Clinical and pathological factors and outcome of central nervous system metastasis in breast cancer.

Background: In Switzerland, approximately 6000 new breast cancer cases and 1300 deaths are reported annually. Brain metastasis from breast cancer (BMBC) has a major effect on prognosis. This study aimed to identify prognostic factors for overall survival (OS) in a cohort of Swiss patients with BMBC. This study evaluated the prognosis on older BMBC, which has not been completely addressed in the literature. Methods: We performed a retrospective chart review analysis with the primary endpoint of OS after a diagnosis of BMBC. The study population was divided into 2 groups based on an OS cut-off value of 12 months after diagnosis. Univariate and multivariate analyses of several risk factors, including age, were performed. To evaluate differences in OS according to age, we performed a secondary analysis to examine the prognostic value of clinical symptoms, metastatic pattern, and lymph node involvement in an older (≥65 years) vs. younger (<65 years) cohort. Results: From 1989 to 2019, 55 patients were identified as having BMBC, among whom 47 patients were confirmed to be dead. The median patient age was 58 years (range 25-83 years). Comorbidities were present in 45 (81.8%) patients. The median survival in the OS <12 and OS ≥12 months groups was 4.3 and 30.7 months, respectively (p<0.001). Multivariate analysis revealed no significant differences in terms of comorbidities, medication use, M-stage, and symptomatology between the 2 groups. Additionally, there was no significant difference in OS in the 2 subgroups of patients aged <65 and ≥65 years. Discussion: We concluded that age should not be a decisive factor in therapy planning for advanced breast cancer patients with BMBC.

Extracorporeal Irradiation and Reimplantation of Tumor-bearing Bone Segments Following Diaphyseal Sarcoma Resection at the Tibia.

BACKGROUND/AIM: Reconstruction of diaphyseal tibial sarcomas with extracorporeal irradiated autograft is a rarely applied technique and is analyzed in this study. PATIENTS AND METHODS: Eight patients with malignant sarcomas received local treatment by means of a wide resection and reimplantation of an extracorporeally-irradiated autograft. The graft was combined with an ipsilateral vascularized fibula when a full-thickness segment of the tibia had to be resected and no cortex could be preserved (n=5). Oncological and functional results were recorded. RESULTS: All patients had clear margins after resection, and with no local recurrence 72 months after treatment. Full weight-bearing was allowed at the time of radiological consolidation of the irradiated grafts (after a median of five months). The functional results were good and excellent in 7 of 8 patients, respectively. CONCLUSION: Extracorporeal irradiation grafting is a suitable method for the treatment of localised and resectable tibial sarcomas.

Comparison of stereotactic radiosurgery and fractionated stereotactic radiotherapy of acoustic neurinomas according to 3-D tumor volume shrinkage and quality of life.

BACKGROUND AND PURPOSE: Stereotactic radiosurgery (SRS) and also fractionated stereotactic radiotherapy (SRT) offer high local control (LC) rates (> 90%). This study aimed to evaluate three-dimensional (3-D) tumor volume (TV) shrinkage and to assess quality of life (QoL) after SRS/SRT. PATIENTS AND METHODS: From 1999 to 2005, 35/74 patients were treated with SRS, and 39/74 with SRT. Median age was 60 years. Treatment was delivered by a linear accelerator. Median single dose was 13 Gy (SRS) or 54 Gy (SRT). Patients were followed up > or = 12 months after SRS/SRT. LC and toxicity were evaluated by clinical examinations and magnetic resonance imaging. 3-D TV shrinkage was evaluated with the planning system. QoL was assessed using the questionnaire Short Form-36. RESULTS: Median follow-up was 50/36 months (SRS/SRT). Actuarial 5-year freedom from progression/overall survival was 88.1%/100% (SRS), and 87.5%/87.2% (SRT). TV shrinkage was 15.1%/40.7% (SRS/SRT; p = 0.01). Single dose (< 13 Gy) was the only determinant factor for TV shrinkage after SRS (p = 0.001). Age, gender, initial TV, and previous operations did not affect TV shrinkage. Acute or late toxicity (> or = grade 3) was never seen. Concerning QoL, no significant differences were observed after SRS/SRT. Previous operations and gender did not affect QoL (p > 0.05). Compared with the German normal population, patients had worse values for all domains except for mental health. CONCLUSION: TV shrinkage was significantly higher after SRT than after SRS. Main symptoms were not affected by SRS/SRT. Retrospectively, QoL was neither affected by SRS nor by SRT.

