Anca-Ligia Grosu

Intensified Chemotherapy and Dose-Reduced Involved-Field Radiotherapy in Patients With Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD11 Trial

PURPOSE Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkins lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied. PATIENTS AND METHODS Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 × 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP(baseline)) + 30 Gy of IFRT; or four cycles of BEACOPP(baseline) + 20 Gy of IFRT. RESULTS With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPP(baseline) was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPP(baseline) and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, -3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPP(baseline), 20 Gy was not inferior to 30 Gy (5-year FFTF difference, -0.8%; 95% CI, -5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, -4.7%; 95% CI, -10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy. CONCLUSION Moderate dose escalation using BEACOPP(baseline) did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.

[18F]Galacto-RGD Positron Emission Tomography for Imaging of αvβ3 Expression on the Neovasculature in Patients with Squamous Cell Carcinoma of the Head and Neck

Purpose: [18F]Galacto-RGD has been developed for positron emission tomography (PET)–imaging of αvβ3 expression, a receptor involved in angiogenesis and metastasis. Our aim was to study the feasibility of PET imaging with [18F]Galacto-RGD in patients with squamous cell carcinoma of the head and neck (SCCHN). Experimental Design: Eleven patients with primary diagnosis of SCCHN were examined. After injection of 140 to 200 MBq [18F]Galacto-RGD, static emission scans 60 min post injection from the head to the abdomen (n = 11) and dynamic scans >60 min covering the tumor region (n = 6) for kinetic modeling were acquired. Standardized uptake values (SUV) were measured in tumors, muscle and oral mucosa. Immunohistochemistry was done using an αvβ3-specific antibody (n = 7). Image fusion with magnetic resonance imaging and/or computed tomography (CT) scans (n = 8) and calculation of tumor subvolumes based on SUVs was done using the iPlan software (BrainLAB). Results: [18F]Galacto-RGD PET identified 10 of 12 tumors, with SUVs ranging from 2.2 to 5.8 (mean, 3.4 ± 1.2). Two tumors <5 mm were missed. Tumor/blood and tumor/muscle ratios were 2.8 ± 1.1 and 5.5 ± 1.6, respectively. Tumor kinetics was consistent with a two-tissue compartmental model with reversible specific binding. Immunohistochemistry confirmed αvβ3 expression in all tumors with αvβ3 being located on the microvessels in all specimens and additionally on tumor cells in one specimen. Image fusion of [18F]Galacto-RGD PET with magnetic resonance imaging/multislice CT and definition of tumor subvolumes was feasible in all cases. Conclusions: [18F]Galacto-RGD PET allows for specific imaging of αvβ3 expression in SCCHN with good contrast. Image fusion and definition of tumor subvolumes is feasible. This technique might be used for the assessment of angiogenesis and for planning and response evaluation of αvβ3-targeted therapies.

Biological imaging in radiation therapy: role of positron emission tomography

In radiation therapy (RT), staging, treatment planning, monitoring and evaluation of response are traditionally based on computed tomography (CT) and magnetic resonance imaging (MRI). These radiological investigations have the significant advantage to show the anatomy with a high resolution, being also called anatomical imaging. In recent years, so called biological imaging methods which visualize metabolic pathways have been developed. These methods offer complementary imaging of various aspects of tumour biology. To date, the most prominent biological imaging system in use is positron emission tomography (PET), whose diagnostic properties have clinically been evaluated for years. The aim of this review is to discuss the valences and implications of PET in RT. We will focus our evaluation on the following topics: the role of biological imaging for tumour tissue detection/delineation of the gross tumour volume (GTV) and for the visualization of heterogeneous tumour biology. We will discuss the role of fluorodeoxyglucose-PET in lung and head and neck cancer and the impact of amino acids (AA)-PET in target volume delineation of brain gliomas. Furthermore, we summarize the data of the literature about tumour hypoxia and proliferation visualized by PET. We conclude that, regarding treatment planning in radiotherapy, PET offers advantages in terms of tumour delineation and the description of biological processes. However, to define the real impact of biological imaging on clinical outcome after radiotherapy, further experimental, clinical and cost/benefit analyses are required.

An Interindividual Comparison of O-(2- [18F]Fluoroethyl)-L-Tyrosine (FET)– and L-[Methyl-11C]Methionine (MET)–PET in Patients With Brain Gliomas and Metastases

PURPOSE L-[methyl-(11)C]methionine (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)F]fluoroethyl)-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). METHODS AND MATERIALS 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. RESULTS 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%. CONCLUSIONS O-(2-[(18)F]fluoroethyl)-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.

