immuno-therapy (N = 19), surgery (N = 6), high-dose chemotherapy and stem cell transplantation (N = 13), radiation (N = 20), and concurrent systemic therapy. Systemic therapy concurrent to RT was given to six patients and included temozolomide (N = 4), carboplatine (N = 1), or anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKI) (N = 1). A median dose of 36 Gy was applied to the 34 recurrent sites. Local RT was applied to 15 patients, while five patients, received craniospinal irradiation for CNS relapse. After a median follow-up (FU) of 20 months (4–66), the estimated rate for local control, distant metastatic free survival, and overall survival at 3 years was 68.0%, 37.9%, and 61.6%, respectively. During RT, ten patients (50%) presented with a higher-grade acute hematologic adverse event. Late higher-grade sequelae included transient myelitis with transverse section (N = 2) and secondary malignancy outside of the RT field (N = 1). Conclusion: Our study demonstrates the efficacy and safety of RT/PBT for recurrent HR NB in a multimodality second-line approach. To better define the role of RT for these patients, prospective studies would be desirable.

The purpose of this study was to investigate adherence to recommended adjuvant radiotherapy (aRT) in radical prostatectomy (RP) patients with adverse pathologic features and to analyse the outcome of patients who followed or denied this recommendation.We included 1140 consecutive RP patients (2006-2015) with non-organ confined (pT3) prostate cancer and either positive surgical margins (R1) and/or lymph node involvement (pN1) and non-detectable postoperative prostate-specific antigen who received multidisciplinary aRT recommendations. Patients were stratified into adherence versus non-adherence to recommendations. Additionally, subgroups within pathologic criteria (pT3R1N0, pT3R0N1, pT3R1N1) were analyzed. Kaplan-Meier, as well as multivariable Cox regression analyses were used to assess biochemical recurrence (BCR)-free survival, metastasis-free survival, cancer-specific survival, and overall survival.Overall, 508 (44.6%) patients were non-adherent. Of those, 273 (53.6%) did not receive any RT, and 235 (46.4%) received salvage RT. At 8 years, BCR-free survival was 57.7 versus 20.1%, metastasis-free survival was 76.5 versus 75.4%, cancer-specific survival was 91.7 versus 87.4%, and overall survival was 80.4 versus 75.8% in adherent versus non-adherent patients, respectively (P .001). In multivariable Cox regression predicting BCR, metastatic progression, cancer-specific mortality, and overall mortality, non-adherence to aRT recommendation represented an independent predictor (hazard ratio [HR], 3.8; 95% confidence interval [CI], 3.1-4.5; HR, 1.6; 95% CI, 1.2-2.2; HR, 2.8; 95% CI, 1.5-5.3; and HR, 1.8; 95% CI, 1.2-2.8, respectively).Only about 55% of patients followed our multidisciplinary recommendations. Adherent patients were significantly less likely to experience BCR, metastatic progression, cancer-specific mortality, and overall mortality. Thus, patients with high risk of recurrence may be advised about the possibility of improved oncologic outcomes in case of adherence to aRT recommendations.

Purpose Several studies have demonstrated the negative impact of radiotherapy protocol deviations on tumor control in medulloblastoma. In the SIOP PNET5 MB trial, a pretreatment radiotherapy quality control (RT-QC) program was introduced. A first analysis for patients enrolled in Germany, Switzerland and Austria with focus on types of deviations in the initial plan proposals and review criteria for modern radiation technologies was performed. Methods and patients Sixty-nine craniospinal irradiation (CSI) plans were available for detailed analyses. RT-QC was performed according to protocol definitions on dose uniformity. Because of the lack of definitions for high-precision 3D conformal radiotherapy within the protocol, additional criteria for RT-QC on delineation and coverage of clinical target volume (CTV) and planning target volume (PTV) were defined and evaluated. Results Target volume (CTV/PTV) deviations occurred in 49.3% of initial CSI plan proposals (33.3% minor, 15.9% major). Dose uniformity deviations were less frequent (43.5%). Modification of the RT plan was recommended in 43.5% of CSI plans. Unacceptable RT plans were predominantly related to incorrect target delineation rather than dose uniformity. Unacceptable plans were negatively correlated to the number of enrolled patients per institution with a cutoff of 5 patients (p = 0.001). Conclusion This prospective pretreatment individual case review study revealed a high rate of deviations and emphasizes the strong need of pretreatment RT-QC in clinical trials for medulloblastoma. Furthermore, the experiences point out the necessity of new RT-QC criteria for high-precision CSI techniques.