Hypofractionated stereotactic reirradiation of recurrent glioblastomas : a beneficial treatment option after high-dose radiotherapy?

BACKGROUND AND PURPOSE: Recurrent malignant gliomas have a very poor prognosis. This trial aimed to evaluate the benefits of reirradiation in case of recurrent glioblastoma multiforme (GBM) using hypofractionated stereotactic radiotherapy (hFSRT) after primary high-dose percutaneous irradiation. PATIENTS AND METHODS: Between 1998 and 2008, 53 patients with recurrent GBM were treated by hFSRT based on CT and MR imaging. At the time of recurrence, a median total dose of 30 Gy (20-60 Gy) was delivered in median fractions of 3 Gy/day (2-5Gy). RESULTS: The reirradiation was well tolerated (no acute or late toxicity > grade 2), despite the relatively large median tumor volume (35.01 ml). Karnofsky Performance Score was the strongest predictor for survival after reirradiation (p = 0.0159). Tumor volume (p = 0.4690), patient age (p = 0.4301), second operation (p = 0.6930), and chemotherapy (p = 0.1466) at the time of reirradiation did not affect survival. After hFSRT, the median survival was 9 months, and the 1-year progression-free survival (PFS) amounted to 22%.The median overall survival from initial diagnosis was 27 months. 1-year survival from first diagnosis was 83%, 2-year survival 45%. The median time to progression from the end of initial irradiation to recurrence was 12 months. 1-year PFS before reirradiation was 40%. CONCLUSION: hFSRT as a secondary treatment of recurrent GBM is a feasible and effective treatment option. Only minor side effects were observed with prolonged life expectancy of 9 months.

Stereotactic radiotherapy for the treatment of nonacoustic schwannomas.

OBJECTIVE: Nonacoustic schwannomas are rare tumors in contrast to the most common neuromas of Cranial Nerve VIII. The current treatment of choice in these cases is microsurgical resection, but the risk of postoperative complications is high, especially in cavernous sinus-invading tumors. In many of these cases, it is not possible to achieve complete tumor removal, resulting in the probability of recurrences. For those patients, radiosurgery (RS) or stereotactic radiotherapy (SRT) can offer an alternate treatment. METHODS: Within a 5-year period (2000-2005), 19 intracranial nonacoustic neuromas were treated with SRT-13 trigeminal neuromas, five neuromas of the lower cranial nerves (jugular foramen), and one located in the orbital region. Of these cases, there were nine women and 10 men who were, on average, 54 years of age (range, 33-83 yr). Eight patients had previously undergone surgery elsewhere and showed progressive tumor growth. All 19 patients were treated with SRT: 15 with normal fractions of 1.8-2 Gy single dose up to 54-59.4 Gy. Their irregular tumor volume ranged from 4.2 to 43.1 ccm (average: 14.1 ccm). Hypofractionation with 6 to 7 x 5 Gy was applied in four cases with an average tumor volume of 4.1 ccm (2.2-6.2 ccm). Clinical results and the efficacy for tumor control with an average follow-up of 35 months (11-63 mo) were evaluated. RESULTS: Local tumor control rate was 95% (18 of 19 cases): one patient previously operated on had a recurrence of tumor progression after SRT, followed by a second subtotal resection. A tumor regression was proved in 11 cases (one neuroma disappeared and four patients had tumor shrinkage of more than 50%, the other six experienced shrinkage between 20% and 40%). Within the first 6 months, two patients developed temporarily increased tumor volume as well as a confirmed reaction to irradiation. In one of these two cases, there were mild side effects according to CTC Grade I. No patient experienced a new or increased neurological deficit. Improvement of their cranial nerve disturbances was achieved in 11 of 19 patients and the other eight showed no clinical changes. The mostly moderate trigeminal pain decreased slowly. CONCLUSION: SRT is a low-risk and effective treatment option for intracranial neuromas. Particularly in cases of sinus cavernous-invading trigeminal and in jugular foramen tumors, SRT can be the treatment of choice. Concerning tumor regression, SRT is as effective as RS.

