Ingmar Schlampp

Temporal Lobe Reactions After Radiotherapy With Carbon Ions: Incidence and Estimation of the Relative Biological Effectiveness by the Local Effect Model

PURPOSE To identify predictors for the development of temporal lobe reactions (TLR) after carbon ion radiation therapy (RT) for radiation-resistant tumors in the central nervous system and to evaluate the predictions of the local effect model (LEM) used for calculation of the biologically effective dose. METHODS AND MATERIALS This retrospective study reports the TLR rates in patients with skull base chordomas and chondrosarcomas irradiated with carbon ions at GSI, Darmstadt, Germany, in the years 2002 and 2003. Calculation of the relative biological effectiveness and dose optimization of treatment plans were performed on the basis of the LEM. Clinical examinations and magnetic resonance imaging (MRI) were performed at 3, 6, and 12 months after RT and annually thereafter. Local contrast medium enhancement in temporal lobes, as detected on MRI, was regarded as radiation-induced TLR. Dose-volume histograms of 118 temporal lobes in 59 patients were analyzed, and 16 therapy-associated and 2 patient-associated factors were statistically evaluated for their predictive value for the occurrence of TLR. RESULTS Median follow-up was 2.5 years (range, 0.3-6.6 years). Age and maximum dose applied to at least 1 cm(3) of the temporal lobe (D(max,V - 1 cm)3, maximum dose in the remaining temporal lobe volume, excluding the volume 1 cm(3) with the highest dose) were found to be the most important predictors for TLR. Dose response curves of D(max,V - 1 cm)3 were calculated. The biologically equivalent tolerance doses for the 5% and 50% probabilities to develop TLR were 68.8 ± 3.3 Gy equivalents (GyE) and 87.3 ± 2.8 GyE, respectively. CONCLUSIONS D(max,V - 1 cm)3 is predictive for radiation-induced TLR. The tolerance doses obtained seem to be consistent with published data for highly conformal photon and proton irradiations. We could not detect any clinically relevant deviations between clinical findings and expectations based on predictions of the LEM.

The effect of resistance training during radiotherapy on spinal bone metastases in cancer patients – A randomized trial

PURPOSE To compare the effects of resistance training versus passive physical therapy on bone density in the metastatic bone during radiation therapy (RT) as combined treatment in patients with spinal bone metastases. Secondly, to quantify pathological fractures after combined treatment. MATERIAL AND METHODS In this randomized trial, 60 patients were allocated from September 2011 until March 2013 into one of the two groups: resistance training (group A) or passive physical therapy (group B) with thirty patients in each group during RT. Bone density in metastatic and non-metastatic vertebral bone was assessed at baseline, 3 and 6 months after RT. RESULTS Bone density in all metastases increased significantly by 28.3% (IQR 11.4-139.0) and 80.3% (IQR 32.6-250.6) after 3 and 6 months in group A (both p < 0.01). The bone density in group A was significantly increased compared to control group after 3 and 6months (both p < 0.01, median 59.7; IQR 21.1-98.3 and median 62.9; IQR -9.7 to 161.7). The bone density data in group B showed no significant increase over the course of time (p = 0.289, median 5.5, IQR 0.0-62.2 and p = 0.057, median 52.1, IQR 0.0-162.7). 23.3% of the patients in group A and 30.0% of the patients in group B had pathological fractures, no fracture was assigned to intervention, and no difference between groups after 3 and 6 months was observed (p = 0.592 and p = 0.604). CONCLUSIONS Our trial demonstrated that resistance training concomitant to RT can improve bone density in spinal bone metastases. This combined treatment is effective, practicable, and without side effects for patients. Importantly, the pathological fracture rate in the intervention group was not increased. The results offer a rationale for future large controlled investigations to confirm these findings. TRIAL REGISTRATION Clinical trial identifier NCT01409720.