Item does not contain fulltext Inhomogeneities in radiotherapy dose distributions covering the vertebrae in children can produce long-term spinal problems, including kyphosis, lordosis, scoliosis, and hypoplasia. In the published literature, many often interrelated variables have been reported to affect the extent of potential radiotherapy damage to the spine. Articles published in the 2D and 3D radiotherapy era instructed radiation oncologists to avoid dose inhomogeneity over growing vertebrae. However, in the present era of highly conformal radiotherapy, steep dose gradients over at-risk structures can be generated and thus less harm is caused to patients. In this report, paediatric radiation oncologists from leading centres in 11 European countries have produced recommendations on how to approach dose coverage for target volumes that are adjacent to vertebrae to minimise the risk of long-term spinal problems. Based on available information, it is advised that homogeneous vertebral radiotherapy doses should be delivered in children who have not yet finished the pubertal growth spurt. If dose fall-off within vertebrae cannot be avoided, acceptable dose gradients for different age groups are detailed here. Vertebral delineation should include all primary ossification centres and growth plates, and therefore include at least the vertebral body and arch. For partial spinal radiotherapy, the number of irradiated vertebrae should be restricted as much as achievable, particularly at the thoracic level in young children (

Introduction The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study. Materials and methods The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models. Results Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42–65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22–25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles. Conclusions Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years.

Combined high-dose-rate brachytherapy (HDR-BT) and external beam radiation therapy (EBRT) is a favorable treatment option in non-metastatic prostate cancer. However, reports on toxicity and outcome have mainly focused on younger patients. We aimed to determine toxicity and biochemical control rates after combined HDR-BT and EBRT in men ≥75 years. From 1999 to 2015, 134 patients aged ≥75 years (median 76 years; 75–82 years) were identified. Patients received 18 Gy of HDR-BT (9 Gy/fraction on days 1 and 8) with an iridium-192 source. After 1 week, supplemental EBRT with a target dose of 50.4 Gy was started (delivered in 1.8 Gy fractions). Median follow-up time was 25 months (0–127 months). No severe (grade 4) gastrointestinal (GIT) or genitourinary (GUT) toxicities were observed. In 76 patients (56.7%), 3D conformal radiation therapy (CRT) and in 34.3% intensity-modulated radiotherapy (IMRT) was applied. CRT-treated patients were at a 2.17-times higher risk (hazard ratio [HR]: 2.17, 95% confidence interval [CI]: 1.31–3.57, p = 0.002) of experiencing GUT. GIT risks could be reduced by 78% using IMRT (HR: 0.22, 95% CI: 0.07–0.75, p = 0.015). Patients with a higher T stage (T2c–3a/b) were less likely to experience GIT or GUT (HR: 0.49, 95% CI: 0.29–0.85, p = 0.011 and HR: 0.5, 95% CI: 0.3–0.81, p = 0.005, respectively). HDR-BT/EBRT is a well-tolerated treatment option for elderly men ≥75 years with a limited number of comorbidities and localized intermediate- or high-risk prostate cancer. IMRT should be favored since side effects were significantly reduced in IMRT-treated patients.

Background While the optimal use and timing of secondary therapy after radical prostatectomy (RP) remain controversial, there are limited data on patient-reported outcomes following multimodal therapy. Objective To assess the impact of additional radiation therapy (RT) and/or androgen deprivation therapy (ADT) on urinary continence, potency, and quality of life (QoL) after RP. Design, setting, and participants Among 13150 men who underwent RP from 1992 to 2013, 905 received RP + RT, 407 RP + ADT and 688 RP + RT + ADT. Outcome measurements and statistical analyses Urinary function, sexual function, and overall QoL were evaluated annually using self-administered validated questionnaires. Propensity score–matched and bootstrap analyses were performed, and the distributions for all functional outcomes were analyzed as a function of time after RP. Results and limitations Patients who received RP + RT had a 4% higher overall incontinence rate 3 yr after surgery, and 1% higher rate for severe incontinence (>3 pads/24h) compared to matched RP-only patients. ADT further increased the overall and severe incontinence rates by 4% and 3%, respectively, compared to matched RP + RT patients. RP + RT was associated with an 18% lower rate of potency compared to RP alone, while RP + RT + ADT was associated with a further 17% reduction compared to RP + RT. Additional RT reduced QoL by 10% and additional ADT by a further 12% compared to RP only and RP + RT, respectively. The timing of RT after RP had no influence on continence, but adjuvant compared to salvage RT was associated with significantly lower potency (37% vs 45%), but higher QoL (60% vs 56%). Limitations of our study include the observational study design and potential for selection bias in the treatments received. Conclusions Secondary RT and ADT after RP have an additive negative influence on urinary function, potency, and QoL. Patients with high-risk disease should be counseled before RP on the potential net impairment of functional outcomes due to multimodal treatment. Patient summary Men with high-risk disease choosing surgery upfront should be counseled on the potential need for additional radiation and or androgen deprivation, and the potential net impairment of functional outcomes arising from multimodal treatment.

