Validation of the Decipher genomic classifier in patients receiving salvage radiotherapy without hormone therapy after radical prostatectomy - an ancillary study of the SAKK 09/10 randomized clinical trial.

BACKGROUND: The Decipher genomic classifier (GC) has shown to independently prognosticate outcomes in prostate cancer. The objective of this study was to validate the GC in a randomized phase III trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy. PATIENTS AND METHODS: A clinical-grade whole-transcriptome assay was carried out on radical prostatectomy samples obtained from patients enrolled in Swiss Group for Clinical Cancer Research (SAKK) 09/10, a phase III trial of 350 men with biochemical recurrence after radical prostatectomy randomized to 64 Gy versus 70 Gy without concurrent hormonal therapy or pelvic nodal RT. A prespecified statistical plan was developed to assess the impact of the GC on clinical outcomes. The primary endpoint was biochemical progression; secondary endpoints were clinical progression and time to hormone therapy. Multivariable analyses adjusted for age, T-category, Gleason score, postradical prostatectomy persistent prostate-specific antigen (PSA), PSA at randomization, and randomization arm were conducted, accounting for competing risks. RESULTS: The analytic cohort of 226 patients was representative of the overall trial, with a median follow-up of 6.3 years (interquartile range 6.1-7.2 years). The GC (high versus low-intermediate) was independently associated with biochemical progression [subdistribution hazard ratio (sHR) 2.26, 95% confidence interval (CI) 1.42-3.60; P < 0.001], clinical progression (HR 2.29, 95% CI 1.32-3.98; P = 0.003), and use of hormone therapy (sHR 2.99, 95% CI 1.55-5.76; P = 0.001). GC high patients had a 5-year freedom from biochemical progression of 45% versus 71% for GC low-intermediate. Dose escalation did not benefit the overall cohort, nor patients with lower versus higher GC scores. CONCLUSIONS: This study represents the first contemporary randomized controlled trial in patients treated with early SRT without concurrent hormone therapy or pelvic nodal RT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and RT dose, high-GC patients were more than twice as likely than lower-GC patients to experience biochemical and clinical progression and receive of salvage hormone therapy. These data confirm the clinical value of Decipher GC to personalize the use of concurrent systemic therapy in the postoperative salvage setting.

Systemic serum amyloid A in early (<24 h) diagnosis of acute synovial structure involvement in horses with penetrating limb injuries.

Synovial structure involvement secondary to limb injury is a common emergency in equine practice, requiring an accurate initial diagnosis for immediate treatment. This study aimed to investigate the clinical usefulness of Serum amyloid A (SAA) in the initial diagnosis of synovial structure involvement caused by acute (<24 h) penetrating limb injuries in horses and to correlate SAA with standard diagnostic parameters. Fifty-five horses with acute limb injuries were divided into two groups: Group 1 (G1, n = 26) with a diagnosis of penetrating synovial trauma and Group 2 (G2, n = 29) without synovial structure penetration. Serum SAA, white blood cell (WBC) count and fibrinogen as well as clinical criteria and synovial fluid parameters were assessed on admission. The two groups were compared using a two-sample t-test (metric parameters) or a Wilcoxon-Mann-Whitney test (ordinal parameters). Correlation was determined between serum SAA and the following parameters: WBC count, fibrinogen, synovial total nucleated cell count (TNCC) and percentage of neutrophils (% N), body temperature and the degree of lameness. Serum SAA concentrations were not different between G1 and G2; however, there were statistically significant differences in general health, the degree of lameness, and synovial fluid parameters. In G1, serum SAA concentrations positively correlated with fibrinogen concentrations and synovial fluid % N. Nonetheless, SAA cannot be used as a sole tool to diagnose synovial structure involvement caused by limb injuries. Synovial fluid parameters remain the most important tool in the diagnosis of synovial penetration. In cases where synoviocentesis fails or is not possible, serum SAA might support diagnosis.

Influence of localization of PSMA-positive oligo-metastases on efficacy of metastasis-directed external-beam radiotherapy-a multicenter retrospective study.