Quality of life and fatigue of patients with spinal bone metastases under combined treatment with resistance training and radiation therapy- a randomized pilot trial

BackgroundThe aim of this trial was to compare the effects of resistance training versus passive physical therapy on quality of life (QoL), fatigue, and emotional distress outcomes during radiation therapy in patients with spinal bone metastases under radiotherapy (RT).MethodsIn this randomized trial, 60 patients were treated from September 2011 until March 2013 into one of the two groups: isometric resistance training or physical therapy with thirty patients in each group during RT. EORTC QLQ-BM22, EORTC QLQ-FA13, and FBK-R10 were assessed at baseline, three months, and six months after RT.ResultsPsychosocial aspects in resistance training group (Arm A) were significantly improved after three (p = 0.001) and six months (p = 0.010). Other rated items of the QLQ-BM22 painful site, and pain characteristics were without significant differences. Functional interference showed a positive trend after six months (p = 0.081). After six months, physical fatigue (p = 0.013), and interference with daily life (p = 0.006) according to the QLQ-FA13 assessment improved in Arm A significantly. Emotional distress was in Arm A lower after six months (p = 0.016). The Cohen’s effect size confirmed the clinically significant improvement of these findings.ConclusionsIn this group of patients we were able to show that guided isometric resistance training of the paravertebral muscles can improve functional capacity, reduce fatigue and thereby enhance QoL over a 6-months period in patients with stable spinal metastases. The results offer a rationale for future large controlled investigations to confirm these findings.Trial registrationClinical trial identifier NCT01409720

Pain response of resistance training of the paravertebral musculature under radiotherapy in patients with spinal bone metastases – a randomized trial

BackgroundTo compare pain response outcomes for patients with spinal bone metastases treated with resistance training of the spinal musculature versus passive physical therapy during radiotherapy (RT).MethodsIn this randomized trial, 60 consecutive patients were treated from September 2011 until March 2013 within one of the two groups: resistance training (Arm A) or passive physical therapy (Arm B) with thirty patients in each group during RT. The course of pain according to visual analog scale (VAS), concurrent medication, and oral morphine equivalent dose (OMED) were assessed at baseline, three months, and six months after RT. Pain response was determined using International Bone Consensus response definitions.ResultsThe course of VAS in the intervention group (Arm A) was significantly lower both during and after RT (AUC, p < .001). The use of analgetic medication showed the same result, with significantly fewer analgetics being necessary both during and after RT in arm A (p < .001). In the course of time, the OMED decreased in arm A, but increased in arm B. After 6 month, 72.2% of patients in arm A, and 22.2% in arm B were responders (p = .014).ConclusionOur trial demonstrated that guided isometric resistance training of the paravertebral muscles can improve pain relief over a 6-months period in patients with stable spinal metastases. Importantly, the intervention was able to reduce OMED as well as concomitant pain medication. The trial is registered in Clinical trial identifier NCT 01409720 (http://www.clinicaltrials.gov/) since 2nd of August 2011.

High-dose single-fraction IMRT versus fractionated external beam radiotherapy for patients with spinal bone metastases: study protocol for a randomized controlled trial

BackgroundStereotactic body radiation therapy (SBRT)using intensity-modulated radiotherapy (IMRT) can be a safe modality for treating spinal bone metastasis with enhanced targeting accuracy and an effective method for achieving good tumor control and a rigorous pain response.Methods/designThis is a single-center, prospective randomized controlled trial to evaluate pain relief after RT and consists of two treatment groups with 30 patients in each group. One group will receive single-fraction intensity-modulated RT with 1×24 Gy, and the other will receive fractionated RT with 10×3 Gy. The target parameters will be measured at baseline and at 3 and 6 months after RT.DiscussionThe aim of this study is to evaluate pain relief after RT in patients with spinal bone metastases by means of two different techniques: stereotactic body radiation therapy and fractionated RT. The primary endpoint is pain relief at the 3-month time-point after RT. Secondly, quality of life, fatigue, overall and bone survival, and local control will be assessed.Trial registrationClinicalTrials.gov identifier NCT02358720 (June 2, 2015).

Stability of spinal bone metastases and survival analysis in renal cancer after radiotherapy.

