Abstract The clinical importance of radiation-induced heart disease, in particular in post-operative radiotherapy of breast cancer patients, has been recognised only recently. There is general ...agreement, that a co-ordinated research effort would be needed to explore all the potential strategies of how to reduce the late risk of radiation-induced heart disease in radiotherapy. This approach would be based, on one hand, on a comprehensive understanding of the radiobiological mechanisms of radiation-induced heart disease after radiotherapy which would require large-scale long-term animal experiments with high precision local heart irradiation. On the other hand – in close co-operation with mechanistic in vivo research studies – clinical studies in patients need to determine the influence of dose distribution in the heart on the risk of radiation-induced heart disease. The aim of these clinical studies would be to identify the critical structures within the organ which need to be spared and their radiation sensitivity as well as a potential volume and dose effect. The results of the mechanistic studies might also provide concepts of how to modify the gradual progression of radiation damage in the heart by drugs or biological molecules. The results of the studies in patients would need to also incorporate detailed dosimetric and imaging studies in order to develop early indicators of impending radiation-induced heart disease which would be a pre-condition to develop sound criteria for treatment plan optimisation.
To analyze the relationship between pre-treatment measurements of tumor oxygen tension (pO
2) and survival in advanced head and neck cancer.
Eppendorf pO
2 measurements in 397 patients from seven ...centers were analyzed using the fraction of pO
2 values ≤2.5
mmHg (HP
2.5), ≤5
mmHg (HP
5) and median tumor pO
2 (mmHg) as descriptors. All patients had intended curative radiation therapy alone or as pre- or post-operative radiotherapy or radio-chemotherapy according to the practice at each center.
The degree of hypoxia varied between tumors with an overall median tumor pO
2=9
mmHg (range 0–62
mmHg), a median HP
2.5=19% (range 0–97%) and HP
5=38%, (range 0–100%). By quadratic regression median tumor pO
2 correlated with Hb (2
P=0.026,
n=357), while HP
2.5 or HP
5 did not. HP
2.5 above the population median was the only parameter that associated with poor overall survival (Kaplan Meier analysis,
P=0.006). In a multivariate Cox Proportional Hazards analysis, stratified according to institution HP
2.5 was by far the most statistically significant factor in explaining the variability in survival. After adjusting for HP
2.5, clinical stage, radiation dose and surgery hemoglobin concentration was not significant in the model. The prognostic model shows that the 5-year survival is almost constant for HP
2.5 values in the range from 0 to 20%, whereas the 5-year survival approaches 0% in the most hypoxic tumors.
This study provides evidence that tumor hypoxia is associated with a poor prognosis in patients with advanced head and neck cancer.
L-methyl-(11)Cmethionine (MET)-positron emission tomography (PET) has a high sensitivity and specificity for imaging of gliomas and metastatic brain tumors. The short half-life of (11)C (20 minutes) ...limits the use of MET-PET to institutions with onsite cyclotron. O-(2-(18)Ffluoroethyl)-L-tyrosine (FET) is labeled with (18)F (half-life, 120 minutes) and could be used much more broadly. This study compares the uptake of FET and MET in gliomas and metastases, as well as treatment-induced changes. Furthermore, it evaluates the gross tumor volume (GTV) of gliomas defined on PET and magnetic resonance imaging (MRI).
We examined 42 patients with pretreated gliomas (29 patients) or brain metastases (13 patients) prospectively by FET- and MET-PET on the same day. Uptake of FET and MET was quantified by standardized uptake values. Imaging contrast was assessed by calculating lesion-to-gray matter ratios. Tumor extension was quantified by contouring GTV in 17 patients with brain gliomas. Gross tumor volume on PET was compared with GTV on MRI. Sensitivity and specificity of MET- and FET-PET for differentiation of viable tumor from benign changes were evaluated by comparing the PET result with histology or clinical follow-up.
