Definitive, intensity modulated tomotherapy with a simultaneous integrated boost for prostate cancer patients - Long term data on toxicity and biochemical control.

AIM: To report long-term data regarding biochemical control and late toxicity of simultaneous integrated boost intensity modulated radiotherapy (SIB-IMRT) with tomotherapy in patients with localized prostate cancer. BACKGROUND: Dose escalation improves cancer control after curative intended radiation therapy (RT) to patients with localized prostate cancer, without increasing toxicity, if IMRT is used. MATERIALS AND METHODS: In this retrospective analysis, we evaluated long-term toxicity and biochemical control of the first 40 patients with intermediate risk prostate cancer receiving SIB-IMRT. Primary target volume (PTV) 1 including the prostate and proximal third of the seminal vesicles with safety margins was treated with 70 Gy in 35 fractions. PTV 2 containing the prostate with smaller safety margins was treated as SIB to a total dose of 76 Gy with 2.17 Gy per fraction. Toxicity was evaluated using an adapted CTCAE-Score (Version 3). RESULTS: Median follow-up of living patients was 66 (20-78) months. No late genitourinary toxicity higher than grade 2 has been reported. Grade 2 genitourinary toxicity rates decreased from 58% at the end of the treatment to 10% at 60 months. Late gastrointestinal (GI) toxicity was also moderate, though the prescribed PTV Dose of 76 Gy was accepted at the anterior rectal wall. 74% of patients reported any GI toxicity during follow up and no toxicity rates higher than grade 2 were observed. Grade 2 side effects were reported by 13% of the patients at 60 months. 5-year freedom from biochemical failure was 95% at our last follow up. CONCLUSION: SIB-IMRT using daily MV-CT guidance showed excellent long-term biochemical control and low toxicity rates.

Optic toxicity in radiation treatment of meningioma: a retrospective study in 213 patients.

In this retrospective evaluation, we correlated radiation dose parameters with occurrence of optical radiation-induced toxicities. 213 meningioma patients received radiation between 2000 and 2013. Radiation dose and clinical data were extracted from planning systems and patients' files. The range of follow-up period was 2-159 months (median 75 months). Median age of patients was 60 years (range 23-86). There were 163 female and 50 male patients. In 140 cases, at least one of the neuro-optic structures (optic nerves and chiasm) was inside the irradiated target volumes. We found 15 dry eye (7 %) and 24 cataract (11.2 %) cases. Median dose to affected lachrymal glands was 1.47 Gy and median dose to affected lenses was 1.05 Gy. Age and blood cholesterol level in patients with cataract were significantly higher. Patients with dry eye were significantly older. Only two patients with visual problems attributable to radiation treatment were seen. They did not have any risk factors. Maximum and median delivered doses to neuro-optic structures were not higher than 57.30 and 54.60 Gy respectively. Low percentages of cases with radiation induced high grade optic toxicities show that modern treatment techniques and doses are safe. In very few patients with optic side effects, doses to organs at risk were higher than the defined constraint doses. This observation leads to the problem of additional risk factors coming into play. The role of risk factors and safety of higher radiation doses in high grade meningiomas should be investigated in more comprehensive studies.

Simultaneous integrated vs. sequential boost in VMAT radiotherapy of high-grade gliomas.

BACKGROUND: In 20 patients with high-grade gliomas, we compared two methods of planning for volumetric-modulated arc therapy (VMAT): simultaneous integrated boost (SIB) vs. sequential boost (SEB). The investigation focused on the analysis of dose distributions in the target volumes and the organs at risk (OARs). METHOD: After contouring the target volumes [planning target volumes (PTVs) and boost volumes (BVs)] and OARs, SIB planning and SEB planning were performed. The SEB method consisted of two plans: in the first plan the PTV received 50 Gy in 25 fractions with a 2-Gy dose per fraction. In the second plan the BV received 10 Gy in 5 fractions with a dose per fraction of 2 Gy. The doses of both plans were summed up to show the total doses delivered. In the SIB method the PTV received 54 Gy in 30 fractions with a dose per fraction of 1.8 Gy, while the BV received 60 Gy in the same fraction number but with a dose per fraction of 2 Gy. RESULTS: All of the OARs showed higher doses (Dmax and Dmean) in the SEB method when compared with the SIB technique. The differences between the two methods were statistically significant in almost all of the OARs. Analysing the total doses of the target volumes we found dose distributions with similar homogeneities and comparable total doses. CONCLUSION: Our analysis shows that the SIB method offers advantages over the SEB method in terms of sparing OARs.

