Tilman Bostel

Sustained Molecular Response With Interferon Alfa Maintenance After Induction Therapy With Imatinib Plus Interferon Alfa in Patients With Chronic Myeloid Leukemia

PURPOSE Imatinib induces sustained remissions in patients with chronic myelogenous leukemia (CML), but fails to eradicate CML stem cells. This is of major concern regarding the issues of cure, long-term imatinib tolerability, and imatinib resistance. We therefore asked whether interferon alfa-2a (IFN) alone could maintain molecular remissions achieved by a prior combination therapy with imatinib and IFN. PATIENTS AND METHODS Imatinib therapy was stopped in 20 patients who had concomitantly been pretreated with imatinib and IFN for a median of 2.4 years (range, 0.2 to 4.8 years) and 2.5 years (range, 0.2 to 4.9 years), respectively. After imatinib discontinuation, remission status was monitored monthly by quantitative analysis of the peripheral-blood BCR-ABL mRNA levels using real-time polymerase chain reaction. Proteinase-3 expression and proteinase-3-specific cytotoxic T cells (CTLs) were longitudinally measured to assess putative markers of IFN response. RESULTS With a median time of 2.4 years after imatinib withdrawal (range, 0.5 to 4.0 years), 15 (75%) of 20 patients remained in remission. The number of patients in complete molecular remission increased under IFN from two patients at baseline to five patients after 2 years. Relapses occurred in five patients within 0.4 years (range, 0.2 to 0.8 years), but patients underwent rescue treatment with imatinib, re-establishing molecular remission. IFN therapy was associated with an increase in the expression of leukemia-associated antigen proteinase 3 and induction of proteinase-3-specific CTLs. CONCLUSION Treatment with IFN enables discontinuation of imatinib in most patients after prior imatinib/IFN combination therapy and may result in improved molecular response. Induction of a proteinase-3-specific CTL response by IFN may contribute to this effect.

A comparison of long-term survivors and short-term survivors with glioblastoma, subventricular zone involvement: a predictive factor for survival?

ObjectiveLong-term survival is rare in patients with glioblastoma (GBM). We set out to determine prognostic factors for patients with favorable and poor prognosis in regard of tumor localization to the subventricular zone (SZV).MethodsWe reviewed the clinical records, pre-operative and post-operative MRI imaging of 50 LTS long-term survivors (LTS) (> 3 years) and 50 short-term survivors (STS) (< 1 year) with glioblastoma. These groups were matched for clinical characteristics being consistently associated with prolonged or shortened survival. All patients had undergone initial surgery or biopsy to confirm GBM diagnosis followed by radio- or chemoradiotherapy.ResultsLTS had a median progression-free survival PFS of 25, 4 months (2, 3–97, 8 months) and overall-survival (OS) of 55, 9 months (38, 2-98, 6 months) compared to STS who had a significantly lower PFS of 4, 2 months (1, 4–10, 2 months) and OS of 6, 6 months (2, 2–11, 6 months) (each p < 0,001).Survival analysis showed that age under 60 years (p < 0,001), total resection status (p < 0,001) and tumor localization without SVZ contact (p = 0,05) were significant factors for prolonged survival.ConclusionOur findings underline that survival in GBM patients is heterogeneous and influenced by multiple factors. This study confirms that tumor location with regard to the SVZ is significantly associated with survival.

Glioblastoma Recurrence Patterns After Radiation Therapy With Regard to the Subventricular Zone

PURPOSE We evaluated the influence of tumor location and tumor spread in primary glioblastoma (GBM), with respect to the subventricular zone (SVZ), on recurrence behavior, progression-free survival (PFS), and overall survival (OS). METHODS AND MATERIALS 607 patients (376 male and 231 female) with a median age of 61.3 years (range, 3.0-87.9 years) and primary GBM treated with radiation therapy (RT) from 2004 to 2012 at a single institution were included in this retrospective study. Preoperative images and follow-up examination results were assessed to evaluate tumor location. Tumors were classified according to the tumor location in relation to the SVZ. RESULTS The median PFS of the study population was 5.2 months (range, 1-91 months), and the median OS was 13.8 months (range, 1-102 months). Kaplan-Meier analysis showed that tumor location in close proximity to the SVZ was associated with a significant decline in PFS and OS (4.8 and 12.3 months, respectively; each P<.001). Furthermore, in cases where tumors were involved with the SVZ, distant cerebral progression (43.8%; P=.005) and multifocal progression (39.8%; P=.008) were more common. Interestingly, opening of the ventricle during the previous surgery showed no impact on PFS and OS. CONCLUSION GBM in close proximity to the SVZ was associated with decreased survival and had a higher risk of multifocal or distant progression. Ventricle opening during surgery had no effect on survival rates.

MR-guidance – a clinical study to evaluate a shuttle- based MR-linac connection to provide MR-guided radiotherapy

BackgroundThe purpose of this clinical study is to investigate the clinical feasibility and safety of a shuttle-based MR-linac connection to provide MR-guided radiotherapy.Methods/DesignA total of 40 patients with an indication for a neoadjuvant, adjuvant or definitive radiation treatment will be recruited including tumors of the head and neck region, thorax, upper gastrointestinal tract and pelvic region. All study patients will receive standard therapy, i.e. highly conformal radiation techniques like CT-guided intensity-modulated radiotherapy (IMRT) with or without concomitant chemotherapy or other antitumor medication, and additionally daily short MR scans in treatment position with the same immobilisation equipment used for irradiation for position verification and imaging of the anatomical and functional changes during the course of radiotherapy. For daily position control, skin marks and a stereotactic frame will be used for both imaging modalities. Patient transfer between the MR device and the linear accelerator will be performed with a shuttle system which uses an air-bearing patient platform for both procedures. The daily acquired MR and CT data sets will be digitally registrated, correlated with the planning CT and compared with each other regarding translational and rotational errors. Aim of this clinical study is to establish a shuttle-based approach for realising MR-guided radiotherapy for certain clinical situations. Second objectives are to compare MR-guided radiotherapy with the gold standard of CT image guidance for quality assurance of radiotherapy, to establish an appropiate MR protocol therefore, and to assess the possibility of using MR-based image guidance not only for position verification but also for adaptive strategies in radiotherapy.DiscussionCompared to CT, MRI might offer the advantage of providing IGRT without delivering an additional radiation dose to the patients and the possibility of optimisation of adaptive therapy strategies due to its superior soft tissue contrast. However, up to now, hybrid MR-linac devices are still under construction and not clinically applicable. For the near future, a shuttle-based approach would be a promising alternative for providing MR-guided radiotherapy, so that the present study was initiated to determine feasibility and safety of such an approach. Besides positioning information, daily MR data under treatment offer the possibility to assess tumor regression and functional parameters, with a potential impact not only on adaptive therapy strategies but also on early assessment of treatment response.

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

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

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.

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.