Fractionated stereotactic radiotherapy of glomus jugulare tumors. Local control, toxicity, symptomatology, and quality of life.

BACKGROUND AND PURPOSE: For glomus jugulare tumors, the goal of treatment is microsurgical excision. To minimize postoperative neurologic deficits, stereotactic radiosurgery (SRS) was performed as an alternative treatment option. Stereotactic fractionated radiotherapy (SRT) could be a further alternative. This study aims at the assessment of local control, side effects, and quality of life (QoL). PATIENTS AND METHODS: Between 1999-2005, 17 patients were treated with SRT. 11/17 underwent previous operations. 6/17 received primary SRT. Treatment was delivered by a linear accelerator with 6-MV photons. Median cumulative dose was 57.0 Gy. Local control, radiologic regression, toxicity, and symptomatology were evaluated half-yearly by clinical examination and MRI scans. QoL was assessed by Short Form-36 (SF-36). RESULTS: Median follow-up was 40 months. Freedom from progression and overall survival for 5 years were 100% and 93.8%. Radiologic regression was seen in 5/16 cases, 11/16 patients were stable. Median tumor shrinkage was 17.9% (p=0.14). Severe acute toxicity (grade 3-4) or any late toxicity was never seen. Main symptoms improved in 9/16 patients, 7/16 were stable. QoL was not affected in patients receiving primary SRT. CONCLUSION: SRT offers an additional treatment option of high efficacy with less side effects, especially in cases of large tumors, morbidity, or recurrences after incomplete resections.

Stereotactic radiotherapy of meningiomas: symptomatology, acute and late toxicity.

BACKGROUND AND PURPOSE: Stereotactic radiosurgery (SRS) is well established in the treatment of skull base meningiomas, but this therapy approach is limited to small tumors only. The fractionated stereotactic radiotherapy (SRT) offers an alternative treatment option. This study aims at local control, symptomatology, and toxicity. PATIENTS AND METHODS: Between 1997-2003, 224 patients were treated with SRT (n = 183), hypofractionated SRT (n = 30), and SRS (n = 11). 95/224 were treated with SRT/SRS alone. 129/224 patients underwent previous operations. Freedom from progression and overall survival, toxicity, and symptomatology were evaluated systematically. Additionally, tumor volume (TV) shrinkage was analyzed three-dimensionally within the planning system. RESULTS: The median follow-up was 36 months (range, 12-100 months). Overall survival and freedom from progression for 5 years were 92.9% and 96.9%. Quantitative TV reduction was 26.2% and 30.3% 12 and 18 months after SRT/SRS (p < 0.0001). 95.9% of the patients improved their symptoms or were stable. Clinically significant acute toxicity (CTC III degrees ) was rarely seen (2.5%). Clinically significant late morbidity (III degrees -IV degrees ) or new cranial nerve palsies did not occur. CONCLUSION: SRT offers an additional treatment option of high efficacy with only few side effects. In the case of large tumor size (> 4 ml) and adjacent critical structures (< 2 mm), SRT is highly recommended.

How to successfully implement E-learning for both students and teachers.

RATIONALE AND OBJECTIVES: Electronic learning (e-learning) may provide a means to enhance learning efficacy. However, introduction of e-learning often fails. We describe a strategy of how an e-learning curriculum was successfully implemented. MATERIALS AND METHODS: The curriculum was designed based on published evidence. It consists of self-directed learning, an online discussion forum, and discussion rounds. The e-content in nuclear medicine and radiotherapy was produced by the k-MED team of medical authors, web designers, and psychologists. The online courses were delivered via a dedicated learning management system. The e-content for diagnostic radiology and physics was provided as PDF/HTML script by the respective teachers who objected to participate in the k-MED project. The exam was taken online. Online evaluation of the curriculum by the students was taken at the end of the course. RESULTS: The new curriculum proved very effective. The time for the preparation for the clinical part of the radiology course could be reduced from 4 to 2 weeks. The students particularly enjoyed the self-directed learning. Although the material provided by k-MED received 90%-99% positive scores, the HTML and PDF scripts scored worse (13%-67% positive ratings). The positive results of the evaluation convinced the teachers responsible for physics and diagnostic radiology to participate in k-MED. CONCLUSIONS: As our example shows, new e-learning curricula can successfully be introduced. The strategy of implementation should be based on the existing evidence from the literature. The new curriculum helped to increase the efficacy of teaching and save time as the duration of the respective part of the course could be reduced by half.