The importance of surrounding tissues and window settings for contouring of moving targets.

AIM: The aim of the study was to assess the importance of surrounding tissues for the delineation of moving targets in tissue-specific phantoms and to find optimal settings for lung, soft tissue, and liver tumors. MATERIALS AND METHODS: Tumor movement was simulated by a water-filled table tennis ball (target volume, TV). Three phantoms were created: corkboards to simulate lung tissue (lung phantom, LunPh), animal fat as fatty soft tissue (fatty tissue phantom, FatPh), and water enhanced with contrast medium as the liver tissue (liver phantom, LivPh). Slow planning three-dimensional compute tomography images (3D-CTs) were acquired with and without phantom movements. One-dimensional tumor movement (1D), three-dimensional tumor movement (3D), as well as a real patient's tumor trajectories were simulated. The TV was contoured using two lung window settings, two soft-tissue window settings, and one liver window setting. The volumes were compared to mathematical calculated values. RESULTS: TVs were underestimated in all phantoms due to movement. The use of soft-tissue windows in the LivPh led to a significant underestimation of the TV (70.8% of calculated TV). When common window settings [LunPh + 200 HU/-1,000 HU (upper window/lower window threshold); FatPh: + 240 HU/-120 HU; LivPh: + 175 HU/+ 50 HU] were used, the contoured TVs were: LivPh, 84.0%; LunPh, 93.2%, and FatPh, 92.8%. The lower window threshold had a significant impact on the size of the delineated TV, whereas changes of the upper threshold led only to small differences. CONCLUSION: The decisive factor for window settings is the lower window threshold (for adequate TV delineation in the lung and fatty-soft tissue it should be lower than density values of surrounding tissue). The use of a liver window should be considered.

Stereotactic body radiotherapy for centrally located stage I NSCLC: a multicenter analysis.

PURPOSE: The purpose of this work is to analyze patterns of care and outcome after stereotactic body radiotherapy (SBRT) for centrally located, early-stage, non-small cell lung cancer (NSCLC) and to address the question of potential risk for increased toxicity in this entity. METHODS AND MATERIALS: A total of 90 patients with centrally located NSCLC were identified among 613 cases in a database of 13 German and Austrian academic radiotherapy centers. The outcome of centrally located NSCLC was compared to that of cases with peripheral tumor location from the same database. RESULTS: Patients with central tumors most commonly presented with UICC stage IB (50 %), while the majority of peripheral lesions were stage IA (56 %). Average tumor diameters were 3.3 cm (central) and 2.8 cm (peripheral). Staging PET/CT was available for 73 and 74 % of peripheral and central tumors, respectively. Biopsy was performed in 84 % (peripheral) and 88 % (central) of cases. Doses varied significantly between central and peripheral lesions with a median BED10 of 72 Gy and 84 Gy, respectively (p < 0.001). Fractionation differed as well with medians of 5 (central) and 3 (peripheral) fractions (p < 0.001). In the Kaplan-Meier analysis, 3-year actuarial overall survival was 29 % (central) and 51 % (peripheral; p = 0.004) and freedom from local progression was 52 % (central) and 84 % (peripheral; p < 0.001). Toxicity after treatment of central tumors was low with no grade III/IV and one grade V event. Mortality rates were 0 and 1 % after 30 and 60 days, respectively. CONCLUSION: Local tumor control in patients treated with SBRT for centrally located, early-stage NSCLC was favorable, provided ablative radiation doses were prescribed. This was, however, not the case in the majority of patients, possibly due to concerns about treatment-related toxicity. Reported toxicity was low, but prospective trials are needed to resolve the existing uncertainties and to establish safe high-dose regimens for this cohort of patients.

Study of Preoperative Radiotherapy for Sarcomas of the Extremities with Intensity-Modulation, Image-Guidance and Small Safety-margins (PREMISS).

