Rades, Dirk

Radiotherapy of lung cancer may cause pneumonitis that generally occurs weeks or months following therapy and can be missed. This prospective trial aimed to pave the way for a mobile application (app) allowing early diagnosis of pneumonitis. The primary goal was the identification of the optimal cut-off of a score to detect pneumonitis of grade ≥2 after radiotherapy for lung cancer. Based on the severity of symptoms (cough, dyspnea, fever), scoring points were 0–9. Receiver operating characteristic (ROC)-curves were used to describe the sensitivity and specificity. The area under the ROC-curve (AUC) was calculated to judge the accuracy of the score, Youden-index was employed to define the optimal cut-off. Until trial termination, 57 of 98 patients were included. Eight of 42 patients evaluable for the primary endpoint (presence or absence of radiation pneumonitis) experienced pneumonitis. AUC was 0.987 (0.961–1.000). The highest sensitivity was achieved with 0–4 points (100%), followed by 5 points (87.5%), highest specificity with 5–6 points (100%). The highest Youden-index was found for 5 points (87.5%). The rate of patient satisfaction with the symptom-based scoring system was 93.5%. A cut-off of 5 points was identified as optimal to differentiate between pneumonitis and no pneumonitis. Moreover, pneumonitis was significantly associated with an increase of ≥3 points from baseline (p < 0.0001). The scoring system provided excellent accuracy and high patient satisfaction. Important foundations for the development of a mobile application were laid.

Survival scores facilitate personalized cancer treatment. Due to demographic changes, very elderly patients are more prevalent than in the past. A score was developed in 94 patients aged ≥ 80 years undergoing whole-brain radiotherapy for brain metastases. Dose fractionation, treatment period, age, sex, performance score (ECOG-PS), tumor type, count of lesions, metastases outside the brain, and interval tumor diagnosis to radiotherapy were retrospectively evaluated. Independent predictors of survival were used for the score. Based on individual scoring points obtained from 3-month survival rates, prognostic groups were designed. Additionally, the score was compared to an existing tool developed in patients ≥ 65 years. ECOG-PS, count of lesions, and extra-cranial metastases were independent prognostic factors. Three groups were created (7, 10, and 13–16 points) with 3-month survival of 6%, 25%, and 67% (p < 0.001), respectively. Positive predictive values (PPVs) regarding death ≤ 3 and survival ≥ 3 months were 94% and 67% (new score) vs. 96% and 48% (existing tool), respectively. PPVs for survival ≥1 and ≥2 months were 88% and 79% vs. 63% and 58%, respectively. Both tools were accurate in predicting death ≤2, ≤3, and ≤6 months. The new score was more precise regarding death ≤1 month and survival (all time periods) and appeared preferable. However, it still needs to be validated.

Survival scores are important for personalized treatment of bone metastases. Elderly patients are considered a separate group. Therefore, a specific score was developed for these patients. Elderly patients (≥65 years) irradiated for bone metastases were randomly assigned to the test (n = 174) or validation (n = 174) cohorts. Thirteen factors were retrospectively analyzed for survival. Factors showing significance (p < 0.05) or a trend (p < 0.06) in the multivariate analysis were used for the score. Based on 6-month survival rates, prognostic groups were formed. The score was compared to an existing tool developed in patients of any age. In the multivariate analysis, performance score, tumor type, and visceral metastases showed significance and gender was a trend. Three groups were designed (17, 18–25 and 27–28 points) with 6-month survival rates of 0%, 51%, and 100%. In the validation cohort, these rates were 9%, 55%, and 86%. Comparisons of prognostic groups between both cohorts did not reveal significant differences. In the test cohort, positive predictive values regarding death ≤6 and survival ≥6 months were 100% with the new score vs. 80% and 88% with the existing tool. The new score was more accurate demonstrating the importance of specific scores for elderly patients.