PURPOSE: Approximately 40-70% of biochemically persistent or recurrent prostate cancer (PCa) patients after radical prostatectomy (RPE) are oligo-metastatic in 68gallium-prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET). Those lesions are frequently located outside the prostate bed, and therefore not cured by the current standards of care like external-beam radiotherapy (EBRT) of the prostatic fossa. This retrospective study analyzes the influence of oligo-metastases' site on outcome after metastasis-directed radiotherapy (MDR). METHODS: Retrospectively, 359 patients with PET-positive PCa recurrences after RPE were analyzed. Biochemical recurrence-free survival (BRFS) (prostate-specific antigen (PSA) < post-radiotherapy nadir + 0.2 ng/mL) was assessed using Kaplan-Meier survival and Cox regression analysis. RESULTS: All patients were initially clinically without distant metastases (cM0). Seventy-five patients had local recurrence within the prostatic fossa, 32 patients had pelvic nodal plus local recurrence, 117 patients had pelvic nodal recurrence, 51 patients had paraaortic lymph node metastases with/without locoregional recurrence, and 84 patients had bone or visceral metastases with/without locoregional recurrence. Median PSA before MDR was 1.2 ng/mL (range, 0.04-47.5). Additive androgen deprivation therapy (ADT) was given in 35% (125/359) of patients. Median PSA nadir after MDR was 0.23 ng/mL (range, < 0.03-18.30). After a median follow-up of 16 months (1-57), 239/351 (68%) patients had no biochemical recurrence. Patients with distant lymph node and/or distant metastases, the so-called oligo-body cohort, had an overall in-field control of 90/98 (91%) but at the same time, an ex-field progress of 44/96 (46%). In comparison, an ex-field progress was detected in 28/154 (18%) patients with local and/or pelvic nodal recurrence (oligo-pelvis group). Compared with the oligo-pelvis group, there was a significantly lower BRFS in oligo-body patients at the last follow-up. CONCLUSION: Overall, BRFS was dependent on patterns of metastatic disease. Thus, MDR of PSMA PET-positive oligo-metastases can be offered considering that about one-third of the patients progressed within a median follow-up of 16 months.

68Ga-PSMA-PET/CT-directed IGRT/SBRT for oligometastases of recurrent prostate cancer after initial surgery.

Background: We evaluated efficacy and toxicity of 68Ga-PSMA-Positron Emission Tomography/Computed Tomography (PET/CT)-directed stereotactic body radiotherapy and image-guided radiotherapy (SBRT/IGRT) for oligometastases of prostate cancer recurrences after previous surgery.Methods: Nineteen patients were analyzed within a prospective PET-registry study (064/2013BO1) and retrospectively analyzed (807/2017BO2) fulfilling the following inclusion criteria: biochemical recurrence after radical prostatectomy, ≤five 68Ga-PSMA-PET/CT positive lesions. Biochemical control was evaluated with EORTC (European Organization for Research and Treatment of Cancer)- and Phenix-definitions. Toxicity was scored according to CTCAE-criteria v. 4.03.Results: A total of 38 oligometastases (19 patients, 2 with re-treatment) were treated with SBRT/IGRT from October 2014 to July 2017. 68Ga-PSMA-PET/CT-positive lesions were detected on average 39 months (5-139) after prostatectomy (pT2b-3b pN0-1 cM0). Mean PSA (Prostate-specific antigen)-level at time of imaging reached 2.2 ng/mL (range 0.2-10.1). PET/CT-positive lesions were treated with different fractionation schedules reaching biological equivalent doses (BED) of 116.7-230.0 Gy. Concomitant androgen deprivation therapy (ADT) was given in seven patients. After a median follow-up of 17 months (4-42) all patients were alive. Estimated 1-year PSA- control (n = 19) reached 80.8% (Phenix) and 67.5% (EORTC). A PSA-decline (≥50%) was detected in 16/19 patients after radiotherapy. Higher graded G3+-acute toxicity did not occur. Temporary late G3-proctitis was detected in one patient.Conclusions: Reaching of nadir ≤0.1 or 0.2 ng/mL was associated by improved DMFS (distant metastases free survival) and could serve as a surrogate endpoint for RT of oligometastases after initial prostatectomy. Short term effects of 68Ga-PSMA-PET/CT-based ablative radiotherapy for oligometastases demonstrated an acceptable toxicity profile and favorable biochemical response.

Precision of T2 TSE MRI-CT-image fusions based on gold fiducials and repetitive T2 TSE MRI-MRI-fusions for adaptive IGRT of prostate cancer by using phantom and patient data.