BACKGROUND: The aim of the trial is to demonstrate that with the use of modern IMRT/IGRT and reduction of safety margins postoperative wound complications can be reduced. METHODS/ DESIGN: The trial is designed as a prospective, monocentric clinical phase II trial. The treatment is performed with helical IMRT on the Tomotherapy HiArt System© or with RapidArc© IMRT as available. All treatments are performed with 6 MV photons and daily online CT-based IGRT. A dose of 50 Gy in 2 Gy single fractions (5 fractions per week) is prescribed. Restaging including MRI of the primary tumor site as well as CT of the thorax/abdomen is planned 4 weeks after RT. PET-examinations or any other imaging can be performed as required clinically. In cases of R1 resection, brachytherapy is anticipated in the 2nd postoperative week. Brachytherapy catheters are implanted into the tumor bed depending on the size and location of the lesion. Surgery is planned 5-6 weeks after completion of neoadjuvant RT. All patients are seen for a first follow-up visit 2 weeks after wound healing is completed, thereafter every 3 months during the first 2 years. The endpoints of the study are evaluated in detail during the first (2 weeks) and second (3 months) follow-up. Functional outcome and QOL are documented prior to treatment and at year 1 and 2. Treatment response and efficacy will be scored according to the RECIST 1.1 criteria. A total patient number of 50 with an expected 20% rate of wound complications were calculated for the study, which translates into a 95% confidence interval of 10.0-33.7% for wound complication rate in a binomial distribution. DISCUSSION: The present study protocol prospectively evaluates the use of IMRT/IGRT for neoadjuvant RT in patients with soft tissue sarcomas of the extremity with the primary endpoint wound complications, which is the major concern with this treatment sequence. Besides complications rates, local control rates and survival rates, as well as QOL, functional outcome and treatment response parameters (imaging and pathology) are part of the protocol. The data of the present PREMISS study will enhance the current literature and support the hypothesis that neoadjuvant RT with IMRT/IGRT offers an excellent risk-benefit ratio in this patient population. TRIAL REGISTRATION: NCT01552239.

Long-term outcomes of trimodality treatment for squamous cell carcinoma of the esophagus with cisplatin and/or 5-FU: more than 20 years' experience at a single institution.

PURPOSE: The purpose of this article is to report the outcome of neoadjuvant radiochemotherapy (N-RCT) + surgery in patients with squamous cell carcinoma of the esophagus at a single institution. METHODS: We retrospectively reviewed data from patients who were referred to our department for N-RCT. From 1988­2011, 103 patients were treated with N-RCT with cisplatin and/or 5-fluorouracil (5-FU). Group 1: (n = 55) from 1988­2006 with 39.6­40 Gy and 5-FU with (n = 17) or without cisplatin (n = 38). Group 2: from 2003­2010 with 44­45 Gy and 5-FU with (n = 40) or without cisplatin (n = 8). All patients underwent radical resection with reconstruction according to tumor location and 2-field lymph node dissection. The degree of histomorphologic regression was defined as grade 1a (pCR, 0 % residual tumor), grade 1b (pSTR, < 10 % residual tumor), grade 2 (10­50 % residual tumor), and grade 3 (> 50 % residual tumor). RESULTS: Median follow-up time from the start of N-RCT was 100 months (range 2­213 months). The median overall survival (OS) for the whole cohort was 42 months and the 5-year OS was 45 ± 5 %. In the multivariate analysis, worse ECOG performance status (p < 0.001), weight loss > 10 % before the start of the N-RCT (p = 0.025), higher pT category (p = 0.001), and grade 2/3 pathologic remission (p < 0.001) were significantly associated with a poor OS. PCR and pSTR rates for group 1 were 36 % and 18 % compared to 53 % and 22 % for group 2 (p = 0.011). There was a tendency for a better outcome in group 2 patients without statistical significance. The 5-year OS, disease-free survival and recurrent-free survival were 36 ± 7 %, 35 ± 6, and 36 ± 7 % for group 1 and 55 ± 7, 49 ± 7, and 53 ± 7 in group 2 (p = 0.117, p = 0.124, and p = 0.087). There was no significant difference between the two groups considering the postoperative morbidity and mortality. CONCLUSION: Higher radiation doses and more use of simultaneous cisplatin lead to higher pathologic response rates to N-RCT and may be associated with better survival outcomes. Prospective controlled trials are needed to assess the true value of intensified N-RCT regimens.