Purpose This retrospective analysis evaluated the outcome of patients with spinal bone metastases of renal cell cancer after radiotherapy (RT) in terms of stability and survival, using a validated scoring system for spinal stability assessment. Materials and Methods The survival rates of 155 patients with bone metastases of renal cancer treated from January 2000 to January 2012 were determined. The stability of irradiated osteolytic lesions of the thoracic and lumbar spine was evaluated retrospectively using the Taneichi score and analyzed for predictive factors. The effects of therapy in terms of changes in neurological signs and tumor-related pain were recorded. Results Follow-up with regular computed tomography (CT) was available for 28 patients, 14 with unstable metastases. One hundred thiry-two patients (85%) died during follow-up. RT could not improve the stability of vertebral bodies after 3 and 6 months. Consequently, none of the examined predictive factors such as age, number of bone metastases and systemic therapy showed a significant correlation with stability 6 months after RT. The median survival of all 155 patients after diagnosis of bone metastases was 12.9 months. Improvement of pain and neurological deficits occurred in 60%, and in 24% of the respective affected in all patients. Conclusions RT was unable to improve the stability of vertebral metastases, probably due to the short overall survival, which resulted in an insufficient number of patients with evaluable follow-up. RT allowed reduction of pain and neurological deficits. A short fractionation schedule may be preferred in this situation.

Temporal Lobe Reactions After Carbon Ion Radiation Therapy: Comparison of Relative Biological Effectiveness–Weighted Tolerance Doses Predicted by Local Effect Models I and IV

PURPOSE To compare the relative biological effectiveness (RBE)-weighted tolerance doses for temporal lobe reactions after carbon ion radiation therapy using 2 different versions of the local effect model (LEM I vs LEM IV) for the same patient collective under identical conditions. METHODS AND MATERIALS In a previous study, 59 patients were investigated, of whom 10 experienced temporal lobe reactions (TLR) after carbon ion radiation therapy for low-grade skull-base chordoma and chondrosarcoma at Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany in 2002 and 2003. TLR were detected as visible contrast enhancements on T1-weighted MRI images within a median follow-up time of 2.5 years. Although the derived RBE-weighted temporal lobe doses were based on the clinically applied LEM I, we have now recalculated the RBE-weighted dose distributions using LEM IV and derived dose-response curves with Dmax,V-1 cm³ (the RBE-weighted maximum dose in the remaining temporal lobe volume, excluding the volume of 1 cm³ with the highest dose) as an independent dosimetric variable. The resulting RBE-weighted tolerance doses were compared with those of the previous study to assess the clinical impact of LEM IV relative to LEM I. RESULTS The dose-response curve of LEM IV is shifted toward higher values compared to that of LEM I. The RBE-weighted tolerance dose for a 5% complication probability (TD5) increases from 68.8 ± 3.3 to 78.3 ± 4.3 Gy (RBE) for LEM IV as compared to LEM I. CONCLUSIONS LEM IV predicts a clinically significant increase of the RBE-weighted tolerance doses for the temporal lobe as compared to the currently applied LEM I. The limited available photon data do not allow a final conclusion as to whether RBE predictions of LEM I or LEM IV better fit better clinical experience in photon therapy. The decision about a future clinical application of LEM IV therefore requires additional analysis of temporal lobe reactions in a comparable photon-treated collective using the same dosimetric variable as in the present study.

Stability, prognostic factors and survival of spinal bone metastases in malignant melanoma patients after palliative radiotherapy

Purpose This retrospective analysis aimed to evaluate the stability of spinal metastases in malignant melanoma patients following radiotherapy (RT), and to assess prognostic factors for survival. Methods Forty-one patients with malignant melanoma and osteolytic spinal bone metastases were irradiated at the university clinics of Heidelberg and Mainz between July 2003 and October 2013. Three and six months after palliative RT, only 20 and 15 patients, respectively, were still alive and were therefore assessed for spinal stability using the Taneichi score based on CT imaging. Additionally, overall survival (OS) and bone survival (BS) rates as well as prognostic factors for BS were evaluated for all study patients. Results Before RT, 19 patients (46.3%) were rated unstable. In the surviving patients, none of the unstable metastases were classified as stable 6 months after RT. Five-year OS was 23.3% and median BS was 4 months (range 0.5-29.8). Accordingly, only 36.6% of the patients were still alive 6 months after RT. Karnofsky performance score (KPS) <70%, visceral metastases and more than one bone metastasis were significantly predictive of poor BS. Conclusions Our study population was characterized by poor BS and a lack of benefit with regard to stabilization of initially unstable spinal bone metastases 3 and 6 months after RT. This applies in particular to patients with a KPS <70%, visceral metastases and multiple bone metastases. Given the limited life expectancy, short fractionated treatment schedules of RT may be preferred in this population.