Validation of a method for automatic image fusion (BrainLAB System) of CT data and 11C-methionine-PET data for stereotactic radiotherapy using a LINAC: first clinical experience

PURPOSE (a) To implement a fully automatic method to integrate (11)C-methionine positron emission tomography (MET-PET) data into stereotactic radiation treatment planning using the commercially available BrainLAB System, by means of CT/MET-PET image fusion. (b) To validate the fully automatic CT/MET-PET image fusion technique with respect to accuracy and robustness. (c) To give a short glance at the clinical consequences for patients with brain tumors. METHODS AND MATERIALS In 12 patients with brain tumors (9 meningeomas, 3 gliomas), CT, MRI, and MET-PET were performed for stereotactic fractionated radiation treatment planning. The CT and MET-PET investigations were performed using a relocatable mask for head fixation. Fifteen external reference markers (5 on each lateral and 5 on the frontal localizer plate) that could be identified in CT and MET-PET were applied on the stereotactic localizer frame; the marker positions were exactly defined for both investigations. The MRI/CT fusion was done completely automatically. The CT/MET-PET fusion was performed using two different methods: The gold standard was the CT/PET fusion based on the reference markers, and the test method was the automatic, intensity-based CT/PET fusion, independent of the external markers. The markers visible on CT and transmission PET were matched using a point-to-line matching algorithm. To quantify the amount of misregistration, the two fusion methods were compared by calculating the mean value of deviation between corresponding points inside a cubic volume of interest of > or =512 cm(3) defined within the cranial cavity. The gross tumor volume (CT/MRI) outlined on CT and T1-MRI with contrast medium was compared with the gross tumor volume (PET) defined in the reoriented MET-PET data sets. The clinical impact of MET-PET in tumor volume definition for stereotactic radiotherapy will be discussed. RESULTS The fully automatic integration of MET-PET into stereotactic radiation treatment planning was successfully realized in all patients investigated. Mean deviation of the intensity-based automatic CT/PET fusion compared with the external marker-based gold standard was 2.4 mm; the standard deviation was 0.5. The algorithms robustness was evaluated, and the discrepancy of fusion results due to different initial image alignments was determined to be below 1 mm inside the test volume of interest. In patients with meningiomas and gliomas, MET-PET was shown to deliver additional information concerning tumor extension. CONCLUSION The precision of the automatic CT/PET image fusion was high. A mean deviation of 2.4 mm is acceptable, considering that it is approximately equal to the pixel size of the PET data sets. MET-PET improves target volume definition for stereotactic fractionated radiotherapy of meningiomas and gliomas.

Salvage Lymph Node Dissection with Adjuvant Radiotherapy for Nodal Recurrence of Prostate Cancer

PURPOSE We evaluated the impact of salvage lymph node dissection with adjuvant radiotherapy in patients with nodal recurrence of prostate cancer. By default, nodal recurrence of prostate cancer is treated with palliative antihormonal therapy, which causes serious side effects and invariably leads to the development of hormone refractory disease. MATERIALS AND METHODS A total of 47 patients with nodal recurrence of prostate cancer based on evidence of (11)C-choline/(18)F-choline ((18)F-fluorethylcholine) positron emission tomography-computerized tomography underwent primary (2 of 52), secondary (45 of 52), tertiary (4 of 52) and quaternary (1 of 52) salvage lymph node dissection with histological confirmation. Of 52 salvage lymph node dissections 27 were followed by radiotherapy. Biochemical response was defined as a prostate specific antigen less than 0.2 ng/ml after salvage therapy. The Kaplan-Meier method, binary logistic regression and Cox regression were used to analyze survival as well as predictors of biochemical response and clinical progression. RESULTS Mean prostate specific antigen at salvage lymph node dissection was 11.1 ng/ml. A mean of 23.3 lymph nodes were removed per salvage lymph node dissection. Median followup was 35.5 months. Of 52 salvage lymph node dissections 24 resulted in complete biochemical response followed by 1-year biochemical recurrence-free survival of 71.8%. Gleason 6 or less (OR 7.58, p = 0.026), Gleason 7a/b (OR 5.91, p = 0.042) and N0 status at primary therapy (OR 8.01, p = 0.011) were identified as independent predictors of biochemical response. Gleason 8-10 (HR 3.5, p = 0.039) as a preoperative variable, retroperitoneal positive lymph nodes (HR 3.76, p = 0.021) and incomplete biochemical response (HR 4.0, p = 0.031) were identified as postoperative predictors of clinical progression. Clinical progression-free survival was 25.6% and cancer specific survival was 77.7% at 5 years. CONCLUSIONS Based on (11)C/(18)F-choline positron emission tomography-computerized tomography as a diagnostic tool, salvage lymph node dissection is feasible for the treatment of nodal recurrence of prostate cancer. Most patients experience biochemical recurrence after salvage lymph node dissection. However, a specific population has a lasting complete prostate specific antigen response.