INTRODUCTION: To increase precision of radiation treatment (RT) delivery in prostate cancer, MRI-based RT as well as the use of fiducials like gold markers (GMs) have shown promising results. Their combined use is currently under investigation in clinical trials. Here, we aimed to evaluate a workflow of image registration based on GMs between CT and MRI as well as weekly MRI-MRI adaption based on T2 TSE sequence. MATERIAL AND METHODS: A gel-phantom with two inserted GMs was scanned with CT and three different MR-scanners of 1.5 and 3 T (T2 TSE and T1 VIBE-Dixon, isotropic, voxel size 2 × 2 × 2 mm). After image fusion, deviations for fiducial and gel match were measured and artifacts were evaluated. Additionally, CT-MRI-match deviations and MRI-MRI-match deviations of 10 Patients from the M-basePro study using GMs were assessed. RESULTS: GMs were visible in all imaging modalities. The outer gel contours were matched with <1 mm deviation, contour volumes varied between 0 and 1%. The deviations of the GMs were less than 2 mm in any direction of MRI/CT. Shifts of peripherally or centrally located GMs were randomly distributed. The average MRI-CT-match precision of 10 patients with GMs was 1.9 mm (range 1.1-3.1 mm). CONCLUSIONS: Match inaccuracies for GMs between reference CT and voxel-isotropic T2-TSE sequences are small. Spatial deviations of CT- and MR-contoured fiducials were less than 2 mm, i.e., below SLT of the applied modalities. In patients, the average CT-MRI-match precision for GMs was 1.9 mm supporting their use in MR-guided high precision RT.

A slow-cycling subpopulation of melanoma cells with highly invasive properties.

Melanoma is a heterogeneous tumor with different subpopulations showing different proliferation rates. Slow-cycling cells were previously identified in melanoma, but not fully biologically characterized. Using the label-retention method, we identified a subpopulation of slow-cycling cells, defined as label-retaining cells (LRC), with strong invasive properties. We demonstrate through live imaging that LRC are leaving the primary tumor mass at a very early stage and disseminate to peripheral organs. Through global proteome analyses, we identified the secreted protein SerpinE2/protease nexin-1 as causative for the highly invasive potential of LRC in melanomas.

Laparoscopic pelvic mesh placement with closure of pelvic floor entrance to prevent small intestine radiation trauma - A retrospective cohort analysis.

BACKGROUND: In most pelvic malignancies radiation therapy is a main part of the treatment concept. The main dose limiting organ is the small intestine. Different mechanical methods to prevent radiation damage to the small intestine have been described. We herein report a retrospective study of laparoscopic placement of an absorbable vicryl mesh in patients requiring pelvic radiotherapy displacing the bowel out of the radiation field. PATIENTS/METHODS: The study included 6 consecutive patients requiring definitive radiotherapy due to locally advanced prostate cancer. All patients had small intestine within the radiation fields despite the use of non-invasive displacement methods. RESULTS: All patients underwent laparoscopic small bowel displacement from the pelvis and closure of the pelvic floor entrance using vicryl mesh placement. Peri- or postoperative complications were not seen. Postoperative radiotherapy planning CT scans confirmed displacement of the small intestine allowing all patients to receive the planned radiotherapy volume. CONCLUSION: Laparoscopic mesh placement represents a safe and efficient procedure in patients requiring high-dose pelvic radiation, presenting with unacceptable small intestine volume in the radiation field. As an alternate to native tissue, the vicryl mesh is a safe, effective substitute for small bowel exclusion from external-beam radiation therapy.

A chemical biology approach identifies AMPK as a modulator of melanoma oncogene MITF.

The microphthalmia-associated transcription factor (MITF) is indispensable for the viability of melanocytic cells, is an oncogene in melanoma and has a cell type-specific expression pattern. As the modulation of MITF activity by direct chemical targeting remains a challenge, we assessed a panel of drugs for their ability to downregulate MITF expression or activity by targeting its upstream modulators. We found that the multi-kinase inhibitors midostaurin and sunitinib downregulate MITF protein levels. To identify the target molecules shared by both the drugs in melanocytic cells, a chemical proteomic approach was applied and AMP-activated kinase (AMPK) was identified as the relevant target for the observed phenotype. RNA interference and chemical inhibition of AMPK led to a decrease in MITF protein levels. Reduction of MITF protein levels was the result of proteasomal degradation, which was preceded by enhanced phosphorylation of MITF mediated by ERK. As expected, downregulation of MITF protein levels by AMPK inhibition was associated with decreased viability. Together, these results identify AMPK as an important regulator for the maintenance of MITF protein levels in melanocytic cells.