There was a strong linear correlation between standardized uptake values calculated for both tracers in cortex and lesions: r = 0.78 (p = 0.001) and r = 0.84 (p < 0.001), respectively. Image contrast was similar for MET- and FET-PET (lesion-to-gray matter ratios of 2.36 ± 1.01 and 2.33 ± 0.77, respectively). Mean GTV in 17 glioma patients was not significantly different on MET- and FET-PET. Both MET- and FET-PET delineated tumor tissue outside of MRI changes. Both tracers provided differentiated tumor tissue and treatment-related changes with a sensitivity of 91% at a specificity of 100%.
O-(2-(18)Ffluoroethyl)-L-tyrosine-PET and MET-PET provide comparable diagnostic information on gliomas and brain metastases. Like MET-PET, FET-PET can be used for differentiation of residual or recurrent tumor from treatment-related changes/pseudoprogression, as well as for delineation of gliomas.
Abstract Background and purpose To report patterns of failure of stereotactic body radiation therapy (SBRT) in inoperable patients with histologically confirmed stage I NSCLC. Materials and methods ...Ninety-two inoperable patients (median age: 75 years) with clinically staged, histologically proven T1 ( n = 31) or T2 ( n = 61), N0, M0 non-small cell lung cancer (NSCLC) were included in this study. Treatment consisted of 3–5 fractions with 7–15 Gy per fraction prescribed to the 60% isodose. Results Freedom from local recurrence at 1, 3 and 5 years was 89%, 83% and 83%, respectively. All 10 local failures were observed in patients with T2 tumors. Isolated regional recurrence was observed in 7.6%. The crude rate of distant progression was 20.7%. Overall survival at 1, 3, and 5 years was 79%, 38% and 17% with a median survival of 29 months. Disease specific survival at 1, 3, and 5 years was 93%, 64% and 48%. Karnofsky performance status, T stage, gross tumor volume and tumor location had no significant impact on overall and disease specific survival. SBRT was generally well tolerated and all patients completed therapy as planned. Conclusion SBRT for stage I lung cancer is very well tolerated in this patient cohort with significant cardiopulmonal comorbidity and results in excellent local control rates, although a considerable portion develops regional and distant metastases.
To update a combined analysis of all published clinical data.
We collected data from 38 additional patients treated in our department or published in four different reports and calculated the ...biologically effective dose (BED) according to the linear-quadratic model using an alpha/beta value of 2 Gy for cervical and thoracic cord and 4 Gy for lumbar cord. In this model, a dose of 50 Gy given in single daily fractions of 2 Gy is equivalent to a BED of 100 Gy(2) or 75 Gy(4).
The 2005 risk score based on three variables (cumulative BED, highest BED of all treatment series in a particular individual, and interval), which discriminate three different risk groups, does not require modification. The low-risk group now contains 1 case of radiation myelopathy (RM) after hypofractionated stereotactic reirradiation. Therefore, the rate increased from 0% to 3%. Intermediate-risk patients developed RM in 25%, and high-risk patients in 90%. When the interval between the two treatment courses is not shorter than 6 months and the dose of each course is < or =98 Gy(2), the cumulative BED where no case of RM has yet been reported is 120 Gy(2).
Based on these updated results, the risk of RM appears small after < or =135.5 Gy(2) when the interval is not shorter than 6 months and the dose of each course is < or =98 Gy(2). We would recommend limiting the dose to the lowest feasible level. The influence of very steep dose gradients from stereotactic and intensity-modulated approaches (i.e., a more complex volume-effect) requires further evaluation.
To develop a valid treatment strategy for recurrent high-grade gliomas using stereotactic hypofractionated reirradiation based on biologic imaging and temozolomide.
The trial included a total of 44 ...patients with recurrent high-grade gliomas (1 patient with anaplastic oligodendroglioma, 8 with anaplastic astrocytoma, 33 with glioblastoma multiforme, and 2 with gliosarcoma) after previous surgery and postoperative conventional radiotherapy +/- chemotherapy. For fractionated stereotactic radiotherapy (SFRT) treatment planning, the gross tumor volume was defined by (11)C-methionine positron emission tomography (MET-PET) or (123)I-alpha-methyl-tyrosine (IMT) single-photon computed emission tomography (SPECT)/computed tomography (CT)/magnetic resonance imaging (MRI) fusion in 82% of the patients and by CT/T1+gadolinium-MRI image fusion in 18% of the patients. Six fractions of 5 Gy were administered in 6 days. In 29 of 44 patients (66%), chemotherapy with temozolomide (200 mg/m(2) body surface/day) was given in one to two cycles before and four to five cycles after SFRT. The patients were evaluated in follow-up by clinical investigators and MRI or CT every 3 months after SFRT until death. In cases suspicious for radiation necrosis, a MET-PET or IMT-SPECT investigation was performed.