First experience with I-123-alpha-methyl-tyrosine spect in the 3-D radiation treatment planning of brain gliomas

PURPOSE This study compares the results of iodine-123-alpha-methyl-tyrosine single photon computed emission tomography (IMT-SPECT) with magnetic resonance imaging (MRI) in tumor volume definition of brain gliomas. Furthermore, it evaluates the influences of the information provided from IMT-SPECT for three-dimensional (3D) conformal treatment planning. METHODS AND MATERIALS In 30 patients with nonresected, histologically proven brain gliomas (glioblastoma-13 patients, astrocytoma Grade III-12 patients, astrocytoma Grade II-3 patients, oligodendroglioma Grade III-1 patient, oligodendroglioma Grade II-1 patient), IMT-SPECT and MRI were performed pretherapeutically in the same week. A special software system allowed the coregistration of the IMT-SPECT and MRI data. The gross tumor volume (GTV) defined on the IMT-SPECT/T2-MRI fusion images (GTV-IMT/T2) was compared with the GTV-T2, defined on the T2-MRI alone. On the IMT-SPECT/T1Gd-MRI overlays, the volume of the IMT tumor uptake (GTV-IMT) was compared with the volume of the gadolinium (Gd) enhancement (GTV-T1Gd). The initial planning target volume (PTV) and the boost volume (BV) outlined on the IMT-SPECT/T2-MRI co-images were analyzed comparatively to the PTV and BV delineated using the T2-MRI alone. RESULTS In all 30 patients a higher IMT uptake of tumor areas, compared to the normal brain tissue was observed. Mean GTV-IMT, mean GTV-T2, and mean GTV-T1Gd were 43, 82, and 16 cm(3), respectively. IMT tumor uptake outside the contrast enhancement regions was observed in all patients. Mean relative increase of tumor volume defined on the fusion images, GTV-IMT/T1Gd versus GTV-T1Gd alone was 78%. IMT tumor uptake areas outside the GTV-T2 were registered in 7 patients (23%). In these patients, the mean increase GTV-IMT/T2 was 33% higher than GTV-T2, defined according to the T2-MRI data alone. The additional information provided by IMT-SPECT modified minimally the initial PTV (mean relative increase PTV-IMT/T2 versus PTV-T2, 5%) but significantly the BV (mean relative increase BV-IMT/T2 versus BV-T2, 37%). CONCLUSION In a significant number of patients, the IMT-SPECT investigation improves tumor detection and delineation in the planning process. This has important consequences in the 3D conformal treatment planning, especially in the delineation of BV and in dose escalation studies.