Effect of concurrent chemotherapy and hyperthermia on outcome of preoperative radiotherapy of high-risk soft tissue sarcomas.

BACKGROUND AND PURPOSE: As treatment results for high-risk soft tissue sarcoma are still disappointing, treatment intensification is warranted. We performed a retrospective analysis of multimodal preoperative treatment to evaluate the additional effect of concurrent chemotherapy and/or locoregional hyperthermia in comparison to radiotherapy alone. PATIENTS AND METHODS: Between 1999 and 2011, 28 patients were treated with neoadjuvant radiotherapy to a median 45 Gy for high-risk soft tissue sarcoma. All tumors were deep-seated and grade 2 or 3, 86% (n = 24) larger than 5 cm. Multimodal treatment (n = 12) consisted of ifosfamide (n = 7), locoregional hyperthermia (n = 3), or both modalities (n = 2) concurrent to radiotherapy. RESULTS: Prognostic factors (grade, size, histology, location) were balanced in the groups with and without concurrent multimodal treatment. There was a significant improvement of disease-specific survival (100% vs. 70% at 3 years, p = 0.03) with multimodal treatment. Distant metastases-free survival was influenced, but was not statistically significant. Local control and disease-free survival did not differ in the two groups. CONCLUSION: Our data suggest that multimodal treatment with ifosfamide and/or locoregional hyperthermia in combination with neoadjuvant radiotherapy might improve outcome in high-risk soft tissue sarcomas.

Toxicity and outcome of pelvic IMRT for node-positive prostate cancer.

BACKGROUND AND PURPOSE: This study reports on the treatment techniques, toxicity, and outcome of pelvic intensity-modulated radiotherapy (IMRT) for lymph node-positive prostate cancer (LNPPC, T1-4, c/pN1 cM0). PATIENTS AND METHODS: Pelvic IMRT to 45-50.4 Gy was applied in 39 cases either after previous surgery of involved lymph nodes (n = 18) or with a radiation boost to suspicious nodes (n = 21) with doses of 60-70 Gy, usually combined with androgen deprivation (n = 37). The prostate and seminal vesicles received 70-74 Gy. In cases of previous prostatectomy, prostatic fossa and remnants of seminal vesicles were given 66-70 Gy. Treatment-related acute and late toxicity was graded according to the RTOG criteria. RESULTS: Acute radiation-related toxicity higher than grade 2 occurred in 2 patients (with the need for urinary catheter/subileus related to adhesions after surgery). Late toxicity was mild (grade 1-2) after a median follow-up of 70 months. Over 50% of the patients reported no late morbidity (grade 0). PSA control and cancer-specific survival reached 67% and 97% at over 5 years. CONCLUSION: Pelvic IMRT after the removal of affected nodes or with a radiation boost to clinically positive nodes led to an acceptable late toxicity (no grade 3/4 events), thus justifying further evaluation of this approach in a larger cohort.

Are there biologic differences between male and female breast cancer explaining inferior outcome of men despite equal stage and treatment?!

BACKGROUND: Reasons for inferior outcome of male compared to female breast cancer are still under debate. Therefore, we retrospectively analyzed male breast cancer cases to figure out possible treatment- and gender-related differences. PATIENTS AND METHODS: A total of 40 men (median age 62 years) were curatively treated with mastectomy and postoperative radiotherapy from 1982-2007. They presented predominantly in stages II and IIIb. Postoperative radiotherapy was applied with doses of 1.8-2.5 Gy to a median of 50 Gy including regional lymphatics in 22 patients. Adjuvant systemic treatment consisted of chemotherapy (22.5%) and antihormonal treatment (55%). For reasons of comparison, we estimated outcome of a virtual female matched cohort for no/equal to men/optimal adjuvant treatment with the Adjuvant!Online(®) 8.0 algorithm. RESULTS: After a median follow-up of 47 months, the estimated 5-year local control rate was 97%, disease-free and distant metastasis-free survival rates reached 79% and 82%, respectively. With update of survival data by tumor registry, mean overall survival reached 120 months with 5- and 10-year overall survival rates of 66% and 43%, respectively. Predominant prognostic factor was T-stage for overall survival (T1/2 vs. T4: > 80% vs. 30%). The generated virtual matched cohorts of women with equal characteristics reached superior 10-year-overall survival for no/equal to men/optimal adjuvant treatment with 55/59/68%. CONCLUSION: Compared to historical and virtual matched cohorts of women, male breast cancer patients had inferior outcome despite of equal stage and treatment which indicates that biological differences (of tumor or population) may contribute to worse prognosis.