Estimating post-treatment ambulatory status can improve treatment personalization of patients irradiated for malignant spinal cord compression (MSCC). A new clinical score was developed from data of 283 patients treated with radiotherapy alone in prospective trials. Radiotherapy regimen, age, gender, tumor type, interval from tumor diagnosis to MSCC, number of affected vertebrae, other bone metastases, visceral metastases, time developing motor deficits, ambulatory status, performance score, sensory deficits, and sphincter dysfunction were evaluated. For factors with prognostic relevance in the multivariable logistic regression model after backward stepwise variable selection, scoring points were calculated (post-radiotherapy ambulatory rate in % divided by 10) and added for each patient. Four factors (primary tumor type, sensory deficits, sphincter dysfunction, ambulatory status) were used for the instrument that includes three prognostic groups (17–21, 22–31, and 32–37 points). Post-radiotherapy ambulatory rates were 10%, 65%, and 97%, respectively, and 2-year local control rates were 100%, 75%, and 88%, respectively. Positive predictive values to predict ambulatory and non-ambulatory status were 97% and 90% using the new score, and 98% and 79% using the previous instrument. The new score appeared more precise in predicting non-ambulatory status. Since patients with 32–37 points had high post-radiotherapy ambulatory and local control rates, they may not require surgery.

For optimal personalization of treatment for metastatic spinal cord compression (MSCC), the patient’s survival prognosis should be considered. Estimation of survival can be facilitated by prognostic factors. This study investigated the prognostic value of pre-treatment preclinical markers, namely hemoglobin, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lactate dehydrogenase (LDH), and c-reactive protein (CRP), in 190 patients from two prospective trials who had poor or intermediate survival prognoses and were irradiated for MSCC with motor deficits. In addition, clinical factors including radiation regimen, age, gender, tumor type, interval from tumor diagnosis to MSCC, number of affected vertebrae, visceral metastases, other bone metastases, time developing motor deficits, ambulatory status, sensory function, and sphincter function were evaluated. On univariate analyses, NLR (p = 0.033), LDH (p < 0.001), CRP (p < 0.001), tumor type (p < 0.001), pre-radiotherapy ambulatory status (p < 0.001), and sphincter function (p = 0.011) were significant. In the subsequent Cox regression analysis, LDH (p = 0.007), CRP (p = 0.047), tumor type (p = 0.003), and ambulatory status (p = 0.010) maintained significance. In addition to clinical factors, preclinical markers may help in estimating the survival of patients irradiated for MSCC. Additional prospective trials are warranted.

In 2005, a randomized trial showed that addition of surgery to radiotherapy improved outcomes in patients with metastatic spinal cord compression (MSCC). Since then, only a few studies compared radiotherapy plus surgery to radiotherapy alone. We performed a retrospective matched-pair study including data from prospective cohorts treated after 2005. Seventy-nine patients receiving radiotherapy alone were matched to 79 patients assigned to surgery plus radiotherapy (propensity score method) for age, gender, performance score, tumor type, affected vertebrae, other bone or visceral metastases, interval tumor diagnosis to MSCC, time developing motor deficits, and ambulatory status. Improvement of motor function by ≥1 Frankel grade occurred more often after surgery plus radiotherapy (39.2% vs. 21.5%, p = 0.015). No significant differences were found for post-treatment ambulatory rates (59.5% vs. 67.1%, p = 0.32), local progression-free survival (p = 0.47), overall survival (p = 0.51), and freedom from in-field recurrence of MSCC (90.1% vs. 76.2% at 12 months, p = 0.58). Ten patients (12.7%) died within 30 days following radiotherapy alone and 12 patients (15.2%) died within 30 days following surgery (p = 0.65); 36.7% of surgically treated patients did not complete radiotherapy as planned. Surgery led to significant early improvement of motor function and non-significantly better long-term control. Patients scheduled for surgery must be carefully selected considering potential benefits and risk of perioperative complications.