11C-Choline PET/pathology image coregistration in primary localized prostate cancer.

PURPOSE: The aim of this study was to develop a methodology for the comparison of pathology specimens after prostatectomy (post-S) with PET images obtained before surgery (pre-S). This method was used to evaluate the merit of (11)C-choline PET/CT for delineation of gross tumour volume (GTV) in prostate cancer (PC). METHODS: In 28 PC patients, (11)C-choline PET/CT was performed before surgery. PET/CT data were coregistered with the pathology specimens. GTV on PET images (GTV-PET) was outlined automatically and corrected manually. Tumour volume in the prostate (TVP) was delineated manually on the pathology specimens. Based on the coregistered PET/pathology images, the following parameters were assessed: SUVmax and SUVmean in the tumoral and nontumoral prostate (NP), GTV-PET (millilitres) and TVP (millilitres). RESULTS: PET/pathology image coregistration was satisfactory. Mean SUVmax in the TVP was lower than in the NP: 5.0 and 5.5, respectively (p = 0.093). Considering the entire prostate, SUVmax was located in the TVP in two patients, in the TVP and NP in 12 patients and exclusively in NP in 14 patients. Partial overlap the TVP and GTV-PET was seen in 71% of patients, and complete overlap in 4%. CONCLUSION: PET/pathology image coregistration can be used for evaluation of different imaging modalities. (11)C-Choline PET failed to distinguish tumour from nontumour tissue.

Scanning irradiation device for mice in vivo with pulsed and continuous proton beams.

A technical set-up for irradiation of subcutaneous tumours in mice with nanosecond-pulsed proton beams or continuous proton beams is described and was successfully used in a first experiment to explore future potential of laser-driven particle beams, which are pulsed due to the acceleration process, for radiation therapy. The chosen concept uses a microbeam approach. By focusing the beam to approximately 100 × 100 µm(2), the necessary fluence of 10(9) protons per cm(2) to deliver a dose of 20 Gy with one-nanosecond shot in the Bragg peak of 23 MeV protons is achieved. Electrical and mechanical beam scanning combines rapid dose delivery with large scan ranges. Aluminium sheets one millimetre in front of the target are used as beam energy degrader, necessary for adjusting the depth-dose profile. The required procedures for treatment planning and dose verification are presented. In a first experiment, 24 tumours in mice were successfully irradiated with 23 MeV protons and a single dose of 20 Gy in pulsed or continuous mode with dose differences between both modes of 10%. So far, no significant difference in tumour growth delay was observed.

Tumor shrinkage assessed by volumetric MRI in the long-term follow-up after stereotactic radiotherapy of meningiomas.

PURPOSE: To evaluate tumor volume reduction in the follow-up of meningiomas after fractionated stereotactic radiotherapy (FSRT) or linac radiosurgery (RS) by using magnetic resonance imaging (MRI). PATIENTS AND METHODS: In 59 patients with skull base meningiomas, gross tumor volume (GTV) was outlined on contrast-enhanced MRI before and median 50 months (range 11-92 months) after stereotactic radiotherapy. MRI was performed as an axial three-dimensional gradient-echo T1-weighted sequence at 1.6 mm slice thickness without gap (3D-MRI). Results were compared to the reports of diagnostic findings. RESULTS: Mean tumor size of all 59 meningiomas was 13.9 ml (0.8-62.9 ml) before treatment. There was shrinkage of the treated meningiomas in all but one patient. Within a median volumetric follow-up of 50 months (11-95 months), an absolute mean volume reduction of 4 ml (0-18 ml) was seen. The mean relative size reduction compared to the volume before radiotherapy was 27% (0-73%). Shrinkage measured by 3D-MRI was greater at longer time intervals after radiotherapy. The mean size reduction was 17%, 23%, and 30% (at < 24 months, 24-48 months, and 48-72 months). CONCLUSION: By using 3D-MRI in almost all patients undergoing radiotherapy of a meningioma, tumor shrinkage is detected. The data presented here demonstrate that volumetric assessment from 3D-MRI provides additional information to routinely used radiologic response measurements. After FSRT or RS, a mean size reduction of 25-45% can be expected within 4 years.

Longitudinal analysis of quality of life in patients receiving conformal radiation therapy for prostate cancer.