Contains fulltext : 219893.pdf (Publisher’s version ) (Closed access) BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children /=1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0.40, 95% CI 0.11-1.41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0.012). Major or clinically relevant non-major bleeding in participants who received >/=1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1.58, 95% CI 0.51-6.27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING: Bayer AG and Janssen Research & Development. 01 januari 2020

The Austrian Haemophilia Registry collects epidemiological data on patients with haemophilia, on treatment modalities and potential side effects. The Registry covers more than 85% of the assumed total number of haemophilia patients in Austria. This report summarizes data on 753 patients: 84.3% (635) have haemophilia A and 15.7% (118) have haemophilia B. Patients' median age is 34 years (range: 1-93 years). Of the total cohort, 39.0% (294) patients have severe haemophilia, 11.3% (85) moderate haemophilia, and 49.4% (372) mild haemophilia. Of the patients with severe haemophilia, 38.4% (113) have been infected with hepatitis C virus (HCV) and 12.6% (37) are human immunodeficiency virus (HIV) positive. Overall, 10.6% (67) of patients with haemophilia A and 1.7% (2) of those with haemophilia B have had an inhibitor in their history. Among patients with severe haemophilia, 68.4% (201) receive prophylaxis and 28.6% (84) receive on-demand therapy. There are 65.0% (191) patients with severe haemophilia who are treated with recombinant products. In conclusion, most patients with severe haemophilia receive prophylactic treatment. HCV and HIV infections are still important issues in the Austrian haemophilia population.Das Österreichische Hämophilieregister sammelt epidemiologische Daten über Patienten mit Hämophilie, über die Behandlungsmodalitäten und über die möglichen Nebenwirkungen. Das Österreichische Hämophilie Register erfasst mehr als 85% der zu erwartenden Anzahl von Hämophilen in Österreich. Im Register sind 753 Patienten erfasst, von denen 84.3% (635) Hämophilie A und 15.7% (118) Hämophilie B haben. Das mediane Alter ist 34 Jahre (1–93). Es haben 39.0% (294) eine schwere, 11.3% (85) eine mittelschwere und 49.4% (372) eine leichte Hämophilie. Von den Patienten mit schwerer Hämophilie wurden 38.4% (113) mit HCV infiziert und 12.6% (37) sind HIV positiv. Insgesamt haben 10.6% (67) aller Patienten mit Hämophilie A und 1.7% (2) aller Patienten mit Hämophilie B einen Hemmkörper in ihrer Anamnese. Von den Patienten mit schwerer Hämophilie erhalten 68.4% (201) eine Prophylaxe und 28.6% (84) eine Bedarfsbehandlung. Von den Patienten mit schwerer Hämophilie erhalten 65.0% (191) ein rekombinantes Produkt. Zusammenfassend erhalten die meisten Patienten mit schwerer Hämophilie eine Prophylaxe. HCV und HIV Infektionen sind immer noch von großer Bedeutung für die österreichischen Hämophilie-Patienten.