e22167 Background: Safe and effective delivery of viral vectors is important for gene therapy. Local application of such vectors is more efficient than systemic application. However, currently available injection systems are not optimal because placement of the injection needle and the vector application itself are generally not reproducibile. We developed a new injection system providing controlled injection of adenoviral vectors in tumors (xeno-transplants) in nude mice (NMRI nu/nu). Methods: The new MAGD consists of two fixation devices mounted on a 40x40cm plexi-glass plate, four injection units, and one pump unit with 4 infusion-pumps (Bee hive, Bioanalytical, Chesire, UK). Each injection unit is linked to a pump with commercially available plastic tube. Because the injection arms can be moved in x-,y- and z-direction, virus injection can easily performed for irregular tumor volumes. The entire injection volume is equally distributed to the 4 injection pumps allowing precise and steady injection rates between 0.1μl/min and 100μl/min. Success was confirmed with MRI-scans (Magnetom symphony, Siemens, Erlangen, Germany) 10 min after the injection. The efficacy of the MAGD was tested in 4 human squamous cell carcinoma cell lines from oro-/hypopharynx (FaDu, UD- SCC2, UD-SCC6, and UD-SCC7a). Virus transfection was performed with an adenovirus (serotype 5) expressing enhanced green fluorescent protein (eGFP). Transfection rates were quantified with flow cytometry. Successfully transfected cells expressed eGFP resulting in green fluorescence. In-vitro cell lines (concentration: 10 particles per cell, MOI 10) of FaDu, UD-SCC2, UD-SCC6 and UD-SCC7a served as controls. Results: The MAGD was easy to handle. Injection of 100μl (25μl per infusion pump) at an injection rate of 5μl/min took only 5 min. The in-vivo transfection rates achieved with the MAGD were 9±1% for FaDu, 39±2% for UD- SCC, 54±1% for UD-SCC6 and 54±9% for UD-SCC7a, respectively. The in-vitro transfection rates (controls) for these 4 cell lines were 2±1%, 23±4%, 29±4% and 3±2%, respectively. Conclusions: The new MAGD provided controlled injection of adenoviral vectors in tumors in nude mice. It proved to be effective, as it resulted in comparably high transfection rates. No significant financial relationships to disclose.

9522 Background: Many MSCC patients live long enough to develop a recurrence in the irradiated spinal area. This is the first prospective study comparing different RT schedules for local control (LC) of MSCC. Methods: 265 patients treated with RT alone (1/06–12/07) were included in this prospective non-randomized study. The primary goal was to compare short-course (1×8 Gy/5×4 Gy, N=131) and long-course RT (10×3 Gy/15×2.5 Gy/20×2 Gy, N=134) for 1-year LC. Secondary endpoints were motor function and 1-year survival (OS). Dutch patients received short-course, and German patients long-course RT. The analysis of LC (no MSCC recurrence in the irradiated spinal area) included the 224 patients with improvement or no change of motor deficits during RT. The difference in 1-year LC was previously reported to be 14% between short- and long-course RT. For a statistical power of 90 % (significance level 5%), ≥218 patients were required to detect this difference. Univariate analyses (UVA) for LC and OS were performed with Kaplan-Meier-method and log-rank test, multivariate analyses (MVA) with the Cox proportional hazards model. UVA and MVA for motor function were performed with the ordered-logit-model. Eleven additional factors were evaluated. Results: 1-year LC was 61% after short-course RT and 81% after long-course RT (P=0.005). On MVA, improved LC was only associated with long-course RT (P=0.018). Motor function improved in 37% after short- and 39% after long-course RT (P=0.95). Improved motor function was associated with better performance status (P=0.015), favorable tumor (P=0.034), and slower development of motor deficits (P<0.001). 1-year OS was 23% after short- and 30% after long-course RT (P=0.28). On MVA, improved OS was associated with better performance status (P<0.001), no visceral metastases (P<0.001), involvement of 1–3 vertebrae (P=0.040), ambulatory status (P=0.038), and bisphosphonates (P<0.001). Conclusions: Long-course RT was associated with better LC, similar functional outcome, and similar OS compared to short-course RT. Patients with a favorable OS prognosis should receive long-course RT, and those with a poor OS prognosis should receive short-course RT. [Table: see text]

