Brain metastases (BM) are frequently diagnosed in patients with HER-2-positive metastatic breast cancer; in addition, an increasing incidence was reported for triple-negative tumours. We aimed to compare brain metastases free survival (BMFS) of breast cancer subtypes in patients treated between 1996 until 2010. Brain metastases free survival was measured as the interval from diagnosis of extracranial breast cancer metastases until diagnosis of BM. HER-2 status was analysed by immunohistochemistry and reanalysed by fluorescent in situ hybridisation if a score of 2+ was gained. Oestrogen-receptor (ER) and progesterone-receptor (PgR) status was analysed by immunohistochemistry. Brain metastases free survival curves were estimated with the Kaplan–Meier method and compared with the log-rank test. Data of 213 patients (46 luminal/124 HER-2/43 triple-negative subtype) with BM from breast cancer were available for the analysis. Brain metastases free survival differed significantly between breast cancer subtypes. Median BMFS in triple-negative tumours was 14 months (95% CI: 11.34–16.66) compared with 18 months (95% CI: 14.46–21.54) in HER-2-positive tumours (P=0.001) and 34 months (95% CI: 23.71–44.29) in luminal tumours (P=0.001), respectively. In HER-2-positive patients, co-positivity for ER and HER-2 prolonged BMFS (26 vs 15 m; P=0.033); in luminal tumours, co-expression of ER and PgR was not significantly associated with BMFS. Brain metastases free survival in patients with lung metastases was significantly shorter (17 vs 21 months; P=0.014). Brain metastases free survival in triple-negative breast cancer, as well as in HER-2-positive/ER-negative, is significantly shorter compared with HER-2/ER co-positive or luminal tumours, mirroring the aggressiveness of these breast cancer subtypes.

The prognosis for patients suffering from malignant gliomas remains dismal. We report on 10 patients with recurring or progressing high-grade gliomas who were treated at our institution with Bevacizumab alone or in combination with cytostatic drugs over the last 2 years. The survival time from the start of the VEGFR antibody therapy on average was 18 weeks (10–30 weeks) and after Avastin was discontinued patients lived an average of 7 weeks (1–14 weeks). The above results support further studies of this very promising drug in the form of randomized studies of malignant glioma. In the primary therapy concept and in the case of recurrence the best combination Bevacizumab with cytostatics, radiation therapy or other targeted therapies have to be clarified.

1076 Background: Since the introduction of trastuzumab (T), different groups reported an increased incidence of brain metastases (BM) in patients (pts) with HER2-positive breast cancer (BC), although one centre published contradicting results. Usually, this is attributed to prolonged survival, in association with the inability of antibodies to pass the blood-brain-barrier. Furthermore, based on preclinical data, it was suggested that HER2-positive BC had an increased affinity to brain tissue. We investigated which factors were potentially associated with shorter time to development of BM. Methods: One hundred ninety-four pts with BM from BC were identified at two Austrian centres. All received whole brain radiotherapy (WBRT) of 30 Gy with or without boost irradiation or surgical resection. All pt data concerning epidemiology, histology, and outcome is available. A multivariate analysis (Cox regression) was performed to identify factors (age, grading, ER/PgR-status, HER2-status, tumour stage at diagnosis, lung metastases, liver metastases, T before diagnosis of BM) significantly associated with shorter time to development of BM. Results: Median age was 55 years (y), range 28 - 81 y, and time to development of BM was 29 months (m), range 2 - 254 m, 95% CI 22.97–35.03. Overall survival following WBRT was 7 m, range 1 - 83 m, 95% CI 5.08–8.92. The following factors predicted shorter time to development of BM: negative endocrine receptor status (p=0.026), HER2-positive disease (p=0.003), stage IV disease at first presentation (p<0.001), and lung metastases (p=0.043). Conclusions: Risk factors associated with increased incidence of BM have been described: ER/PgR-negative, HER2-positive disease, high grade, and lung metastases. Some groups reported an increase in pts on T. Our data show that HER2-positive BC is significantly associated with shorter time to development of BM, while no influence of T treatment was observed. These results underline preclinical data suggesting a higher affinity of HER2-positive BC to the brain. T, on the other hand, had no prophylactic effect. Therefore, trials evaluating the combination of T with substances able to penetrate into the brain are warranted in this population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Pfizer, sanofi-aventis Amgen