Introduction: The EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.) was the first prospective international study for patients 41-65 years old with high-grade bone sarcoma treated with an intensive chemotherapy regimen derived from protocols for younger patients with high-grade skeletal osteosarcoma. Methods: Chemotherapy based on doxorubicin, cisplatin, ifosfamide, and methotrexate was suggested, but patients treated with other regimens at the investigators’ choice were also eligible for the study. Results: The present report focuses on the subgroup of 218 patients with primary high-grade osteosarcoma. With a median follow-up of 47 months, the 5-year probability of overall survival (OS) was 66% in patients with localized disease and 22% in case of synchronous metastases. The 5-year OS in patients with localized disease was 29% in pelvic tumors, and 70% and 73% for extremity or craniofacial locations, respectively. In primary chemotherapy, tumor necrosis ≥90% was reported in 21% of the patients. There were no toxic deaths; however, hematological toxicity was considerable with 32% of patients experiencing 1 or more episodes of neutropenic fever. The incidence of nephrotoxicity and neurotoxicity (mainly peripheral) was 28% and 24%, respectively. After methotrexate, 23% of patients experienced delayed excretion, in 4 cases with nephrotoxicity. Conclusions: In patients over 40 years of age with primary high-grade osteosarcoma, an aggressive approach with chemotherapy and surgery can offer the probability of survival similar to that achieved in younger patients. Chemotherapy-related toxicity is significant and generally higher than that reported in younger cohorts of osteosarcoma patients treated with more intensive regimens.

To determine the impact of Gallium-68-labled prostate-specific membrane antigen positron-emission tomography/computed tomography ([A total of 106 patients with prostate cancer scheduled for radiation therapy underwent 120 [[[

To evaluate the outcome of holmium laser enucleation of the prostate (HoLEP) in the known presence of prostate cancer (PCa) and concomitant lower urinary tract symptoms (LUTS).We retrospectively identified 62 patients who underwent HoLEP for LUTS in the known presence of PCa at our center. Perioperative data were assessed including complications, functional outcomes, and quality of life (QoL). Giving respect to different disease characteristics, patients were stratified according to treatment strategy setting into palliative (I), radiation (II), and surveillance (III) groups and compared accordingly.Median follow-up (FU) of the entire study cohort was 27 months (range 2-65 mos). Medians of functional parameters (International Prostate Symptom Score): 18.5 vs 4.5, QoL: 4 vs 1, maximal flow rate: 9.0 vs 18.8 mL/s and residual urine: 100 vs 0 mL, all P0.05) improved significantly in all groups. Perioperative complications were low and without any statistically significant difference between the groups. Postoperatively, voiding was successful in 90.3% of all patients; at last FU, 17% had some degree of urinary incontinence. Treatment strategy groups showed comparable functional outcomes after HoLEP.In the presence of PCa and LUTS, HoLEP represents a feasible, safe, and effective treatment option for patients unfit or without indication for radical prostatectomy. This applies as well in a palliative situation of advanced, obstructive PCa as for patients with LUTS who are scheduled for radiation therapy or surveillance in presumably indolent disease.

Recurrence rates of 20-40% after prostatectomy are described. This review will discuss curative treatment options for salvage after primary therapy. Relevant information was identified through searches of published studies, abstracts from scientific meetings, and review articles. Clinical experience in salvage therapy is limited. Conformal radiotherapy to the prostatic bed for PSA relapse and biopsy proven local recurrences after prostatectomy remains the only potentially curative therapy. It can provide durable biochemical control in a range from 17 to 78%. Salvage radiotherapy is well tolerated. Some prognostic factors exist which can help to select the right patient for this treatment. Patients have to be treated early for PSA relapse. Conformal radiotherapy to the prostatic bed for PSA relapse and biopsy proven local recurrences after prostatectomy is a good documented curative therapy. In a patient with a high probability of local recurrence early radiotherapy for PSA relapse is suggested.

To evaluate the accuracy of virtual simulation, which is less time-consuming than physical simulation, with the new laser system Dorado CT4 in 96 prostate cancer patients.Virtual simulation was based on a spiral scan with 8 mm reconstruction index and 8 mm slice thickness in 64 patients (group A), and 3 mm reconstruction index and 3 mm slice thickness in 32 patients (group B). Both groups were evaluated for impact on maximum difference (Deltamax) regarding the isocenters obtained from virtual simulation versus those obtained from physical simulation.In the entire cohort, mean differences were as follows: Deltamax 5.7 +/- 3.5 mm, Deltax (left/right) 2.8 +/- 2.9 mm, Deltay (anterior/posterior) 4.5 +/- 3.8 mm, and Deltaz (cranial/caudal) 2.1 +/- 2.2 mm. In group A, mean values were Deltamax 6.2 +/- 3.8 mm, Deltax 2.9 +/- 3.1 mm, Deltay 4.9 +/- 4.2 mm, and Deltaz 2.3 +/- 2.3 mm. In group B, mean values were Deltamax 4.8 +/- 2.8 mm, Deltax 2.7 +/- 2.7 mm, Deltay 3.7 +/- 2.7 mm, and Deltaz 1.7 +/- 2.0 mm. Time of radiotherapy (primary vs. salvage RT) and radiation regimen (external-beam radiotherapy [EBRT] vs. high-dose-rate brachytherapy [HDR-BT] plus EBRT) had no significant impact on Deltamax.Virtual simulation with the new laser system Dorado CT4 was very precise for both primary and salvage RT in the treatment of prostate cancer patients. High precision was achieved for both EBRT and HDR-BT plus EBRT. Virtual simulation should be performed with a planning CT with 3 mm reconstruction index and 3 mm slice thickness for high accuracy.