Significant tumor volume reduction of meningiomas after stereotactic radiotherapy: results of a prospective multicenter study.

OBJECTIVE: Stereotactic radiosurgery (SRS) is well established in the treatment of cranial base meningiomas. Fractionated stereotactic radiotherapy (SRT) offers an additional treatment option. Data for radiological regression differ, ranging from 13 to 61%. Therefore, the aims of this prospective study were to quantitatively analyze tumor volume (TV) shrinkage and to calculate determining factors. METHODS: Eighty-four patients were examined under equal conditions before and after SRT. Fat-saturated axial T1-weighted contrast-enhanced magnetic resonance imaging scans with 1- to 3-mm slice thickness were used. After image fusion, TV was drawn in each slice to analyze TV shrinkage three-dimensionally by the planning system. RESULTS: Mean TV had shrunk by 33% at 24 months (P = 0.02) and by 36% at 36 months (P = 0.0007) after SRT. With regard to half-year intervals, TV reduction decreased continuously towards a steady state (P < 0.0001). Younger age (P = 0.001) and smaller TV (P = 0.01) are determining factors. There was no correlation between TV reduction, prescribed dose, histological classification, sex, or previous operations. CONCLUSION: Meningiomas shrink significantly after SRT. TV shrinkage declines towards a steady state, which is not yet defined. Younger age and smaller TV are determining factors. Previous operations, sex, prescribed dose, or histological subtypes do not affect TV shrinkage. Eighteen to 24 months after irradiation, when symptoms are clinically stable, is the best time for the first magnetic resonance imaging scans evaluating tumor control and shrinkage.

Open-label simultaneous radio-chemotherapy of glioblastoma multiforme with topotecan in adults.

BACKGROUND: Due to its radioresistance, the prognosis of glioblastoma multiforme (GBM) remains poor. Therefore, we investigated the impact of simultaneous radio-chemotherapy with topotecan (Hycamtin) on clinical outcome, tolerability and quality of life. PATIENTS AND METHODS: In this multicenter trial, 60 patients (19 females, 41 males) with histologically proven (5x biopsy, 31x subtotal resection, 24x total resection) GBM were included. Radio-Chemotherapy was performed with daily doses of 2.0 Gy (total, 60 Gy), and 0.5 mg (absolute dose) of topotecan intravenously 1 h prior to irradiation. Toxicity was assessed using common toxicity criteria (CTC). General condition and quality of life were assessed at baseline, at the end of therapy, and 6 weeks post-therapy. Local control and length of survival were compared with an historical control group of 67 patients only treated with postoperative radiotherapy following stereotactic biopsy (15x), subtotal resection (39x), or total resection (13x). RESULTS: 57 patients completed the therapy. Median radiation dose was 60 Gy (range 16-76 Gy). Median cumulative topotecan dose was 15 mg (range 7.5-18.5 mg). CTC toxicity grade 3 was observed in six patients and grade 4 toxicity in two patients (three events). Two patients died of septic disease. Mean Karnofsky index was 87% at baseline, 81% at the end of therapy, and 80% at 6 weeks post-therapy. Median survival time was 15 months, significantly longer than the 11 months seen in the control group (P < 0.002). Extent of tumour resection or patient age did not have a significant effect on survival. CONCLUSION: This multimodal approach is well tolerated, and quality of life remains preserved. The relatively long median survival time is promising but a further randomised double blind placebo controlled parallel designed clinical trial should be performed to confirm these results.

Expression of p53 and p21 in primary glioblastomas.