Randomized phase II trial evaluating pain response in patients with spinal metastases following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy

BACKGROUND To report the primary endpoint of a randomized trial comparing pain response following palliative stereotactic body radiation therapy (SBRT) versus conventionally-fractionated 3D-conformal radiotherapy (3DCRT) for previously untreated spinal metastases. METHODS Fifty-five patients with histologically/radiologically confirmed painful spinal metastases were analyzed in this single-institutional, non-blinded, randomized explorative trial. Participants were randomly assigned (1:1) to receive single-fraction SBRT (24 Gy) or 3DCRT (30 Gy in 10 fractions). The primary endpoint was pain relief of >2 points on the visual analog scale (VAS) measured within the irradiated region at 3 months following radiotherapy completion. Other recorded parameters included pain response (per International Bone Consensus response definitions), use of concurrent medications and opioid usage (oral morphine equivalent dose, OMED). All parameters were assessed at baseline and at three and six months after RT. Intention-to-treat analysis was applied. This trial is registered with ClinicalTrials.gov, number NCT02358720. FINDINGS Despite no significant differences for VAS at 3 months between groups (p = 0.13), pain values decreased faster within this time period in the SBRT arm (p = 0.01). At 6 months following RT, significantly lower VAS values were reported in the SBRT group (p = 0.002). There were no differences in OMED consumption at 3 (p = 0.761) and 6 months (p = 0.174). There was a trend toward improved pain response in the SBRT arm at 3 months (p = 0.057), but significantly so after 6 months (p = 0.003). No patient in the SBRT group experienced grade ≥3 toxicities according to the Common Terminology Criteria for Adverse Events v.4.03. CONCLUSIONS This randomized trial demonstrates the utility of palliative SBRT for spinal metastases, which was associated with a quicker and improved pain response. Larger ongoing randomized studies will assist in further addressing these endpoints.

Stability of Spinal Bone Lesions in Patients With Multiple Myeloma After Radiotherapy—A Retrospective Analysis of 130 Cases

Micro‐Abstract This retrospective analysis evaluated the response regarding bone density and stability of patients with osteolytic spinal bone lesions due to multiple myeloma after palliative radiotherapy. The rate of unstable lesions decreased from 51% to 24%, and the bone density showed a significant increase 6 months after radiotherapy. Palliative radiotherapy is an effective method resulting in a significant increase for local response and stability without severe RT‐related toxicity. Background: The objective of the present retrospective analysis was the response evaluation regarding bone density and stability of patients with osteolytic spinal bone lesions due to multiple myeloma after palliative radiotherapy (RT). Patients and Methods: Patients with multiple myeloma who had undergone spinal RT from March 2003 to May 2016 were analyzed before and 3 and 6 months after RT. Assessment of spinal stability and bone density was performed using the internationally recognized Taneichi scoring system and measurement of bone density using computed tomography imaging‐based Hounsfield units. For statistical analysis, we used the Bowker test, McNemar test, and &kgr; statistics to detect possible asymmetries in the distribution of the Taneichi score over time. We used the Student t test for comparison of the density values (Hounsfield units) before and after treatment. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. Additionally, overall survival was calculated using the Kaplan‐Meier method. Results: We evaluated 130 patients (69% male; 31% female) with multiple myeloma and a median age of 58 years. The median follow‐up period was 41 months. Before treatment, 51% of the lesions were classified as unstable. At 3 and 6 months after RT, this rate had decreased to 41% (P = .0047) and 24% (P = .2393), respectively. The computed tomography measurements showed a significant increase in bone density at 3 and 6 months after RT. Acute RT‐related grade 1 and 2 complications were detected in 34% of patients. Late side effects (grade 1‐2) were detected in 23% of the patients. No severe grade 3 or 4 acute or late toxicities were identified. The median overall survival was 19.7 months for all patients and 6.6 months for patients with a Karnofsky performance score of ≤ 70%. Conclusion: To the best of our knowledge, ours is the first report to analyze the bone density and stability in patients with multiple myeloma after RT using a validated scoring system and computed tomography imaging. Palliative RT is an effective method resulting in a significant increase in bone density for local response and stability without severe RT‐related toxicity. Furthermore, recalcification could already be detected at 3 months after treatment.