High-dose-rate brachytherapy (HDR-BT) with external-beam radiation therapy and radical prostatectomy (RP) are common treatment options for clinically localized prostate cancer. The aim was to describe risk factors for biochemical recurrence (BCR) and death, as well as BCR rates and overall survival (OS) rates in both treatment groups.Overall, 5,619 patients with localized prostate cancer underwent either RP (n = 5,200) or HDR-BT (n = 419) between 1999 and 2009. Median follow-up time was 72.4 months. Kaplan-Meier analyses and multivariable Cox regression analyses were performed for the overall cohort and for a propensity score-matched cohort to predict BCR and OS rates. Within the matched cohort, stratified analyses were repeated for HDR-BT alone (n = 206) and HDR-BT plus androgen deprivation therapy (ADT) (n = 213). Sensitivity analyses were performed to adjust for prostate-specific antigen rebound.The 5-year BCR-free survival rates were 82.1% vs. 80.3% (P0.01) for RP and HDR-BT, respectively. Corresponding 5-year OS rates were 97.1% vs. 92.4% (P0.01). In the propensity score-matched cohort, 5-year BCR-free survival rates were 80.3% vs. 77.1%; P = 0.06 and 5-year OS rates were 95.7% vs. 92.4%; P = 0.5. In multivariable models, the overall HDR-BT exerted no significant effect on BCR, and the same results were recorded in the matched cohort. In stratified analyses, HDR-BT alone vs. RP increased BCR risk (1.45; P0.01); conversely, HDR-BT plus ADT vs. RP decreased BCR risk (hazard ratio = 0.66; P = 0.02).First, RP offers equivalent oncological control without the need for concurrent hormone therapy and its morbidity. Second, patients who have RP avoid ADT (2%) and the need for salvage and adjuvant external-beam radiation therapy is low at 11% and 3%, respectively.

The role of additional androgen deprivation therapy (ADT) in prostate cancer (PCa) patients treated with combined HDR brachytherapy (HDR-BT) and external beam radiotherapy (EBRT) is still unknown.Consecutive PCa patients classified as D'Amico intermediate and high-risk who underwent HDR-BT and EBRT treatment ± ADT at our institution between January 1999 and February 2009 were assessed. Multivariable Cox regression models predicting biochemical recurrence (BCR) were performed. BCR-free survival was assessed with Kaplan-Meier analyses.Overall, 392 patients were assessable. Of these, 221 (56.4 %) underwent trimodality (HDR-BT and EBRT and ADT) and 171 (43.6 %) bimodality (HDR-BT and EBRT) treatment. Additional ADT administration reduced the risk of BCR (HR: 0.4, 95 % CI: 0.3-0.7, p 0.001). D'Amico high-risk patients had superior BCR-free survival when additional ADT was administered (log-rank p 0.001). No significant difference for BCR-free survival was recorded when additional ADT was administered to D'Amico intermediate-risk patients (log-rank p = 0.2).Additional ADT administration improves biochemical control in D'Amico high-risk patients when HDR-BT and EBRT are combined. Physicians should consider the oncological benefit of ADT administration for these patients during the decision-making process.

