A prolonged overall treatment time (OTT) has been demonstrated to adversely affect the primary radiation therapy (RT) outcome in various solid tumors, including non-small cell lung cancer (NSCLC). Retrospective data from our group suggested an advantage of shorter OTT also for postoperative RT (PORT) in patients with NSCLC. The PORTAF trial (ClinicalTrials.gov: NCT02189967) was initiated to prospectively test this hypothesis. The multicenter prospective randomized phase II trial in patients with NSCLC investigated whether an accelerated schedule of PORT (7 fractions per week, 2 Gy per fraction, OTT 3.5–4 weeks) improved outcome compared to conventional fractionation (5 fractions per week, 2 Gy per fraction, OTT 5–6 weeks). Target volumes and total radiation doses were stratified in both treatment arms based on individual risk factors. Primary endpoint of the study was locoregional tumor control (LRTC) 36 months after PORT, with 154 patients to be included in each arm. Due to slow accrual and changed indications for PORT, we prematurely closed the trial in 2019. Between 2014 and 2019, eight recruiting centers included 27 evaluable patients. An interim safety analysis performed for the first 21 patients showed nonsignificant differences regarding grade 3 toxicities between the treatment arms, thus not meeting the termination criteria. LRTC was not significantly different between accelerated (73

Abstract PURPOSE To evaluate prognostic factors and impact of participation in a randomized trial in non-metastatic medulloblastoma. METHODS AND PATIENTS 382 patients with non-metastatic medulloblastoma aged 4–21 years with primary neurosurgical resections between 2001 and 2011 were enrolled into the HIT 2000 trial and centrally reviewed. Between 2001 and 2006, 176 of these patients participated in the randomized trial HIT-SIOP PNET 4. Three different radiotherapy protocols were applied. Molecular subgroup was available for 157 patients. RESULTS Median follow-up was 6.35 [0.09–13.86] years. The 5-year progression-free (PFS) and overall survival (OS) rates were 80.3 % ± 2.1 % and 86.5 % ± 1.8 %, respectively. On univariate analysis, there was no difference in PFS and OS according to radiotherapy protocols or in patients who participated in the HIT-SIOP PNET 4 trial or not, while histology, molecular subgroup and postoperative residual tumor influenced PFS significantly. Time interval between surgery and irradiation (≤48 days vs. ≥49 days) failed the significance level (p=0.052). On multivariate analyses, molecular subgroup (WNT activated vs. Group3 HR 5.49; p=0.014) and time interval between surgery and irradiation (HR 2.2; p=0.018) were confirmed as independent risk factors. CONCLUSION Using a centralized review system, multiprofessional and multiinstitutional collaboration as established for pediatric brain tumor patients in Germany, and risk-stratified therapy, outcome for non-metastatic medulloblastoma treated within HIT-SIOP PNET4 could be maintained outside the randomized trial. Prolonged time to radiotherapy negatively influenced survival.

PURPOSE:We aimed to compare treatment results in and outside of a randomized trial and to confirm factors influencing outcome in a large retrospective cohort of nonmetastatic medulloblastoma treated in Austria, Switzerland and Germany. METHODS AND MATERIALS:Patients with nonmetastatic medulloblastoma (n = 382) aged 4 to 21 years and primary neurosurgical resection between 2001 and 2011 were assessed. Between 2001 and 2006, 176 of these patients (46.1%) were included in the randomized HIT SIOP PNET 4 trial. From 2001 to 2011 an additional 206 patients were registered to the HIT 2000 study center and underwent the identical central review program. Three different radiation therapy protocols were applied. Genetically defined tumor entity (former molecular subgroup) was available for 157 patients. RESULTS:Median follow-up time was 7.3 (range, 0.09-13.86) years. There was no difference between HIT SIOP PNET 4 trial patients and observational patients outside the randomized trial, with 7 years progression-free survival rates (PFS) of 79.5% ± 3.1% versus 78.7% ± 3.1% (P = .62). On univariate analysis, the time interval between surgery and irradiation (≤ 48 days vs ≥ 49 days) showed a strong trend to affect PFS (80.4% ± 2.2% vs 64.6% ± 9.1%; P = .052). Furthermore, histologically and genetically defined tumor entities and the extent of postoperative residual tumor influenced PFS. On multivariate analyses, a genetically defined tumor entity wingless-related integration site-activated vs non-wingless-related integration site/non-SHH, group 3 hazard ratio, 5.49; P = .014) and time interval between surgery and irradiation (hazard ratio, 2.2; P = .018) were confirmed as independent risk factors. CONCLUSIONS:Using a centralized review program and risk-stratified therapy for all patients registered to the study center, outcome was identical for patients with nonmetastatic medulloblastoma treated on and off the randomized HIT SIOP PNET 4 trial. The prognostic values of prolonged time to RT and genetically defined tumor entity were confirmed.