AIMS:In patients with early breast cancer sentinel node biopsy (SNB) proved to be an accurate procedure for axillary staging with significantly reduced morbidity. Medium- and long-term observational studies are needed to establish, whether SNB alone is able to prevent locoregional recurrence without impairing long-term survival. METHODS:298 patients with invasive breast cancer were subjected to SNB in a prospective audit. Lymphatic mapping was performed with blue dye and radiocolloids. 180 patients had SNB alone (group 1), while 118 subsequently underwent axillary dissection (AD; group 2). In ten patients AD was omitted despite the tumor burden in the SN. Clinical follow-up studies were performed at regular intervals. The mean follow-up time was 47months in group 1 (range 7-90) and 46months in group two (range 1-87months). RESULTS:Sentinel nodes were identified in 286 out of 298 patients (96%). One patient in group 1 developed axillary and simultaneous supraclavicular lymph node recurrence. After AD regional relapses have so far not been observed. One ipsilateral local recurrence was detected in each group. Five patients in group 1 and 15 patients in group 2 developed distant metastases. Three out of six and eight out of nine patients, respectively, died of their advanced disease. All patients with SN tumor infiltration not subjected to AD are alive and well. CONCLUSIONS:Axillary recurrence is rare after sentinel node biopsy alone. Its rate is comparable to that after AD, even in patients with SN micrometastases. These conclusions are confirmed by reports in the literature.

OBJECTIVESLittle is known about the radiation sensitivity of bile duct carcinomas. The current study was undertaken to prospectively assess the objective response rates in bile duct carcinomas treated with radiotherapy and razoxane.MATERIALS AND METHODSTwenty-three patients with advanced cancer of the biliary tree were irradiated together with the radiosensitizer razoxane at a dose of 125 mg twice daily by mouth. There were 16 females and 7 males, median age 68 years. They received a total tumor dose of 48 Gy (range 1.7-60) at the ICRU point with single fractions of 1.7 to 2 Gy.RESULTSAmong the 23 patients, 14 had measurable disease. Objective tumor responses were seen in 4/4 gallbladder carcinomas (1 CR, 3 PR), 4/5 extrahepatic cholangiocarcinomas (2 CR 2 PR), and 1/5 hepatobiliary cancers (1 PR), leading to an overall response rate of 64%. The tumors remained locally controlled in 12 out of 16 assessable patients (75%). On an intention-to-treat basis, all patients with different biliary cancer without distant metastases had a median-survival time of 10 months (range 1 to 48) from the start of the radiotherapy; the 1-year survival was 43%. No patient survived beyond 4 years. Tolerance to the treatment was fairly good. Nausea and vomiting of grade 1 and 2 (WHO) was noted in 61%, and reversible leukopenia of grade 3 and 4 in 9% of the cases. The rate of inherent complications was high.CONCLUSIONCombined radiotherapy and razoxane led to local response rates which are superior to data from the literature when radiotherapy alone is used. Obstacles to the treatment were complications of the disease and frequent metastasis.

BACKGROUND:The planned MedAustron hadron therapy facility is designed to compare proton and carbon ion beam therapy under the same technical conditions. For the calculation of the number of potential patients for hadron therapy so far, only epidemiological estimations on cancer incidence are available without inclusion of the percentage of patients routinely referred to conventional radiotherapy.MATERIALS AND METHODS:Nationwide prospective survey to collect disease and treatment related data on patients receiving conventional radiotherapy at all 12 treatment facilities. Epidemiological cancer incidence (Statistic Austria 1999) were correlated with the number of patients receiving conventional radiotherapy. Based on published clinical and experimental results on proton and carbon ion therapy, a calculation of patient's subgroups suitable for hadron therapy was performed at five European University hospitals involved in the HICAT, CNAO, ETOILE and MEDAustron project. Using the mean values of the University specific percentages per tumour site, the number of potential patients was estimated.RESULTS:In Austria, a total of 3783 patients started radiotherapy during the study period of 3 months resulting in an approximated number of 15132 patients per year. The number of potential patients was estimated to 2044 per year, representing 5.6% of all newly diagnosed cancer patients and 13.5% of all irradiated cancer patients.CONCLUSION:There is a clear place for a hadron therapy facility in Austria, based on pattern of care in radiotherapy, cancer incidence and indications.