Objective In an international, multicenter, double-blind, randomized clinical trial we evaluated the short-term (3 months) and long-term (12 months) efficacy and safety of 2 different doses of meloxicam oral suspension compared with the efficacy and safety of naproxen oral suspension in children with oligoarticular-course (oligo-course) or polyarticular-course (poly-course) juvenile idiopathic arthritis (JIA). Methods Children ages 2–16 years who had active oligo-course or poly-course JIA and who required therapy with a nonsteroidal antiinflammatory drug were eligible for this trial. Patients were randomly allocated to receive therapy with meloxicam oral suspension, 0.125 mg/kg body weight in a single daily dose; meloxicam oral suspension, 0.25 mg/kg body weight in a single daily dose; or naproxen, 10 mg/kg body weight in 2 daily doses. The trial drugs were administered in a double-blind, double-dummy design for up to 12 months. Response rates were determined according to the American College of Rheumatology pediatric 30% improvement criteria (ACR pediatric 30). Safety parameters were assessed by evaluating the frequency of adverse events in the 3 groups. Results Of 232 patients enrolled, 225 received treatment, 6 were not eligible for randomization, and 1 randomized patient was not treated. One hundred eighty-two patients (81%) completed the 12-month treatment period. Response rates according to the ACR pediatric 30 criteria improved from month 3 to month 12, as follows: from 63% to 77% in the meloxicam 0.125 mg/kg group, from 58% to 76% in the meloxicam 0.25 mg/kg group, and from 64% to 74% in the naproxen group. No statistically significant differences in response rates were observed between the groups. There were no differences in the frequency of adverse events or abnormal laboratory values between the 3 groups. Conclusion The short- and long-term safety and efficacy of meloxicam oral suspension appear to be comparable with the safety and efficacy of naproxen oral suspension in the treatment of oligo-course and poly-course JIA. The once-daily administration of meloxicam oral suspension might represent an improvement in the treatment of JIA.

Background The aims of this analysis were to investigate features and outcome of high-grade osteosarcomas of the mobile spine. Patients and methods Since 1977, 20 Cooperative Osteosarcoma Study Group patients had a diagnosis of high-grade osteosarcomas of the mobile spine and were included in this retrospective analysis of patient-, tumor- and treatment-related variables and outcome. Results The median age was 29 years (range 5-58). Most frequent tumor sites were thoracic and lumbar spine. All but three patients had nonmetastatic disease at diagnosis. Treatment included surgery and chemotherapy for all patients, 13 were also irradiated. Eight patients failed to achieve a macroscopically complete surgical remission (five local, one primary metastases, two both), six died, two are alive, both with radiotherapy. Of 12 patients with complete remission at all sites, three had a recurrence (two local, one metastases) and died. The median follow-up of the 11 survivors was 8.7 years (range 3.1-22.3), 5-year overall and event-free survival rates were 60% and 43%. Age

Experiences with a new high-dose-rate brachytherapy (HDR-BT) boost technique in 41 patients with stage T3b prostate cancer are presented.The patients received 18 Gy of HDR-BT (9 Gy on days 1 + 8) plus 50.4 Gy of EBRT. 20 patients (group A) had BT applicators placed into the prostate alone resulting in 18 Gy to prostate and 0 Gy (tip) to 12 Gy (base) to seminal vesicles (SV). The cumulative EQD2 (equivalent dose in 2-Gy fractions, alpha/beta 1.5 Gy) to the SV was 47.5-73.3 Gy. 21 patients (group B) had BT applicators placed into both prostate and SV resulting in 18 Gy to prostate and to80% (but not 100%) of the SV (cumulative EQD2 81.5-101.5 Gy). Both groups were compared for acute and late toxicity and for biochemical relapse-free survival (bRFS).The 3-year bRFS was 57% for group A and 79% for group B patients (p = 0.29). A grade 3 acute toxicity (CTC 2.0) was not observed. Grade 2 acute toxicity (proctitis, cystitis, skin toxicity) was comparable in both groups. A grade 3 late toxicity did not occur. Impotence rates were 35% in group A and 24% in group B, respectively (p = 0.73).The new HDR-BT technique (group B) was associated only with minor acute and late toxicity and appears to result in better bRFS than the conventional HDR-BT technique (group A). The results must be confirmed in a prospective trial.