BACKGROUND AND PURPOSE: Primary glioblastomas (GBMs) are highly radioresistant, and in contrast to secondary GBMs, they bear wild-type (wt) p53 protein, which is stabilized in a proportion of these tumors. Therefore, it was investigated in vivo whether p53 expression has prognostic value in patients undergoing radiochemotherapy. Additionally, the authors tried to identify, in vitro, subgroups of primary GBM with different susceptibilities to irradiation, on the basis of their p53 and p21 responses to ionizing radiation. MATERIAL AND METHODS: Tumor tissue samples from 31 patients suffering from primary GBM undergoing a combined radiochemotherapy with topotecan were investigated. The percentage of cells expressing p53 protein was determined immunohistochemically. Additionally, primary cultures from eleven primary GBMs were established and investigated. p53 and p21 expressions were evaluated before irradiation with 10 Gy and at 2 and 8 h after irradiation. p53 protein expression was measured by Western analysis and p21 mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The percentage of p53-positive cells within the tumor specimens obtained from the 31 patients ranged from 0% to 28%, the median value being 4.3%. No significant correlation with disease-free survival or overall survival was found. In vitro, p53 protein was detected in seven of eleven cultures from primary GBM. After irradiation a decrease in p53 protein expression was seen in six of the seven p53-positive cultures. Half of the cultures (two of four) without basal p53 expression showed an increase in p53 expression after irradiation. Basal overexpression of p21 was detected in six of the eleven cultures; in four out of six irradiation led to a decrease in p21 expression. In all cell lines (five of eleven) initially showing absent p21 expression, irradiation induced p21 expression. Despite these responses, G1 arrest was not detectable in any of the GBM cultures. CONCLUSION: p53 protein expression in vivo does not correlate with the outcome of patients with primary GBM. Therefore, p53 protein content per se does not appear to be a helpful prognostic factor for prognosis-adapted therapy in primary GBM. By contrast, primary GBM cells in vitro show different and independent responses in their p53 and p21 pathways to ionizing radiation. The failure of G1 arrest seems to be due to a functional defect in the p53 pathway, either because p21 was not induced or because of an unidentified defect downstream from p21.

Assessment of the accuracy of a conventional simulation for radiotherapy of head and skull base tumors.

In this prospective study we investigated the absolute accuracy of the conventional simulation in head and skull base tumors. 41 isocenters in 40 consecutive patients with tumors of the head and skull base were included. In all cases a rigid stereotactic mask system was used for non-invasive fixation. The stereotactic ("calculated") coordinates of the isocenter were defined by the treatment planning computer. Each patient underwent a physical simulation using exclusively anatomical reference points to define the "preliminary" isocenter. The displacement between its coordinates and those of the stereotactic target point was recorded in X-, Y- and Z-direction with help of the targeting device, and the spatial error was calculated. Additionally, the patients were stratified by basal or calvarial tumor site to estimate the importance of the basal bone structures in the simulation accuracy. The influence of the learning effect on simulation accuracy was also determined. The results showed an accuracy of set-up at the linac within 1 mm in all three directions as calculated from orthogonal portal films. Mean shift of the isocenter coordinates obtained from physical simulation compared to the calculated stereotactic coordinates was 2.15 mm, 2.54 mm, and 2.69 mm for X-, Y-, and Z-direction, respectively. Mean spatial displacement amounted 5.06 mm, and the median was 4.50 mm. No significant difference could be noted between basal and calvarial location of the isocenter. A significant "learning effect" was observed with a decrease in spatial shift with increasing patient numbers. This effect was stronger in basal lesions, whereas calvarial lesions showed only a minor, insignificant effect. In conclusion, a physical simulation requires a safety margin of 5 mm in PTV definition in addition to other factors, e.g. organ movement.

In vitro chemo- and radio-resistance in small cell lung cancer correlates with cell adhesion and constitutive activation of AKT and MAP kinase pathways.

Most small cell lung cancer (SCLC) patients relapse within 12 months of starting combination chemotherapy plus radio-therapy, due to the development of acquired chemo- and radio-resistance. This phenomenon relates to the induction of tumour differentiation, resulting in apoptosis-resistant, morphologically variant (v-SCLC) cells, which lack the neuroendocrine expression of classic (c-) SCLC cells. In this study spontaneously adherent SCLC sublines were shown by differential gene expression analysis to provide an in vitro model of variant differentiation in SCLC, with down-regulation of neuroendocrine markers and up-regulation of epithelial differentiation markers cyclin D1, endothelin, the cell adhesion molecules CD 44 and integrin subunits alpha2, beta3 and beta4. The sensitivity of adherent SCLC sublines to etoposide, cyclophosphamide and gamma radiation was significantly diminished relative to parent suspension cell lines. Western blot analysis using phosphorylation-specific antibodies to Akt and MAP kinase revealed markedly elevated activation in adherent SCLC sublines, paralleled by increased levels of phosphorylated Bad protein and activated NF-kappaB. Subcultivation of the adherent sublines on uncoated surfaces reversed their adherent phenotype immediately and under these conditions Akt activity reverted to low levels. These results suggest that c-SCLC cells can differentiate spontaneously to v-SCLC and that the associated cellular adhesion may trigger Akt-dependent inhibition of apoptosis in SCLC cells, thus leading to acquired chemo- and radio-resistance.