Purpose: In Austria a national survey was conducted by Med AUSTRON / Osterreichische Gesellschaft fur Radio - Onkologie, Radiobiologie und Medizinische Radiophysik ( OGRO) in order to estimate the indications, patient numbers and radiotherapy treatment planning procedures and performances at all Austrian radiotherapy institutes. Results were correlated with incidence rates (Austrian cancer registry) to determine patterns of radiotherapy practice in Austria.Material and Methods: At 12 radiotherapy departments of Austria data of all patients receiving irradiation within a 3 months (2002/2003) period were assessed. On the basis of a questionnaire number of treated patients, indications, and parameters of disease (stage, histology) and treatment modalities were evaluated. Results were analysed with regard to different tumour groups, according to academic and non academic hospitals, and correlated with epidemiological data on cancer incidence.Results: In total, 3783 patients were registered within this period. According to the different tumour entities percentages of patients receiving radiotherapy within initial treatment varied from 3% to 90% (e.g. brain tumours: 77%, breast cancer: 90%, prostate cancer: 35%). The most frequent indications to radiotherapy per radiotherapy department were breast cancer (range 22%-35%; mean 26%), urological tumours (range 6%-27%; mean 12%) and bone metastases (mean 10%, range 3%-17%).Conclusion: In Austria breast cancer, urological tumours and bone metastases are representing the most common indications to radiotherapy. Among the different departments variations in indications to radiotherapy were observed. Our study is the first evaluation of radiotherapeutic management in Austria.

BACKGROUND:Malignant hemangioendotheliomas of the thyroid are rare tumors predominantly seen in areas with endemic goiter such as the Alpine regions. The estimated incidence of the disease is between 0.15 and 0.25 per 100.000 inhabitants annually for Western Austria. The tumor is regarded as radio-resistant, and its prognosis is reported to be dismal. PATIENTS AND METHODS:Between 1982 and 1999, 12 cases with immunohistochemically confirmed malignant hemangioendotheliomas of the thyroid were referred for postoperative or palliative treatment. There were 8 men and 4 women with a median age of 67 years (range, 55-81 years). With surgery, clear margins were achieved in 5, microscopic residues were left in 3, and gross residual disease in 3 patients. One patient had an inoperable primary tumor. Postoperative radiotherapy was given to 8 cases, 6 of them received the radiosensitizer razoxane on radiation days. Total tumor doses ranged between 54 and 65 Gy. Two patients with clear margins at surgery received no adjuvant radiotherapy and were observed only. RESULTS:Local tumor control was achieved in 11 of 12 patients; 5 lived longer than 5 years. The median survival time of all cases is presently 14 months (range, 0.5-196 months). If 3 cases with metastasis at diagnosis were left out of the analysis, the median survival is 70 months. Noteworthy is a complete regression of 2 lung metastases in a 72-year-old man treated with the combination of vindesine, razoxane, and radiotherapy; the patient is still in complete remission more than 94 months after 3-year maintenance therapy with vindesine and razoxane. Fibrinogen, factor VIII, and factor VIII-related antigen in the serum could serve as surrogate markers during the follow-up. The tolerance to the combined modality treatment was good to fair, local chemoradiation reactions of normal tissues have to be considered as the principal toxicity. It may also be of interest that 5 of 12 patients were exposed to vinyl chloride and other polymeric materials during their working life. CONCLUSIONS:This small series indicates that the course of the disease is not uniformly bleak and that the resistance to radiotherapy reported in the literature has to be questioned. It appears that adequate surgery together with rapid radiation therapy in combination with razoxane, a radiosensitizer and agent that can normalize tumor blood vessels, is able to improve the local control rate and thus perhaps to alter the natural history of this disease. In addition, the data offer new evidence of the occurrence of vinyl-chloride-induced angiosarcomas outside the liver, and support similar observations that have already been published in case reports.

The histology of colorectal tumors was correlated with the presence of liver metastases in a retrospective study performed on 179 patients who were autopsied between 1975 and 1990. For the analysis of metastatic patterns, 116 cases with at least one distant metastatic site were selected. A distinct relationship between mucin expression of colorectal tumors and liver involvement was found. Pure adenocarcinomas and their papillary variants showed the highest affinity to the hepatic tissue regarding the frequency as well as extent of involvement. A subtotal replacement of the liver by metastases was restricted to these two variants. An extracellular mucin component was associated with a lower frequency of liver involvement and a tendency to solitary or oligotopic metastases. Ten cases of signet ring cell carcinomas had no metastases in the liver. The results described here for colorectal cancers are similar to those previously reported for gastric cancer. The therapeutic implications were discussed. A detailed link between these clinical findings and the results found at the level of molecular biology is yet to be determined.