In patients with follicular lymphoma, secondary transformation to aggressive lymphoma (tFL) implies a poor prognosis. In principle, allogeneic haematopoietic cell transplantation (allo-HCT) offers a chance of cure for tFL but is rarely practiced. Aim of this retrospective multicenter study was to define the actual significance of allo-HCT in treatment of tFL.

PURPOSE:This retrospective analysis aimed to address the efficacy of total nodal irradiation (TNI)-based reconditioning regimens in pediatric patients with graft failure/rejection after allogeneic hematopoietic cell transplantation. METHODS AND MATERIALS:Thirty-three pediatric patients with malignant (n = 25) and nonmalignant diseases (n = 8) were treated with a TNI-based reconditioning regimen. All patients received a 7-Gy single dose combined with anti-T lymphocyte antibody OKT3 (n = 16), anti-thymocyte globulin (n = 24), fludarabine (n = 31), and/or thiotepa (n = 28), followed by an infusion of peripheral blood stem cells (n = 31) or bone marrow transplant (n = 2). Twenty-eight of 33 patients had haploidentical family donors. RESULTS:After a median of 11 days, engraftment was seen in 32 of 33 children. Two children died 34 days after retransplantation because of either disease relapse or treatment-related multiple organ failure. Severe acute toxicity was reported in only 1 child (systemic inflammatory response syndrome-like reaction; recovery after cortisone treatment). The average follow-up was 60.2 months (range, 1.1-162.5 months). Event-free and overall survival rates at 2/5 years follow-up were 62.0%/58.6% and 65.1%/61.7%, respectively. Despite sustained engraftment, 12 patients died from disease relapse (n = 3), Moschkowitz syndrome (n = 1), or multiple organ failure (n = 8). Follow-up data were available for 18 of 21 survivors, with a median follow-up of 92.8 months (range, 3.6-162.5 months). Hypothyroidism was present in 78.6% of patients, and sex/growth hormonal insufficiencies were reported for 37.5%. Mean forced expiratory volume in 1 second after TNI was 84%; mean vital capacity was 79%. Severe growth failure (<3rd percentile) occurred in 28.6% (height) and 35.7% (weight) of patients. No secondary malignancies were reported. CONCLUSIONS:In the high-risk group of patients with graft failure/rejection after allogeneic hematopoietic cell transplantation, the TNI-based reconditioning regimen seems to allow sustained engraftment combined with a favorable toxicity profile, leading to long-term event-free and overall survival. Late toxicity after a median follow-up of over 7.5 years includes growth failure, manageable hormonal deficiencies, and a low risk of decrease of lung function.

Local failure is a major cause for low overall survival rates in advanced non small cell lung cancer (NSCLC). Among others, radioresistant tumor clones as well as geographical miss can explain these high local failure rates. One reason for geographical miss is a change of tumor related atelectasis in the course of radiotherapy. We present the case of a patient with UICC Stage IIIb NSCLC who presented with a large tumor related atelectasis. During definitive radiochemotherapy, the atelectasis resolved, which resulted in a massive tumor shift out of the planning target volume within 2 days. Without close monitoring by cone beam CTs and prompt replanning, this would have led to a geographical miss and relevant underdosage of the tumor. Furthermore, changes in anatomy and pulmonary function during treatment had implications for organs at risk and opened windows for dose escalation. We suggest at least biweekly CBCTs in patients with poststenotic atelectasis to ensure the rapid detection of geographical changes of the target and subsequent intervention if necessary.