The median survival time in the whole group was 8 months. Treatment planning based on PET(SPECT)/CT/MRI imaging was associated with improved survival in comparison to treatment planning using CT/MRI alone: median survival time 9 months vs. 5 months (p = 0.03, log-rank). Median survival time were 11 months for patients who received SFRT based on biologic imaging plus temozolomide and significantly lower, 6 months for patients treated with SFRT without biologic imaging, without temozolomide or without both (p = 0.008, log rank). The most important prognostic factor in univariate analysis was a long interval between initial diagnosis and recurrence (p = 0.0002, log-rank). In the multivariate model, time interval to retreatment (p = 0.006) and temozolomide (p = 0.04) remained statistically significant. No acute neurologic toxicity Grade 3 or higher and no Grade 4 hematologic toxicity was observed.
This is the first study of biologic imaging optimized SFRT plus temozolomide in recurrent high-grade gliomas. It demonstrates the feasibility and safety of this approach. The most striking result of the trial is the statistically significant longer survival time in the univariate analysis for patients reirradiated using MET-PET or IMT-SPECT/CT/MRI image fusion in the treatment planning, in comparison to patients treated based on MRI/CT alone. Multivariate analysis confirmed a significant survival benefit from multimodal treatment (i.e., addition of temozolomide), despite the limited number of patients. Whether treatment planning with SPECT/PET independently influences survival has to be studied in a larger series of patients.
Hypoxia is well known to limit curability of tumors by ionizing radiation. Here, we show that hypoxia treatment of tumor cells causes coexpression of heat shock protein 70 (Hsp70) and ...phosphatidylserine (PS) on the cell surface. Colocalization of Hsp70 and PS, as determined by confocal microscopy, also occurs when exogenous FITC-labeled Hsp70 protein is added to normoxic and hypoxic tumor cells. Moreover, the interaction of Hsp70 with PS was demonstrated in artificial unilamellar phosphatidylcholine/ phosphatidylserine (PC/PS) liposomes at the physiological ratio of 8/2. Indeed, the Hsp70-liposome interaction gradually increased with elevating PS molar ratios (8/2greater-than-or-equal7/3<5/5<4/6<3/7<2/8). In contrast, only a weak Hsp70 interaction was detected in phosphatidylcholine/phosphatidylglycerol (PC/PG) liposomes, thus demonstrating that the interaction was not a charge-related effect. The interaction of Hsp70 with surface PS significantly reduces clonogenic cell survival in normoxic (EC₅₀ of Hsp70=85 μg/ml) and hypoxic (EC₅₀ of Hsp70=55 μg/ml) tumor cells. The radiation-induced tumor cell killing was significantly enhanced by the addition of Hsp70 protein (50 μg/ml). Since apoptosis was not significantly enhanced in normoxic and hypoxic tumor cells by the addition of Hsp70, we hypothesize that the Hsp70 protein-induced reduction in clonogenic cell survival might be through necrosis rather than apoptosis.--Schilling, D., Gehrmann, M., Steinem, C., De Maio, A., Pockley, A. G., Abend, M., Molls, M., Multhoff, G. Binding of heat shock protein 70 to extracellular phosphatidylserine promotes killing of normoxic and hypoxic tumor cells.
To evaluate tumor control and side effects associated with radiosurgery (RS) and stereotactic fractionated radiotherapy (SFR) for vestibular schwannomas (VSs) in a group of patients treated at the ...same institution.
Between May 1997 and June 2007, 115 consecutive cases of VS were treated in our department. The SFR group (47 patients), including larger tumors (maximum diameter >1.5 cm), received a total dose of 54 Gy at 1.8 Gy per fraction. The RS group (68 patients, maximum diameter <1.5 cm) received a total dose of 12 Gy at the 100% isodose. Evaluation included serial imaging tests (magnetic resonance imaging) and neurologic and functional hearing examinations.