Background: Malignant hemangioendothelioma of the thyroid is a rare tumor predominantly described in areas with endemic goiter like the Alpine regions. The estimated incidence of the disease is between 0.15 and 0.25 per 100.000 inhabitants per year for Western Austria. The prognosis is reported to be dismal. Materials and methods: Between 1982 and 1995, 10 cases with immunohistochemically confirmed malignant hemangioendotheliomas of the thyroid were referred to our department for postoperative or palliative treatment. Two patients with clear margins at surgery received no adjuvant radiotherapy and were only observed. By surgery, clear margins (R-O resection) were achieved in 5, microscopic residuals (R-l) were left in 3, and gross residual disease in 1 patient. One patient had an inoperable primary tumor. Postoperative radiotherapy was administered in 6 cases, 4 of them additionally received the radiosensitizer razoxane. Total tumor doses ranged between 58 and 65 Gy. Results: Local tumor control was achieved in 9 of 10 patients; 4 of 10 lived longer than 4 years. The median survival time has not yet been reached, and is presently between 7,5 and 21+ months. - Noteworthy is a complete regression of 2 lung metastases in a 72-year-old man by a combination of vindesine, razoxane and radiotherapy. The patient is still in complete remission under a maintenance therapy with vindesine and razoxane since 14 months. - It may also be of interest that 4 of the 10 patients were strongly exposed to vinyl chloride and other polymeric materials during their occupational life. Conclusions: This small series may indicate that the outcome of this disease may not be uniformly deleterious, and that the resistance to radiotherapy reported in the literature may be questioned. - The data offer new evidence of the occurrence of vinyl chloride-induced angiosarcomas outside the liver, and support observations which have already been published in case reports.

BACKGROUND:Malignant hemangioendothelioma of the thyroid is a rare tumor predominantly described in areas with endemic goiter like the Alpine regions. The estimated incidence of the disease is between 0.15 and 0.25 per 100,000 inhabitants per year for Western Austria. The prognosis is reported to be dismal.MATERIALS AND METHODS:Between 1982 and 1995, 10 cases with immunohistochemically confirmed malignant hemangioendotheliomas of the thyroid were referred to our department for postoperative or palliative treatment. Two patients with clear margins at surgery received no adjuvant radiotherapy and were only observed. By surgery, clear margins (R-0 resection) were achieved in 5, microscopic residuals (R-1) were left in 3, and gross residual disease in 1 patient. One patient had an inoperable primary tumor. Postoperative radiotherapy was administered in 6 cases, 4 of them additionally received the radiosensitizer razoxane. Total tumor doses ranged between 58 and 65 Gy.RESULTS:Local tumor control was achieved in 9 of 10 patients; 4 of 10 lived longer than 4 years. The median survival time has not yet been reached and is presently between 7.5 and 21+ months.--Noteworthy is a complete regression of 2 lung metastases in a 72-year-old man by a combination of vindesine, razoxane and radiotherapy. The patient is still in complete remission under a maintenance therapy with vindesine and razoxane since 14 months.--It may also be of interest that 4 of the 10 patients were strongly exposed to vinyl chloride and other polymeric materials during their occupational life.CONCLUSIONS:This small series may indicate that the outcome of this disease may not be uniformly deleterious, and that the resistance to radiotherapy reported in the literature may be questioned.--The data offer new evidence of the occurrence of vinyl chloride-induced angiosarcomas outside the liver, and support observations which have already been published in case reports.