Summary Graft failure is a life‐threatening complication after allogeneic haematopoietic stem cell transplantation ( HSCT ). We report a cohort of 19 consecutive patients (median age: 8·5 years) with acute leukaemias ( n = 14) and non‐malignant diseases ( n = 5) who experienced graft failure after previous HSCT from matched ( n = 3) or haploidentical donors ( n = 16) between 2003 and 2012. After total nodal irradiation ( TNI )‐based reconditioning combined with fludarabine, thiotepa and anti‐T cell serotherapy, all patients received T cell‐depleted peripheral blood stem cell grafts from a second, haploidentical donor. Median time between graft failure and retransplantation was 14 d (range 7–40). Sustained engraftment (median: 10 d, range 9–32) and complete donor chimerism was observed in all evaluable patients. 5 patients additionally received donor lymphocyte infusions. Graft‐versus‐host disease (Gv HD ) grade II and III occurred in 1 patient each (22%); no Gv HD grade IV was observed. 2 patients had transient chronic Gv HD . The regimen was well tolerated with transient interstitial pneumonitis in one patient. Treatment‐related mortality after one year was 11%. Event‐free survival and overall survival 3 years after retransplantation were 63% and 68%. Thus, a TNI ‐based reconditioning regimen followed by transplantation of haploidentical stem cells is an option to rescue patients with graft failure within a short time span and with low toxicity.

PURPOSE:A confirmatory analysis was performed to determine the prognostic value of metabolic response during induction chemotherapy followed by bimodality/trimodality treatment of patients with operable locally advanced non-small-cell lung cancer.PATIENTS AND METHODS:Patients with potentially operable stage IIIA(N2) or selected stage IIIB non-small-cell lung cancer received three cycles of cisplatin/paclitaxel (induction chemotherapy) followed by neoadjuvant radiochemotherapy (RCT) to 45 Gy (1.5 Gy twice per day concurrent cisplatin/vinorelbine) within the ESPATUE (Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA[N2] and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy) trial. Positron emission tomography scans were recommended before (t0) and after (t2) induction chemotherapy. Patients who were eligible for surgery after neoadjuvant RCT were randomly assigned to definitive RCT or surgery. The prognostic value of percentage of maximum standardized uptake value (%SUVmax) remaining in the primary tumor after induction chemotherapy-%SUVremaining = SUVmax(t2)/SUVmax(t0)-was assessed by proportional hazard analysis and receiver operating characteristic analysis.RESULTS:Overall, 161 patients were randomly assigned (155 from the Essen and Tübingen centers), and 124 of these received positron emission tomography scans at t0 and t2. %SUVremaining as a continuous variable was prognostic for the three end points of overall survival, progression-free survival, and freedom from extracerebral progression in univariable and multivariable analysis (P < .016). The respective hazard ratios per 50% increase in %SUVremaining from multivariable analysis were 2.3 (95% CI, 1.5 to 3.4; P < .001), 1.8 (95% CI, 1.3 to 2.5; P < .001), and 1.8 (95% CI, 1.2 to 2.7; P = .006) for the three end points. %SUVremaining dichotomized at a cut point of maximum sum of sensitivity and specificity from receiver operating characteristic analysis at 36 months was also prognostic. Exploratory analysis revealed that %SUVremaining was likewise prognostic for overall survival in both treatment arms and was more closely associated with extracerebral distant metastases (P = .016) than with isolated locoregional relapses (P = .97).CONCLUSION:%SUVremaining is a predictor for survival and other end points after multimodality treatment and can serve as a parameter for treatment stratification after induction chemotherapy or for evaluation of adjuvant new systemic treatment options for high-risk patients.