IMPLICATIONS OF IMT-SPECT FOR POSTOPERATIVE RADIOTHERAPY PLANNING IN PATIENTS WITH GLIOMAS

PURPOSE Using MRI, residual tumor cannot be differentiated from nonspecific postoperative changes in patients with brain gliomas after surgical resection. The goal of this study was to analyze the value of 123I-alpha-methyl-tyrosine-single photon emission CT (IMT-SPECT) in radiotherapy planning of patients with brain gliomas after surgical resection. METHODS AND MATERIALS In 66 patients with surgically resected brain gliomas (33 glioblastomas, 20 anaplastic astrocytomas, 7 anaplastic oligodendrogliomas, and 6 low-grade astrocytomas), IMT-SPECT and MRI were performed for radiotherapy planning. On the MRI/IMT-SPECT fusion images, the volume with IMT uptake was compared with the volume of the hyperintensity areas of T(2)-weighted MRI and with the volume of contrast enhancement on T(1)-weighted MRI. The regions with IMT uptake and/or MRI changes (composite Vol-MRI/IMT), regions with overlay of IMT uptake and MRI changes (common Vol-MRI/IMT), area with IMT uptake without MRI changes (increase Vol-MRI/IMT), and area with only MRI changes (Vol-MRI minus IMT) were analyzed separately. The planning target volume and boost volume defined using MRI information alone was compared with the planning target volume and boost volume defined by also using the SPECT information. RESULTS Focally increased IMT uptake was observed in 25 (38%) of 66 patients, contrast enhancement on MRI was outlined in 59 (89%) of 66 patients, and hyperintensity areas on T(2)-weighted MRI were found in all 66 investigated patients. The mean composite Vol-T(2)/IMT was 73 cm(3). The relative increase Vol-T(2)/IMT, mean relative common Vol-T(2)/IMT, and mean relative Vol-T(2) minus IMT was 4%, 6%, and 90% of the composite Vol-T(2)/IMT, respectively. The mean composite Vol-T(1)/IMT was 14 cm(3) and the mean relative increase Vol-T(1)/IMT, mean relative common Vol-T(1)/IMT, and mean relative Vol-T(1) minus IMT was 21%, 4%, and 64% of the mean composite Vol-T(1)/IMT, respectively. In 19 (29%) of 66 patients, the focal IMT uptake was located outside the MRI changes. In this subgroup, the mean residual volume defined by focal IMT uptake in MRI/IMT-SPECT images, mean Vol-T(1), and mean Vol-T(2) was 19 cm(3), 10 cm(3), and 70 cm(3), respectively. The mean relative increase T(2)/IMT was 14% and T(1)/IMT was 61%. In this subgroup, the additional information of SPECT led to an increase in boost volume (mean relative increase BV-IMT) by 20%. CONCLUSION In patients with surgically resected brain gliomas, the size and location of residual IMT uptake differs considerably from the abnormalities found on postoperative MRI. Because of the known high specificity of IMT uptake for tumor tissue, the findings on IMT-SPECT may significantly modify the target volumes for radiotherapy planning. This will help to focus the high irradiation dose on the tumor area and to spare normal brain tissue.

Chloroquine or chloroquine-PI3K/Akt pathway inhibitor combinations strongly promote γ-irradiation-induced cell death in primary stem-like glioma cells.

We asked whether inhibitors of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is highly active in cancer stem cells (CSCs) and upregulated in response to genotoxic treatments, promote γ-irradiationγIR)-induced cell death in highly radioresistant, patient-derived stem-like glioma cells (SLGCs). Surprisingly, in most cases the inhibitors did not promote γIR-induced cell death. In contrast, the strongly cytostatic Ly294002 and PI-103 even tended to reduce it. Since autophagy was induced we examined whether addition of the clinically applicable autophagy inhibitor chloroquine (CQ) would trigger cell death in SLGCs. Triple therapy with CQ at doses as low as 5 to 10 µM indeed caused strong apoptosis. At slightly higher doses, CQ alone strongly promoted γIR-induced apoptosis in all SLGC lines examined. The strong apoptosis in combinations with CQ was invariably associated with strong accumulation of the autophagosomal marker LC3-II, indicating inhibition of late autophagy. Thus, autophagy-promoting effects of PI3K/Akt pathway inhibitors apparently hinder cell death induction in γ-irradiated SLGCs. However, as we show here for the first time, the late autophagy inhibitor CQ strongly promotes γIR-induced cell death in highly radioresistant CSCs, and triple combinations of CQ, γIR and a PI3K/Akt pathway inhibitor permit reduction of the CQ dose required to trigger cell death.

Effect of 11C-Methionine-Positron Emission Tomography on Gross Tumor Volume Delineation in Stereotactic Radiotherapy of Skull Base Meningiomas

PURPOSE To evaluate the effect of trimodal image fusion using computed tomography (CT), magnetic resonance imaging (MRI) and (11)C-methionine positron emission tomography (MET-PET) for gross tumor volume delineation in fractionated stereotactic radiotherapy of skull base meningiomas. PATIENTS AND METHODS In 32 patients with skull base meningiomas, the gross tumor volume (GTV) was outlined on CT scans fused to contrast-enhanced MRI (GTV-MRI/CT). A second GTV, encompassing the MET-PET positive region only (GTV-PET), was generated. The additional information obtained by MET-PET concerning the GTV delineation was evaluated using the PET/CT/MRI co-registered images. The sizes of the overlapping regions of GTV-MRI/CT and GTV-PET were calculated and the amounts of additional volumes added by the complementing modality determined. RESULTS The addition of MET-PET was beneficial for GTV delineation in all but 3 patients. MET-PET detected small tumor portions with a mean volume of 1.6 +/- 1.7 cm(3) that were not identified by CT or MRI. The mean percentage of enlargement of the GTV using MET-PET as an additional imaging method was 9.4% +/- 10.7%. CONCLUSIONS Our data have demonstrated that integration of MET-PET in radiotherapy planning of skull base meningiomas can influence the GTV, possibly resulting in an increase, as well as in a decrease.