Cerebral metastases in extrapulmonary cell carcinoma. Implications for the use of prophylactic cranial irradiation.

BACKGROUND AND PURPOSE: Extrapulmonary small cell carcinoma (EPSCC) is a rare disease. Standard treatment is performed in analogy to small cell lung cancer; however, due to the differences in rates of cerebral metastases (CM), prophylactic cranial irradiation (PCI) is not routinely used. Therefore, we evaluated the characteristics of all patients developing brain metastases in a population of EPSCC patients and calculated a number needed to treat (NNT) for the prevention of cerebral metastases by PCI. PATIENTS, METHODS, AND RESULTS: Of 51 patients treated at our institution from 1999-2011 for EPSCC, 11 presented with CM, 5 at initial diagnosis, 6 in the course of their disease. Median overall survival after primary diagnosis of EPSCC was 12 months. Overall survival after diagnosis of CM was significantly in favor of primarily cerebrally metastasized patients with 9 compared to 2 months for secondary CM (p = 0.04), median survival for all patients being 4 months. The NNT calculation was based on the 6 patients with secondary brain metastases in our series and a relative risk reduction of 60% observed in the studies of PCI for small cell lung cancer (SCLC), resulting in an NNT of 13. CONCLUSION: Although the frequency of brain metastases in EPSCC was lower than in SCLC, the NNT of 13 for the prevention of CM, as well as the poor median survival after diagnosis of secondary brain metastases of 2 months might be a reason to discuss and evaluate PCI for EPSCC patients responding to initial therapy.

Limited disease of extra-pulmonary small cell carcinoma. Impact of local treatment and nodal status, role of cranial irradiation.

PURPOSE: As extra-pulmonary small cell carcinoma (EPSCC) is a rare entity of tumors, the available treatment recommendations are mainly based on retrospective analyses and deduction from treatment of small cell lung cancer. The aim of this study was to provide a detailed analysis concerning prognostic factors and treatment modalities. PATIENTS AND METHODS: A total of 20 patients with limited disease (LD) of EPSCC treated at our institution from 1999­2009 were retrospectively analyzed. Data were gathered from chart review. Localization, lymph node involvement, as well as local and systemic treatment were documented and their impact on pattern of failure and survival times statistically evaluated. RESULTS: With a median follow-up of 21 months, the estimated median overall- and disease-free survival were 59 and 25 months, respectively. Local control was excellent with 100% at 2 years. Nodal involvement was observed in 74% (n = 14/19) of evaluable patients. However, outcome was not altered by this parameter. Local treatment consisted of surgery in 10 cases, radiotherapy in 7 cases, and a combination of both in 3 cases. Only 3 patients (15%) developed hematogenous central nervous system metastases, while none of the patients received prophylactic cranial irradiation. CONCLUSION: Nodal involvement did not worsen prognosis. Local control was excellent irrespective of local treatment modality and the leading cause of failure was distant metastasis. Therefore, systemic treatment should not be omitted. Prophylactic cranial irradiation might be dispensable but discussed for head and neck malignancies.

Outcome after whole brain radiotherapy alone in intracranial leptomeningeal carcinomatosis from solid tumors.