Purpose To study five radiotherapy (RT) schedules and potential prognostic factors for functional outcome in metastatic spinal cord compression (MSCC). Patients and Methods One thousand three hundred four patients who were irradiated from January 1992 to December 2003 were included in this retrospective review. The schedules of 1 × 8 Gy in 1 day (n = 261), 5 × 4 Gy in 1 week (n = 279), 10 × 3 Gy in 2 weeks (n = 274), 15 × 2.5 Gy in 3 weeks (n = 233), and 20 × 2 Gy in 4 weeks (n = 257) were compared for motor function, ambulatory status, and in-field recurrences. The following potential prognostic factors were investigated: age, sex, performance status, histology, number of involved vertebra, interval from cancer diagnosis to MSCC, pretreatment ambulatory status, and time of developing motor deficits before RT. A multivariate analysis was performed with the ordered logit model. Results Motor function improved in 26% (1 × 8 Gy), 28% (5 × 4 Gy), 27% (10 × 3 Gy), 31% (15 × 2.5 Gy), and 28% (20 × 2 Gy); and posttreatment ambulatory rates were 69%, 68%, 63%, 66%, and 74% (P = .578), respectively. On multivariate analysis, age, performance status, primary tumor, involved vertebra, interval from cancer diagnosis to MSCC, pretreatment ambulatory status, and time of developing motor deficits were significantly associated with functional outcome, whereas the RT schedule was not. Acute toxicity was mild, and late toxicity was not observed. In-field recurrence rates at 2 years were 24% (1 × 8 Gy), 26% (5 × 4 Gy), 14% (10 × 3 Gy), 9% (15 × 2.5 Gy), and 7% (20 × 2 Gy) (P < .001). Neither the difference between 1 × 8 Gy and 5 × 4 Gy (P = .44) nor between 10 × 3 Gy, 15 × 2.5 Gy, and 20 × 2 Gy (P = .71) was significant. Conclusion The five RT schedules provided similar functional outcome. The three more protracted schedules seemed to result in fewer in-field recurrences. To minimize treatment time, the following two schedules are recommended: 1 × 8 Gy for patients with poor predicted survival and 10 × 3 Gy for other patients. Results should be confirmed in a prospective randomized trial.

Analysis of the efficacy of fast neutron radiotherapy in the treatment of adenoid cystic carcinomas (ACC) of the salivary glands, identification of prognostic variables and dedifferentiation after radiotherapy.Histological slides of primary and recurrent lesions of 71 patients were reviewed to confirm the diagnosis and to analyse subtypes. Median follow-up was 52 months. Local control rate and overall survival were analysed in multivariate analysis. Complications are also described.Primary vs. recurrent therapy (p=0.001), margin-status (p=0.01) and subtype (p=0.019) influenced overall survival. Primary vs. recurrent therapy (p=0.001), margin-status (p=0.018) and T-stage (p=0.043) influenced local control rate. Dedifferentiation was seen in only 1/17 cases.The calculated prognostic factors illustrate the importance of a radical primary therapy. Histological subtype is a significant additional factor for overall survival and, in case of dedifferentiation, it is a strong predictor of a detrimental outcome.

It has been suggested that hemoglobin levels of 12-14 g/dL are optimal for tumor oxygenation, radiosensitivity, and prognosis. In this prospective study, the authors evaluated the effectiveness of epoetin-alpha to maintain hemoglobin levels at 12-14 g/dL during radiotherapy (RT) for patients with UICC Stage III esophageal carcinoma, and they examined the impact of erythropoetin on overall survival (OS), metastatic-free survival (MFS), and local control (LC).Sixty patients who received RT between March, 2001 and September, 2004, were included in this prospective, nonrandomized study. Thirty patients received epoetin-alpha (150 IU/kg 3 times per week) during RT (Group A), and 30 patients did not receive epoetin-alpha (Group B). Epoetin-alpha was started at hemoglobin levels13 g/dL and was stopped at hemoglobin levelsor = 14 g/dL. Hemoglobin was measured before RT and once weekly during RT.Both patient groups were balanced for age, gender, performance status, tumor location/length, histology, grading, tumor classification, lymph node status, chemotherapy, treatment (45-50.4 grays [Gy] plus resection vs. 45.0-50.4 Gy vs. 59.4-66.0 Gy), and hemoglobin level before RT. In 20 of 30 patients (67%) from Group A and in 3 of 30 patients (10%) from Group B,or = 60% of hemoglobin levels during RT were 12-14 g/dL (P = 0.003). The median change in hemoglobin was + 0.4 g/dL per week in Group A and - 0.4 g/dL per week in Group B. LC was significantly better in Group A (66% vs. 38% at 1 year, respectively; P = 0.012), a trend was observed for OS (59% vs. 33%, respectively; P = 0.08), and MFS did not differ significantly (43% vs. 38%, respectively; P = 0.34). No epoetin-alpha-related toxicity was observed.Epoetin-alpha was effective in maintaining the hemoglobin levels at 12-14 g/dL during RT. The application of epoetin-alpha significantly improved LC, and a trend was observed for OS.