Abstract Abstract 1956 Graft failure is a rare but life-threatening complication after hematopoetic stem cell transplantation. Treatment comprises immunoablative reconditioning regimens and a second stem cell donation as soon as possible to minimize the time of pancytopenia and its sequelae. We report a cohort of 21 pediatric patients with acute leukemias (complete remission (CR)1-2 n= 7, active disease n=4; lymphatic n=7, myeloic n=4), myelodysplastic syndrome (n=2), immunodeficiencies (n=3), aplastic anemias (n=3), and hemoglobinopathies (n=2) who experienced graft failure (nonengraftment n=1; rejection n=20) after busulphan or melphalan based myeloablative transplantation from mismatched related donors (n=14) or matched unrelated or related donors (n=7). All patients were retransplanted with T cell depleted grafts (CD34 positive selection n=3 or CD3/CD19 depleted grafts n=18) from a haploidentical donor. Median time from diagnosis of graft rejection to second transplantation was 19 days. Reconditioning regimens consisted of irradiation (total lymphnode irradiation 7Gray (Gy) or TBI 2 Gy), fludarabine (120mg/m2) in combination with thiotepa (5mg/kg) or cyclophosphamide (60mg/kg body weight (bw)) and ATG/OKT3. A median number of 15×106/kg of body weight stem cells with 54×103/kg residual T cells were infused. Mofetilmycophenolat was given as Graft vs. Host Disease (GvHD) prophylaxis, if residual T cells exceeded 25 000/kg bw. Sustained engraftment was achieved in 20 out of 21 patients. One patient died before engraftment. Median time to absolute neutrophile counts above 500/μl was 9 (9–24) days. Independence from platelet substitution was reached at a median time of 10 (8–22) days. Only 1 patient developed GvHD °III, 10% developed GvHD °II, 33% of all patients developed GvHD °I, and 52% had no signs of GvHD. T cell recovery was delayed, however no lethal viral infection occurred. Severe organ toxicity was observed in 5 patients (bronchiolitis obliterans n=1, hemorrhagic cystitis n=2, leukencephalopathy n=2). Event free survival (EFS) of all patients at 5 years was 71%. 5 year EFS of patients with leukemias in complete remission was 83%. Patients with non-malignant diseases had 5 year EFS of 80%. Transplant related mortality at one year was 10%. Causes of death were: multi organ failure (n=1), fungal infection (n=1) and bronchiolitis obliterans organizing pneumonia, 4 patients with acute leukemias relapsed. None of the patients rejected the second graft. Thus, transplantation of stem cells from haploidentical donors after reconditioning is a realistic option to rescue patients with graft failure within a short time span. Graft rejection itself may have an antileukemic effect since patients with malignant diseases showed a favourable EFS. The use of a different donor in combination with irradiation based conditioning regimens may help to avoid a second rejection and results in a robust engraftment and low TRM. Disclosures: No relevant conflicts of interest to declare.

BACKGROUND AND PURPOSE:Multimodality treatment approaches provide high local control and satisfying overall survival (OS) for children with localized bladder and/or prostate rhabdomyosarcoma (BP-RMS). However, current strategies including surgery and conventional radiotherapy are compromised by high rates of long-term genitourinary adverse effects. Therefore, a planning study combining organ preserving surgery with three different innovative adjuvant radiotherapy approaches was performed.PATIENTS AND METHODS:A case of a 21-month-old boy with BP-RMS treated with polychemotherapy according to the CWS 2002-P protocol, prostatectomy, partial cystectomy, and adjuvant high dose rate brachytherapy (HDR-BT) was used to perform a planning study comparing HDR-BT with intensity-modulated radiotherapy (IMRT) and intensity-modulated proton therapy (IMPT) planning.RESULTS:All modalities provide good coverage of the target volume and spare critical normal tissues. Rectum doses could be reduced by 2/3 using IMPT and by 1/3 using BT compared to IMRT. In terms of sparing the pelvis growth plates, BT and IMPT are also superior to IMRT.CONCLUSION:All modalities provide good sparing of normal tissue. BT and IMPT are superior to IMRT with regard to doses on rectum and growth plates. BT is equivalent to IMPT in adequately selected tumors.

Non-Hodgkin’s lymphomas (NHL), a heterogenous group of malignancies arising from lymphoid tissue, account for almost 5% of all cancers occurring in the United States [1]. With an estimated 63,190 new cases and 18,660 cancer deaths projected in 2007 in the United States, NHL is the fifth most common malignant neoplasm after the breast, prostate, lung, and colon [2]. The incidence and mortality rates were reported to have risen steadily in Western countries over the past decades and have doubled between 1950 and 1989, from 5.9 to 13.7 per 100,000 persons per year [3] but the incidence rate had slowed to 1-2% in the 1990s [4, 5].