BACKGROUND: The purpose of the present study was to investigate outcome after whole brain radiotherapy (WBRT) alone as a palliative treatment without concomitant chemotherapy for intracranial leptomeningeal carcinomatosis (LMC). PATIENTS AND METHODS: Overall survival and treatment response were retrospectively analyzed in 27 consecutive patients with LMC from breast and lung cancer. All patients had evidence of intracranial manifestations of LMC. Seven potential prognostic factors were evaluated. RESULTS: Median overall survival (OS) for the entire group was 8.1 weeks. OS rates after 6 and 12 months were 26% and 15%, respectively. Improvement of neurological deficits was observed in 3 patients. In 3 of 4 patients with follow-up MRI studies, a decreased size of contrast-enhanced lesions was observed. Prognostic factors for improved OS on univariate analysis were absence of cranial nerve dysfunction, Karnofsky Performance Score (KPS) > 60%, and time interval > 35 months between the initial diagnosis of malignant disease and development of LMC. On multivariate analysis, absence of cranial nerve dysfunction remained the only significant prognosticator for OS (median 3.7 vs. 19.4 weeks, p < 0.001). CONCLUSION: WBRT alone is an effective palliative treatment for patients unfit/unsuitable for chemotherapy and low performance status suffering from intracranial LMC. However, prognostic factors should be considered in order to identify patients who are likely to benefit from WBRT.

Aciclovir protects against quinolinic-acid-induced oxidative neurotoxicity.

AIDS-related encephalopathy, including AIDS dementia complex (ADC) and the opportunistic disease, herpes simplex encephalitis (HSE), are postulated to arise due to the release of neurotoxic products, such as quinolinic acid (QUIN), by activated microglial cells in the brain. QUIN causes a cascade of events to occur, which leads to the production of reactive oxygen species (ROS), these being ultimately responsible for oxidative neurotoxicity. The antiherpes antiviral aciclovir has been reported to protect against neuron loss in HSE, but the mechanism for this neuroprotection is unknown. Therefore, this study was conducted to investigate whether aciclovir has the ability to inhibit QUIN-induced lipid peroxidation in rat brain homogenates, after in-vitro and in-vivo exposure to QUIN and aciclovir. The thiobarbituric acid (TBA) assay was the method used to analyse lipid peroxidation. Rat brains were also examined histologically after in-vivo exposure to visually assess whether neuron loss was suppressed. The results show that aciclovir inhibits the QUIN-induced lipid peroxidation, in a dose-dependent manner. Furthermore, aciclovir reduced necrosis of hippocampal neurons and retained the characteristic morphology, integrity and arrangement of these cells. Thus, it appears that aciclovir has neuroprotective properties, which could possibly be useful in the treatment of AIDS-related encephalopathy.

[Radiotherapy of eye and orbit tumors]. / Radiotherapie von Augen- und Orbitatumoren.

Malignant diseases of the orbit are multifaceted and require in the majority of the cases an interdisciplinary treatment. Advances in radiotherapy, surgery and chemotherapy make a high cure rate possible, especially in children's tumors. In adults these tumors reach a tumor control rate of nearly 90 %, even with preservation of the eye in most of the cases. There are only two curative therapy options for tumors in this region: radiotherapy and surgery. The therapy for tumors of the eye and the orbit require the total spectrum of the radiotherapeutic techniques depending on the tumor entity, its spread and localization. In a prevailing number of malignant tumors (tumors of the eyelids, tear glands, orbit, metastases) the application of the radiotherapy as an external, fractionated radiotherapy is standard practice, if necessary in combination with operation and/or chemotherapy. Particularly in the therapy for ocular tumors brachytherapy with radionuclides (e. g., ruthenium) is possible and in a few centers world-wide proton therapy is available. As an alternative procedure in special modalities, stereotactic radiotherapy may be considered. Altogether the new radiotherapy techniques permit a dose increase in the tumor region and/or a reduction of the doses to healthy tissues and lead so to a better local tumor control rate and a decrease in acute and chronic side effects.

[Radiotherapy for Graves' ophthalmopathy]. / Radiotherapie der endokrinen Orbitopathie.