2075 Background: This study was performed to create and validate scoring systems to estimate survival and intracerebral local control at 6 months of patients irradiated for brain metastases. Methods: Data of 1,797 patients irradiated for brain metastases (1,346 whole-brain radiotherapy [WBRT], 131 radiosurgery [RS], 61 WBRT + RS, 259 resection + WBRT) were retrospectively analyzed. Patients were randomly assigned to the test group (N = 1,198) or the validation group (N = 599). In the test group, multivariate analyses (MVA, Cox proportional hazards model) were performed for survival (OS) and local control (LC). Based on the MVA results, two scoring systems were developed, one for OS and another for LC. The scores included the prognostic factors found significant on MVA. Age, performance status, extracranial metastases, interval from tumor diagnosis to RT, and number of brain metastases were significant for OS. Tumor type, performance status, interval from tumor diagnosis to RT, and number of brain metastases were significant for LC. The score for each factor was determined by dividing the 6-month OS or LC rate (%) by 10. The total score represented the sum of the scores for each factor. For OS, total scores ranged from 15–30 points, and patients were divided into three groups (15–19, 20–25, and 26–30 points). For LC, total scores ranged from 14–27 points, and patients were divided into three groups (14–18, 19–23, and 24–27 points). Results: In the test group, the 6-month OS rates were 9 ± 1% for patients with scores of 15–19 points, 41 ± 2% for those with 20–25 points, and 78 ± 2% for those with 26–30 points (p < 0.0001). The corresponding OS rates in the validation group were 7 ± 2%, 39 ± 3%, and 79 ± 3%, respectively (p < 0.0001).In the test group, the 6-month LC rates were 17 ± 3% for patients with 14–18 points, 49 ± 3% for those with 19–23 points, and 77 ± 2% for those with 24–27 points (p < 0.0001). The corresponding LC rates in the validation group were 19 ± 4%, 52 ± 4%, and 77 ± 3%, respectively (p < 0.0001). Conclusions: Patients irradiated for brain metastases can be grouped with these scores to estimate OS and LC. The OS and LC rates of the validation group were almost identical to the test group, which demonstrates the high validity and reproducibility of both scores. No significant financial relationships to disclose.

Abstract Background: Erythropoiesis stimulating agents (ESAs) consistently have been shown to decrease transfusions in anemic oncology patients. However, whether they increase mortality in cancer patients is under debate. Results from individual studies conflict, and results from literature based meta-analyses are inconclusive. We conducted a meta-analysis based on individual patient data (IPD) from all available randomized controlled trials (RCTs). Meta-analyses with individual patient data offer several advantages over study-level analysis, including the ability to gain statistical power and increase validity using time-to-event analyses, to adjust for prognostic variables that may have confounded the original treatment comparisons and to investigate subgroups in which treatment may be either more or less effective or harmful. Methods: An international collaboration conducted an individual patent data meta-analysis of ESA effects on mortality in cancer patients. With guidance from an independent steering committee of international experts in hematology, oncology, radiotherapy, epidemiology, medical statistics and a consumer representative, we developed a detailed protocol and statistical analysis plan. Independent RCT investigators and representatives from pharmaceutical companies who submitted data provided additional input through the project’s advisory board. IPD from RCTs of ESA plus red blood cell transfusion (RBCT) (as needed) versus placebo or no ESA plus RBCT (as needed), for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy, were included. Hazard ratios and 95% confidence intervals (CIs) were calculated per study and meta-analyzed with fixed-effects and random-effects models. Primary endpoints were overall survival (during active study phase and for the longest follow-up available) for patients receiving chemotherapy, and for all cancer patients regardless of anticancer treatment. Stratified multivariable Cox-regression analyses were conducted to assess the impact of baseline imbalances and to identify potential effect modifiers. Duplicate main statistical analyses were conducted independently at two academic statistical departments. Results: Data on 13933 patients enrolled in 53 studies were included in the analysis. Data were provided by the companies Amgen Inc., Johnson & Johnson Pharmaceutical Research & Development, L.L.C., and F. Hoffmann-La Roche Ltd.; and by five independent investigators. Results are currently undergoing internal verification and final evaluation and will be presented at the meeting. Conclusion: Final conclusions will be presented at the meeting. Future analyses using IPD will be conducted to estimate the risks (clots, tumor progression) and potential benefits (transfusion needs and quality of life/fatigue) from other outcomes.