[The effectiveness of radiation treatment in comparison with extracorporeal shockwave therapy (ESWT) in supraspinatus tendon syndrome]. / Die Wertigkeit der Strahlenbehandlung im Vergleich zur extrakorporalen Stosswellentherapie (ESWT) beim Supraspinatussehnensyndrom.

BACKGROUND AND AIM: Supraspinatus tendinitis is usually treated by antiinflammatoric drugs, local injections, physiotherapy or low-dose irradiation. A novel approach is the use of Extracorporeal Shock Wave Therapy (ESWT) if conservative therapies have failed. So far there has been no controlled study comparing the effectiveness of ESWT with an established conservative method of therapy such as X-ray stimulation radiotherapy. PATIENTS AND METHOD: 30 patients with chronic supraspinatus tendinitis were admitted into the prospective randomized study. After randomization the patients were treated either with X-ray stimulation radiotherapy with 6 x 0.5 Gy on the ICRU reference point (1 fraction/day) with cobalt 60 gamma rays or three times with 2000 pulses (energy flux density ED+ 0.1 mJ/mm2) in 1 week intervals using a Storz Minilith SL1. Primary endpoint was the age-corrected constant score 3 months after intervention. RESULTS: Acute side effects caused by the irradiation were not observed, as expected. One patient described pain and one patient showed a moderate skin irritation after ESWT. In the radiotherapy group average the age-corrected constant score improved from 47.6 through 79.5 points to 87.4 points. In the ESWT group it rose from 50.1 points before ESWT to 91.4 points after 12 weeks and 97.8 after 52 weeks. CONCLUSION: No statistically significant differences were proven between ESWT and radiotherapy. ESWT appears to be equivalent but not superior to radiotherapy in treating chronic supraspinatus tendinitis syndrome. A comprehensive randomized study is, however, necessary to ensure the equivalence of ESWT.

[Precision of conventional simulation: which extent of accuracy is reachable in head and neck region?]. / Präzision der konventionellen Simulation: Welche Genauigkeit ist im Kopf-Hals-Bereich möglich?

PURPOSE: In this prospective investigation we tested the absolute accuracy of a conventional localization of the isocenter obtained from a three-dimensional treatment plan in conformal radiotherapy of head and neck tumors. PATIENTS AND METHODS: 41 isocenters in 41 consecutive patients with histologically proven tumors of the brain or head and neck region were included into this investigation. In all cases a stereotactic mask (Stryker-Leibinger) was made for fixation and positioning of the patients. The stereotactically guided fractionated radiotherapy was carried out on the base of CT and MRI. The stereotactic coordinates were defined by an external localization system. Afterwards each patient underwent a conventional simulation using exclusively anatomical reference points. Additionally, the patients were adjusted to the linac isocenter using a stereotactic targeting device. Deviations between the simulated and the external adjusted target point coordinates were recorded in X-, Y- and Z-direction and spatial error was calculated. RESULTS: Mean deviation was 2.15, 2.54, and 2.69 mm for X-, Y-, and Z-direction, respectively. The largest deviation was found in Z-direction with a maximum of over 11 mm. The spatial deviation per patient amounted 1.3-12.2 mm with a mean of 5.1 and a median value of 4.5 mm. That means that in half of the cases a deviation of 5 up to over 12 mm occurs in conventional simulation. Only in a quarter of the sample the deviation was 4 mm or below. CONCLUSION: The planning target volume definition requires a consideration of the inaccuracy of the conventional simulation. A reduction of the safety margin in the planning target volume assumes the use of the stereotactic target positioner. This is to postulate especially for the treatment of benign lesions or lesions or lesions adjacent to critical structures.