Graves' ophthalmopathy (GO) is the most frequent extrathyroidal manifestation of Graves' disease, an autoimmune disorder of the thyroid, whereas the precise pathogenesis still remains unclear. In Hashimoto's thyroiditis the occurrence of proptosis is an extremely rare event. The therapy for middle and severe courses of GO shows in partly disappointing results, although several therapy modalities are possible (glucocorticoid therapy, radiotherapy, antithyroid drug treatment, surgery). All these therapies lead in only 40 - 70 % to an improvement of the pathogenic symptoms. An intensive interdisciplinary cooperation is necessary to satisfy the requirements for the treatment of Graves' ophthalmopathy. As a consequence of the very different results of the few of clinical studies that were accomplished with reference to this topic, treatment by radiotherapy in the management of the disease is presently controversially discussed. In the German-speaking countries the radiotherapy is, however, firmly established as a therapy option in the treatment of the moderate disease classes (class 2-5 according to NO SPECS), especially if diplopia is present. This article describes the sequences, dosages and fractionation schemes as well as the risks and side effects of the radiotherapy. Altogether, radiotherapy is assessed as an effective and sure method. The administration of glucocorticoids can take place before the beginning of or during the radiotherapy. For the success of treatment the correct selection of patients who may possibly profit from a radiotherapy is absolutely essential. By realising that GO proceeds normally over a period of 2-5 years, which is followed by a period of fibrotic alteration, the application of the radiotherapy in the early, active phase is indispensable. A precise explanation for the effects of radiotherapy in treatment of the GO does not exist at present. The determination of the most effective irradiation doses was made from retrospectively evaluated collectives. Recently the results of a national survey of all German RT departments were published, initiated by the working group of the DEGRO (German Society of Radiooncology). In the most of the German radiooncology departments irradiation with 8 to 10 x 1.8-2.0 Gy 5 x weekly to 16 or 20 Gy is standard. Two recently published prospective German studies pointed out the equivalence of the effectiveness of a short therapy in low dose ranges up to 2.4 Gy as well as of a low proportioned irradiation during a longer period in relation to a standard therapy with 20 Gy. That is why at the moment it is not possible to give a definite recommendation with reference to dosages or the fractionation schemes. In 2003 the first European group (European Group on Graves ' Orbitopathy Experience -- EUGOGO) was founded for pursuing investigations of GO in multi-centric studies, mainly to improve therapy results.

Intermittent use of amifostine during postoperative radiochemotherapy and acute toxicity in rectal cancer patients.

PURPOSE: Amifostine has been shown to be able to reduce acute radiation toxicity if administered daily prior to radiation during a course of a conventionally fractionated radiotherapy. A disadvantage is the necessity of daily intravenous injection. We have used amifostin in patients undergoing adjuvant radiochemotherapy for rectal cancer. Amifostine was administered only in the first and fifth week of radiotherapy together with 5-FU chemotherapy. The objective was to determine whether the intermittent use of amifostine may be effective in reducing acute radiation toxicity. PATIENTS AND METHODS: From September 1997 through October 1998, 30 patients with stage II/III rectal cancer underwent postoperative radiochemotherapy at our department. All patients had undergone curative (R0) resection and received 50.4 Gy to the pelvis with a 3-field technique using a belly board followed by a boost of 5.4 Gy to the presacral space in conventional fractionation with 1.8 Gy per fraction. 5-FU chemotherapy was administered as 120-hours continuous infusion in the first and fifth radiation week via a central venous catheter in a daily dosage of 1,000 mg/m2. All patients were offered to participate in a phase-II study using additional amifostine. Fifteen patients participated and received 500 mg amifostine daily on chemotherapy days (days 1 to 5 and 29 to 33) immediately prior to the daily radiation fraction. Fifteen patients did not participate and served as non-randomized control. The study was approved by the ethical committee of the Martin-Luther-University and informed consent was obtained from all patients. RESULTS: The distribution of patients' characteristics and prognostic parameters was comparable in both groups. Side effects of amifostine were mild and included hypotension (53% grade I, 7% grade II) and nausea (47% grade I, 13% grade II). Antiemetics were not routinely used. All patients completed radiochemotherapy plus amifostine without unplanned breaks or dose reductions. One patient developed a cerebral infarction which was considered to be not related to the use of amifostine. As compared to the non-randomized control group, patients with additional amifostine had less acute skin and bowel toxicity (maximum erythema score 1.47 +/- 0.64 without vs 0.87 +/- 0.52 with amifostine, p = 0.009 and maximum diarrhea score 1.07 +/- 1.03 vs 0.40 +/- 0.63, p = 0.044). Oral 5-FU-related mucositis and hematological toxicity were not significantly different. CONCLUSIONS: In this phase-II study, amifostine significantly reduced acute skin and bowel toxicity of adjuvant chemoradiation in patients with rectal cancer even if the drug was administered only intermittently and not during the whole course of radiotherapy. This finding might be important with regard to intense combined regimes and should be further investigated.