Purpose To evaluate the impact of patient, tumor, and treatment-related factors on outcome in unselected patients with recurrent osteosarcoma. Patients and Methods Five hundred seventy-six consecutive patients who had achieved a first complete surgical remission (CR) during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols and then developed recurrent osteosarcoma were analyzed (median time from biopsy to relapse, 1.6 years; range, 0.1 to 14.3 years). There were 501 patients with metastases, 44 with local recurrences, and 31 with both. Metastases involved lungs (469 patients), bones (90 patients), and/or other sites (54 patients). Results After a median follow-up of 1.2 years for all patients and 4.2 years for survivors, actuarial overall survival (OS) rates at 2, 5, and 10 years were 0.38, 0.23, and 0.18, respectively. Five-year OS was 0.39 for 339 patients with and 0.00 for 229 patients without a second surgical CR (P < .0001). A long time to relapse, a solitary lesion, and, in the case of pulmonary metastases, unilateral disease and the absence of pleural disruption, were of positive prognostic value in uni- and multivariate analyses, as were a second surgical CR and the use of second-line chemotherapy. Radiotherapy was associated with moderately prolonged survival in patients without a second CR. The very limited prognostic differences associated with the use of second-line chemotherapy appeared to be more pronounced with polychemotherapy. Conclusion Time to relapse and tumor burden correlate with postrelapse outcome in osteosarcoma. Complete surgery is an essential component of curative second-line therapy. Chemotherapy, particularly chemotherapy with more than one agent, may contribute to limited improvements in outcome.

Analysis of treatment results of combined three–dimensional conformal radiotherapy (3DCRT) and hormonal therapy in patients with locally recurrent prostate cancer after radical prostatectomy. Between 1992 and 1998, 24 patients presented with a rising prostate–specific antigen (PSA) between 4 and 152 months following radical prostatectomy and a local recurrence demonstrated by imaging. Recurrence was biopsy–proven in 13 cases. All patients were treated with 3DCRT to a total dose of 60–70 Gy. 21 patients (88%) received adjuvant hormone therapy up to a maximum of 6 months. All patients showed a response in PSA values after therapy. Median follow–up is 43 months. Overall survival is 80% and 67% at 3 and 5 years, respectively. Biochemical control rates are 53% and 38% at 3 and 5 years, respectively. 14 patients developed a second PSA relapse. Acute and late toxicities, classified with the RTOG score, were moderate. Radiotherapy and short–term adjuvant hormone therapy represent an effective and well–tolerated treatment for locally recurrent prostate cancer after radical prostatectomy resulting in good local control. Long–term prognosis in terms of biochemical control and disease–specific survival remains poor.

Summary Thirty-four patients with recurrent oral and oropharyngeal carcinomas were treated over a period of 4 years, by interstitial high-dose rate (HDR) brachytherapy (BT) using an iridium-192 source (Gammamed 2i ™and 12i ™equipment, Sauerwein, Germany) and fractionated application (1 up to 3 times, weekly recovery phases, single maximum dose 10 Gy). Pretreatment characteristics of patients in terms of irradiation (RT) and surgery differed (22 had external RT alone, with a total dose between 60.0 and 75.6 Gy; RT and surgery: 7; surgery alone: 1). The initial TNM-stages (UICC, Hermanek et al., 1987) of patients were: I=2, II=3, III=7, IV=22. In the majority of cases, clinical indications for HDR-BT included tumour recurrence or progression following external RT, and second primary tumours of the oral cavity. Therapy was successful in most cases, i.e. complete remission: 11, partial remission: 16, no change: 2, progression: 5. Local control and overall survival rates, including patients surgically treated after BT, were at 6 months 58% and 62%, and 44% and 53% at 12 months, respectively. This type of treatment is recommended in patients with local recurrence or second primary tumours after previous external RT in the head and neck region. However, the benefit of interstitial HDR-BT remains questionable, particularly in patients with large tumours and lymph node metastases.

Results of fast neutron therapy are reviewed with special reference to the main indications for this type of treatment and the experience of five German centers. Neutron therapy seems beneficial compared to conventional radiotherapy in advanced salivary gland tumors, inoperable or unresectable soft tissue sarcomas, some bone tumors, prostate cancer stage C and some rare low-grade tumors. About 3 000 patients with malignancies have been treated with neutrons at the German centers Berlin/Rossendorf, Essen, Hamburg, Heidelberg and Munster. Treatment results and treatment-related morbidity depend on the treatment techniques and the physical selectivity of the neutron machines. A critical appraisal suggests that fast neutrons are of advantage in about 5% of all radiotherapy patients.