PURPOSE: To prospectively assess quality of life (QoL) in patients receiving conformal radiation therapy (CRT) for prostate cancer. PATIENTS AND METHODS: 78 men with definitive CRT for prostate cancer were entered into the study. Patients were assessed before CRT, at 40 and 60 Gy, and 2, 12 and 24 months after the end of treatment. QoL was assessed using the EORTC Quality of Life Questionnaire C30 and the prostate module PR25. Changes in mean QoL scores with time of >or= 10 points were considered clinically relevant. RESULTS: Global QoL did not change statistically significant during CRT and was slightly above baseline levels during follow-up. CRT had a statistically significant negative short-term impact on role functioning, fatigue, and PR25 urinary symptoms. The scores recovered within 2 months to 1 year after CRT. Emotional functioning and social functioning scores slightly increased during and after CRT. Role functioning decreased by > 10 points at 60 Gy and urinary symptoms decreased by > 10 points at 40 and 60 Gy. All other differences were < 10 points. A high number of concomitant diseases and having no children were negative pretreatment predictors for long-term global QoL. CONCLUSION: Definitive CRT for prostate cancer does not compromise global QoL during therapy and up to 2 years after treatment. It has a limited negative effect on role functioning, urinary symptoms and, to a lesser extent, on fatigue with restitution within 2 months to 1 year after treatment.

A new modification of combining vacuum therapy and brachytherapy in large subfascial soft -tissue sarcomas of the extremities.

PURPOSE: To present a modification of a technique combining the advantages of brachytherapy for local radiation treatment and vacuum therapy for wound conditioning after resection of subfascial soft-tissue sarcomas (STS) of the extremities. PATIENTS AND METHODS: Between January and May 2008, four patients with large (> 10 cm) subfascial STS of the thigh underwent marginal tumor excision followed by early postoperative HDR (high-dose-rate) brachytherapy (iridium-192) and vacuum therapy as part of their interdisciplinary treatment. The sponge of the vacuum system was used to stabilize brachytherapy applicators in parallel positions and to allow for a maximal wound contraction in the early postoperative phase, thus preventing seroma and deterioration of local dose distribution as optimized in computed tomography-(CT-)based three-dimensional conformal treatment planning. In three patients this was followed by external-beam radiotherapy. Acute wound complications and late effects according to LENT-SOMA after 4-8 months of follow-up were recorded. RESULTS: The combination of vacuum and brachytherapy was applicable in all patients. CT scans from the 1st postoperative day showed the shrinkage of the sponge located in the tumor bed with the brachytherapy applicators in the intended position and easily visible. 15-18 Gy in fractions of 3 Gy bid prescribed to 5 mm tissue depth were applied over the next days with removal of the sponge and applicators on days 5-8. No early or late toxicity exceeding grade 2 was observed. The mean Enneking Score for functional outcome was 63% (perfect function = 100%). CONCLUSION: The combination of vacuum and brachytherapy is applicable and safe in the treatment of large subfascial STS.

Binding of heat shock protein 70 to extracellular phosphatidylserine promotes killing of normoxic and hypoxic tumor cells.

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 (8/2 > or = 7/3 < 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 (EC(50) of Hsp70=85 microg/ml) and hypoxic (EC(50) of Hsp70=55 microg/ml) tumor cells. The radiation-induced tumor cell killing was significantly enhanced by the addition of Hsp70 protein (50 microg/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.

Targeted Natural Killer Cell-Based Adoptive Immunotherapy for the Treatment of Patients with NSCLC after Radiochemotherapy: A Randomized Phase II Clinical Trial.