The tumor control rate was 97.9% in the SFR group for a mean follow-up time of 32.1 months and 98.5% in the RS group for a mean follow-up time of 30.1 months. Hearing function was preserved after RS in 85% of the patients and after SFR in 79%. Facial and trigeminal nerve function remained mostly unaffected after SFR. After RS, new trigeminal neuropathy occurred in 9 of 68 patients (13%).
A high tumor control rate and low number of side effects are registered after SFR and RS of VS. These results confirm that considering tumor diameter, both RS and SFR are good treatment modalities for VS.
To evaluate the role of hypoxia positron emission tomography (PET) using 18Ffluoroazomycin-arabinoside (FAZA) in head and neck cancer for radiation treatment planning using intensity-modulated ...radiotherapy and dose painting.
Eighteen patients with advanced squamous cell head and neck cancer were included. Both FAZA-PET and axial CT were performed using mask fixation. The data were coregistered using software based on mutual information. Contours of tumor (primary gross tumor volume, GTV/CT-P) and lymph node metastases (GTV/CT-N) were outlined manually, and FAZA standardized uptake values (SUVs) were calculated automatically. The hypoxic subvolume (GTV/PET-FAZA) having at least 50% more FAZA uptake than background (mean SUV) neck muscle tissue was contoured automatically within GTV/CT-P (GTV/PET-FAZA-P) and GTV/CT-N (GTV/PET-FAZA-N).
The median GTV/PET-FAZA-P was 4.6 mL, representing 10.8% (range, 0.7-52%) of the GTV/CT-P. The GTV/PET-FAZA-P failed to correlate significantly with the GTV/CT-P (p = 0.06). The median GTV/PET-FAZA-N was 4.1 mL, representing 8.3% (range, 2.2-51.3%) of the GTV/CT-N. It was significantly correlated with the GTV/PET-N (p = 0.006). The GTV/PET-FAZA-P was located in a single confluent area in 11 of 18 patients (61%) and was diffusely dispersed in the whole GTV/CT-P in 4 of 18 patients (22%), whereas no hypoxic areas were identified in 3 of 18 patients (17%). The GTV/PET-FAZA-N was outlined as a single confluent region in 7 of 18 patients (39%), in multiple diffuse hypoxic regions in 4 of 18 patients (22%), and was not delineated in 7 of 18 patients (39%).
This study demonstrates that FAZA-PET imaging could be used for a hypoxia-directed intensity-modulated radiotherapy approach in head and neck cancer.
To report on outcome and toxicity of stereotactic body radiotherapy (SBRT) for liver metastases in patients not eligible for surgery.
From 2000 to 2009, 74 patients with 91 liver metastases from ...different primaries have been treated with SBRT at our institution. Median planning target volume was 123 ccm (range: 10.6-1074 ccm). Treatment consisted of 3-5 fractions with 5-12.5 Gy/ fraction prescribed to the surrounding 60-95% isodose with daily image guidance. Regular follow-up included CT or MRI imaging until tumor progression.
Median local recurrence-free interval was 23 months with a local control rate of 74.7%, 48.3% and 48.3% after 1, 2 and 3 years. Only minimum biologically effective dose (BED) to gross tumor volume (GTV) remained as independent significant factor for local control in multivariate analysis. No local recurrences were observed in lesions (n = 12) which received a minimal BED to the GTV of 120 Gy. Including 26 local recurrences, 67 patients (91%) showed disease progression after SBRT with a median time of 5 months. Median overall survival was 27 months with survival rates of 77%, 30% and 27% at 1, 3 and 5 years. On multivariate analysis only GTV volume remained as independent significant prognostic factor for overall survival (p = 0.002). No grade 3 to 5 acute toxicity and no grade 4 or 5 late toxicity occurred.
SBRT for liver metastases was well tolerated in this non-selected patient cohort and yielded good local control despite the considerable size of most lesions treated. Long-term survival is possible after SBRT.
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