In patients with advanced-stage III/IV follicular lymphoma (FL), there are many treatment options available. The current challenge is to choose the optimal strategy for the individual patient.

In patients with advanced-stage follicular lymphoma (FL) there are many treatment options available. Besides watchful waiting in asymptomatic patients, current first-line treatment strategies include rituximab ± single-agent chemotherapy, chemoimmunotherapy and radioimmunotherapy. In case of relapse, the use of chemoimmunotherapy, radioimmunotherapy and autologous haematopoietic stem cell transplantation (HSCT) results in enhanced response rates, progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone. However, long-term results are marred by high relapse rates and the risk of secondary malignancies after autologous HSCT. To date, in patients with relapsed/chemoresistant disease, myeloablative/reduced intensity conditioning protocols in combination with allogeneic HSCT presumably constitute the only curative approach but are associated with high treatment-related mortality. Although advances in supportive care have resulted in improved outcomes, reliable strategies for adequate patient selection are mandatory. In the palliative setting, low-dose involved-field irradiation constitutes an effective treatment option in order to control local symptoms with potential long-lasting response.

To clarify the role of external-beam radiotherapy (RT) in patients with stage I and II nodal follicular lymphoma (FL).

PURPOSE:To evaluate residents' satisfaction with their training in radiation oncology, the first nationwide survey was done in 2006. Results were presented at the 2006 annual meeting of the German Society of Radiation Oncology (DEGRO). MATERIAL AND METHODS:A questionnaire with 39 questions regarding training in radiation oncology in Germany was developed and sent by e-mail. Questionnaires were returned by mail and analyzed anonymously. RESULTS:96 questionnaires were received. A total of 88% of respondents are pleased with their decision of training in radiation oncology. Residents are strongly motivated by their interest in oncology. Quality of training is heterogeneous and not optimal. Training in three-dimensional treatment planning, radiochemotherapy and intracavitary brachytherapy is judged adequate, whereas special techniques such as intensity-modulated radiotherapy (IMRT) and permanent prostate implants are not covered by the majority of institutions. Organization of training in the departments is often judged insufficient. CONCLUSION:Radiation oncology is attractive for young doctors. However, training quality for radiation oncologists in Germany was judged to be heterogeneous and needs to be optimized. For this, results of this survey may be helpful. The overall positive judgment may help to attract more students into the field of radiation oncology, an issue that becomes increasingly important given the shortage of doctors and the strong competition with other disciplines. Modern techniques, such as IMRT, need to be integrated into training programs in order to maintain the high standard of radiation oncology in Germany.

Graft failure is a life-threatening complication after transplantation of hematopoietic stem cells. We report a cohort of 11 pediatric patients with leukemias (n=8) and severe aplastic anemia (n=3) who experienced graft rejection after myeloablative transplantation from mismatched related donors (n=6) or after cord blood or matched unrelated donor transplantation (n=5). In the latter, the original donor was not available anymore. All patients were re-transplanted with CD34(+) selected or CD3/CD19 depleted stem cells from a second, haploidentical donor. Median time span from diagnosis of rejection to second transplant was 9 days. Reconditioning regimens comprised total lymphoid irradiation, thiotepa, fludarabine, ATG/OKT3 and were well tolerated. A median number of 23.5x10(6)/kg stem cells with 95,000/kg residual T-cells were infused. Sustained engraftment of neutrophiles/platelets and complete donor chimerism was achieved in all patients (ANC>500/microl: 9 (11-32) days). No GvHD>grade II was observed. 8/11 patients are disease free (median follow up 1.9 years; 1 year-EFS=72%). Causes of death were: pneumonitis, infection, relapse. Thus, haploidentical transplantation represents a realistic option to rescue patients with graft failure within a short time span, for whom a second donation from the original donor is not available. The use of different donors may contribute to avoid a second rejection.