PURPOSE: Non-small cell lung cancer (NSCLC) is a fatal disease with poor prognosis. A membrane-bound form of Hsp70 (mHsp70) which is selectively expressed on high-risk tumors serves as a target for mHsp70-targeting natural killer (NK) cells. Patients with advanced mHsp70-positive NSCLC may therefore benefit from a therapeutic intervention involving mHsp70-targeting NK cells. The randomized phase II clinical trial (EudraCT2008-002130-30) explores tolerability and efficacy of ex vivo-activated NK cells in patients with NSCLC after radiochemotherapy (RCT). PATIENTS AND METHODS: Patients with unresectable, mHsp70-positive NSCLC (stage IIIa/b) received 4 cycles of autologous NK cells activated ex vivo with TKD/IL2 [interventional arm (INT)] after RCT (60-70 Gy, platinum-based chemotherapy) or RCT alone [control arm (CTRL)]. The primary objective was progression-free survival (PFS), and secondary objectives were the assessment of quality of life (QoL, QLQ-LC13), toxicity, and immunobiological responses. RESULTS: The NK-cell therapy after RCT was well tolerated, and no differences in QoL parameters between the two study arms were detected. Estimated 1-year probabilities for PFS were 67% [95% confidence interval (CI), 19%-90%] for the INT arm and 33% (95% CI, 5%-68%) for the CTRL arm (P = 0.36, 1-sided log-rank test). Clinical responses in the INT group were associated with an increase in the prevalence of activated NK cells in their peripheral blood. CONCLUSIONS: Ex vivo TKD/IL2-activated, autologous NK cells are well tolerated and deliver positive clinical responses in patients with advanced NSCLC after RCT.

Anti-tumor activity of patient-derived NK cells after cell-based immunotherapy--a case report.

BACKGROUND: Membrane-bound heat shock protein 70 (Hsp70) serves as a tumor-specific recognition structure for Hsp70-peptide (TKD) plus IL-2 activated NK cells. A phase I clinical trial has shown that repeated re-infusions of ex vivo TKD/IL-2-activated, autologous leukapheresis product is safe. This study investigated the maintenance of the cytolytic activity of NK cells against K562 cells and autologous tumor after 6 plus 3 infusions of TKD/IL-2-activated effector cells. METHODS: A stable tumor cell line was generated from the resected anastomotic relapse of a patient with colon carcinoma (pT3, N2, M0, G2). Two months after surgery, the patient received the first monthly i.v. infusion of his ex vivo TKD/IL-2-activated peripheral blood mononuclear cells (PBMNC). After 6 infusions and a pause of 3 months, the patient received another 3 cell infusions. The phenotypic characteristics and activation status of tumor and effector cells were determined immediately before and at times after each infusion. RESULTS: The NK cell ligands Hsp70, MICA/B, and ULBP-1,2,3 were expressed on the patient's anastomotic relapse. An increased density of activatory NK cell receptors following ex vivo stimulation correlated with an enhanced anti-tumoricidal activity. After 4 re-infusion cycles, the intrinsic cytolytic activity of non-stimulated PBMNC was significantly elevated and this heightened responsiveness persisted for up to 3 months after the last infusion. Another 2 re-stimulations with TKD/IL-2 restored the cytolytic activity after the therapeutic pause. CONCLUSION: In a patient with colon carcinoma, repeated infusions of ex vivo TKD/IL-2-activated PBMNC initiate an intrinsic NK cell-mediated cytolytic activity against autologous tumor cells.

Moderate risk-adapted dose escalation with three-dimensional conformal radiotherapy of localized prostate cancer from 70 to 74 Gy. First report on 5-year morbidity and biochemical control from a prospective Austrian-German multicenter phase II trial.

PURPOSE: Evaluation of late side effects and biochemical control (bNED) 5 years after three-dimensional radiotherapy with moderate, risk-adapted dose escalation. PATIENTS AND METHODS: From 03/1999 to 07/2002, 486 patients have been registered in the prospective Austrian-German multicenter phase II trial (AUGE). 399 (82%) localized prostate cancer patients (T1-3 Nx/N0 M0) were evaluated. The low- and intermediate-risk groups were treated with 70 Gy, the high-risk group with 74 Gy, respectively. Additional hormonal therapy (HT) was recommended for intermediate- and high-risk group patients. Late toxicity (EORTC/RTOG) and bNED (ASTRO and Phoenix) were prospectively assessed. RESULTS: Median follow-up was 65 months. Distribution concerning risk groups (low-, intermediate-, high-risk group) showed 29%, 50% and 21% of patients, respectively. HT was given in 87% of patients. The 5-year actuarial rates of late side effects grade > or = 2 for 70 Gy/74 Gy were 28%/30% (gastrointestinal; p = 0.73) and 19%/34% (urogenital; p = 0,06). The 5-year actuarial bNED rate stratified by risk groups (low-, intermediate-, high-risk group) was 74%, 66% and 50% (ASTRO), and 81%, 80% and 60% (Phoenix), respectively. Within multivariate analysis T-stage and initial prostate specific antigen were significant factors influencing bNED (ASTRO) whereas Gleason Score and duration of HT were not. CONCLUSION: Dose escalation within standard three-dimensional conformal radiotherapy (3D-CRT) up to a level of 74 Gy did not result in significantly increased gastrointestinal side effects, whereas urogenital side effects showed an increase close to significance. However, the total number of patients with severe toxicity was low. To achieve high tumor control rates with acceptable treatment-related morbidity, local doses of at least 74 Gy should be considered, in particular for intermediate- or high-risk patients applying 3D-CRT.