BACKGROUND:In the treatment of breast cancer, the indication for adjuvant systemic treatment was extended also to nodal negative tumor stages in the last years. For that reason, the indicator status of axillary dissection lost some of its importance. Therefore, in node negative patients, the necessity of axillary dissection and the use of definitive axillary radiotherapy, which causes less morbidity, may be reconsidered.METHODS:In a review of the related literature, we present international treatment experiences related to axillary dissection, axillary radiotherapy and "sentinel node dissection" (SLND). In addition, our long-term experiences in 19 patients with clinically negative axillary nodes treated by conservative surgery without axillary dissection but axillary radiotherapy, are reported.RESULTS:The median rate of axillary recurrences with axillary radiotherapy is 2.0%, the regional (supraclavicular and retrosternal) recurrence rate 2.7%. With axillary dissection, axillary recurrences occur in 1 to 2%, in nodal negative stages in 0 to 1%, the median regional recurrence rate is 2.2%. A meta-analysis presented in 1995 by the Early Breast Cancer Study Group showed no significant difference in the regional recurrence rate or the overall survival between axillary dissection and axillary radiotherapy. With SLND, usually only one axillary node is excised. With the help of molecular and immunohistochemical methods, SLND may predict axillary involvement with high precision.CONCLUSIONS:Definitive radiotherapy of the axilla is a valid treatment option for patients without palpable axillary nodes with the potential advantage of being less cost intensive and better tolerated. If the indication for systemic therapy is no more dependent on the axillary status, axillary dissection may be replaced by axillary radiotherapy. In small tumors without risk factors and without indication for systemic therapy, SLND seems to be the best treatment option.

The effect of the radiosensitizer razoxane was prospectively evaluated in advanced and recurrent gastric cancer. Endpoints of the study were mainly palliation, local response rates, and achievement of local control. From 1984 to 1993, razoxane (Rz) was given together with radiation therapy (RT) to 28 patients. Twenty-three patients had inoperable primary, recurrent, or metastatic disease, and 5 patients received the treatment having microscopic residuals. The dose of Rz was 150 mg/M2 daily orally starting 5 days before the first irradiation. The drug was then given each radiation day until the end of treatment. The median dose of radiation was 50 (16–56) Gy in the evaluable patients. A complete follow-up was performed in all but one patient (96%). Taking all patients together, there was an 89% rate of partial responses for all measurable and evaluable tumors. The local control rate was 64%, and the median time to an in-field recurrence was 7 months. A detailed analysis of the outcome for the various disease conditions is given. Rapid pain relief was achieved in all but one patient. There was no case of an immediate tumor progression at the site of the irradiation. The treatment is easy to administer and was associated with a moderate toxicity. The toxicity is dependent on the volume irradiated. In conclusion, the combination of RT and Rz is an excellent tool for palliation in gastric cancer. It seems that the combined treatment with Rz may lead to better response rates compared to results where irradiation alone was used. Radiat Oncol Invest 1996;4:27–32. ©1996 Wiley-Liss, Inc.

Purpose: The effect of the sensitizer razoxane was prospectively evaluated in recurrent rectal cancer. Endpoints of the study were mainly local response rates and survival.Methods and Materials: From 1984 to 1990 razoxane was given together with radiation therapy to 40 patients with recurrent inoperable rectal cancer. Loco-regional relapses in the pelvis were isolated in 24 and associated with distant metastases in 16 patients. Special attention was given to the subset of 24 patients with isolated local recurrences. This group was compared with historical controls treated with radiotherapy alone. The dosage of razoxane was 150 mg/m(2) daily orally starting 5 days before the first irradiation. The drug was then given each radiation day until the end of treatment. The median radiation dose was 60 (40-62) Gy in the evaluable patients. The minimum follow-up was 32 months and the median 72 months.Results: The rates of complete plus partial responses were 57% and 54%, respectively, for recurrent patients without and with distant metastasis. The 23 evaluable patients with isolated local relapses had a median survival of 24 months (12-94+); all patients surviving at least 1 year.Conclusion: The combination of radiotherapy and razoxane may lead to better local control and improved median survival compared to our historical controls and literature reports where radiotherapy alone was used. The treatment is easy to administer and is associated with a moderate toxicity.

Five new cases of malignant hemangioendothelioma of the thyroid are reported. This rare malignant tumor is described predominantly in regions with endemic goiter such as the Alpine zone. The estimated incidence of the disease is between 0.15 and 0.25 per 100,000 inhabitants per year for Western Austria. Two of the five patients were heavily exposed to vinyl chloride occupationally for 9 and 30 years respectively. Surgically, a R-0 resection was performed in two patients, R-1 in two, and R-2 in one patient. Postoperative radiotherapy was given in four cases. The tumor doses were between 58 and 65 Gy. Three patients received the sensitizer razoxane in addition. Local tumor control was achieved in 4 of 5 patients. The survival times of the 5 patients were 78, 68+, 38+, 7.5 and 3 months. Two patients are still alive after 68 and 38 months. This small series may indicate that the outcome of the disease may not be uniformly deleterious and the resistance to radiotherapy reported in the literature [3, 10] is debatable.