Prognostic scores in brain metastases from breast cancer.

BACKGROUND: Prognostic scores might be useful tools both in clinical practice and clinical trials, where they can be used as stratification parameter. The available scores for patients with brain metastases have never been tested specifically in patients with primary breast cancer. It is therefore unknown which score is most appropriate for these patients. METHODS: Five previously published prognostic scores were evaluated in a group of 83 patients with brain metastases from breast cancer. All patients had been treated with whole-brain radiotherapy with or without radiosurgery or surgical resection. In addition, it was tested whether the parameters that form the basis of these scores actually have a prognostic impact in this biologically distinct group of brain metastases patients. RESULTS: The scores that performed best were the recursive partitioning analysis (RPA) classes and the score index for radiosurgery (SIR). However, disagreement between the parameters that form the basis of these scores and those that determine survival in the present group of patients and many reported data from the literature on brain metastases from breast cancer was found. With the four statistically significant prognostic factors identified here, a 3-tiered score can be created that performs slightly better than RPA and SIR. In addition, a 4-tiered score is also possible, which performs better than the three previous 4-tiered scores, incl. graded prognostic assessment (GPA) score and basic score for brain metastases (BSBM). CONCLUSION: A variety of prognostic models describe the survival of patients with brain metastases from breast cancer to a more or less satisfactory degree. However, the standard brain metastases scores might not fully appreciate the unique biology and time course of this disease, e.g., compared to lung cancer. It appears possible that inclusion of emerging prognostic factors will improve the results and allow for development and validation of a consensus score for broad clinical application. The model that is based on the authors own patient group, which is not large enough to fully evaluate a large number of potential prognostic factors, is meant to illustrate this point rather than to provide the definitive score.

Chromosomes are predominantly located randomly with respect to each other in interphase human cells.

To test quantitatively whether there are systematic chromosome-chromosome associations within human interphase nuclei, interchanges between all possible heterologous pairs of chromosomes were measured with 24-color whole-chromosome painting (multiplex FISH), after damage to interphase lymphocytes by sparsely ionizing radiation in vitro. An excess of interchanges for a specific chromosome pair would indicate spatial proximity between the chromosomes comprising that pair. The experimental design was such that quite small deviations from randomness (extra pairwise interchanges within a group of chromosomes) would be detectable. The only statistically significant chromosome cluster was a group of five chromosomes previously observed to be preferentially located near the center of the nucleus. However, quantitatively, the overall deviation from randomness within the whole genome was small. Thus, whereas some chromosome-chromosome associations are clearly present, at the whole-chromosomal level, the predominant overall pattern appears to be spatially random.

Validation of the graded prognostic assessment index for patients with brain metastases.

BACKGROUND: The purpose of this study is to evaluate the performance of the new "Graded Prognostic Assessment" (GPA) index, which recently was developed from data in the Radiation Therapy Oncology Group (RTOG) database, in patients with brain metastases treated outside of randomized clinical trials. MATERIAL AND METHODS: The authors analyzed 232 patients with brain metastases and assigned these patients to the four indices previously evaluated by the RTOG (recursive partitioning analysis class, Score Index for Radiosurgery, Basic Score for Brain Metastases, and GPA). RESULTS: The present data confirm the results of the RTOG analysis. Each of the four indices splits the data set into prognostically different groups. In the GPA groups, median survival was 10.3, 5.6, 3.5, and 1.9 months, respectively (p<0.01). In the RTOG analysis, these figures were 11.0, 6.9, 3.8, and 2.6 months, respectively. CONCLUSION: These results confirm the validity of the GPA index in a patient population that most likely is more representative of the normal clinical situation than patients included in randomized trials.