Functional and mutational analysis after radiation and cetuximab treatment on prostate carcinoma cell line DU145.

BACKGROUND: Epidermal Growth Factor Receptor is often overexpressed in advanced prostate carcinoma. In-vitro-studies in prostate carcinoma cell line DU145 have demonstrated increased sensibility to radiation after cetuximab treatment, but clinical data are not sufficient to date. METHODS: We analyzed effects of radiation and cetuximab in DU145 and A431 using proliferation, colony-forming-unit- and annexin-V-apoptosis-assays. Changes in protein expression of pEGFR and pERK1/2 after radiation and cetuximab treatment were analyzed. Using NGS we also investigated the impact of cetuximab long-term treatment. RESULTS: Cell counts in DU145 were reduced by 44% after 4 Gy (p = 0.006) and 55% after 4 Gy and cetuximab (p < 0.001). The surviving fraction (SF) was 0.69 after 2 Gy, 0.41 after 4 Gy and 0.15 after 6 Gy (each p < 0.001). Cetuximab treatment did not alter significantly growth reduction in 4 Gy radiated DU145 cells, p > 0.05 or SF, p > 0.05, but minor effects on apoptotic cell fraction in DU145 were detected. Using western blot, there were no detectable pEGFR and pERK1/2 protein signals after cetuximab treatment. No RAS mutation or HER2 amplification was detected, however a TP53 gen-mutation c.820G > T was found. CONCLUSIONS: Radiation inhibits cell-proliferation and colony-growth and induces apoptosis in DU145. Despite blocking MAP-Kinase-pathway using cetuximab, no significant radiation-sensitizing-effect was detected. Cetuximab treatment did not induce resistance-mutations. Further research must clarify which combination of anti-EGFR treatment strategies can increase radiation-sensitizing-effects.

Biliary duct stenosis after image-guided high-dose-rate interstitial brachytherapy of central and hilar liver tumors : A systematic analysis of 102 cases.

OBJECTIVE: Image-guided high-dose-rate interstitial brachytherapy (iBT) with iridium-192 is an effective treatment option for patients with liver malignancies. Little is known about long-term radiation effects on the bile duct system when central hepatic structures are exposed to iBT. This retrospective analysis investigates the occurrence of posthepatic cholestasis (PHC) and associated complications in patients undergoing iBT. MATERIALS AND METHODS: We identified patients who underwent iBT of hepatic malignancies and had point doses of ≥1 Gy to central bile duct structures. Patients with known bile duct-related diseases or prior bile duct manipulation were excluded. RESULTS: 102 patients were retrospectively included. Twenty-two patients (22%) developed morphologic PHC after a median of 17 (3-54) months; 18 of them were treated using percutaneous transhepatic cholangiopancreatography drainage or endoscopic retrograde cholangiopancreatography. The median point dose was 24.8 (4.4-80) Gy in patients with PHC versus 14.2 (1.8-61.7) Gy in those without PHC (p = 0.028). A dose of 20.8 Gy (biological effective dose, BED3/10 = 165/64.1 Gy) was identified to be the optimal cutoff dose (p = 0.028; 59% sensitivity, 24% specificity). Abscess/cholangitis was more common in patients with PHC compared to those without (4 of 22 vs. 2 of 80; p = 0.029). Median survival did not differ between patients with and without PHC (43 vs. 36 months; p = 0.571). CONCLUSION: iBT of liver malignancies located near the hilum can cause PHC when the central bile ducts are exposed to high point doses. Given the long latency and absence of impact of iBT-induced PHC on median survival, the rate of cholestasis and complications seen in our patients appears to be acceptable.

Inverse planning and inverse implanting for breast interstitial brachytherapy. Introducing a new anatomy specific breast interstitial template (ASBIT).

An innovative template, based on thoracic cage surface reconstructions for breast interstitial brachytherapy was developed. Hybrid-inverse-planning-optimisation-based implantations and brachytherapy plans, using three custom anthropomorphic breast phantoms, were utilised for its validation. A user independent, inverse planning and inverse implanting technique is proposed.

Assessment of Iterative Closest Point Registration Accuracy for Different Phantom Surfaces Captured by an Optical 3D Sensor in Radiotherapy.

An optical 3D sensor provides an additional tool for verification of correct patient settlement on a Tomotherapy treatment machine. The patient's position in the actual treatment is compared with the intended position defined in treatment planning. A commercially available optical 3D sensor measures parts of the body surface and estimates the deviation from the desired position without markers. The registration precision of the in-built algorithm and of selected ICP (iterative closest point) algorithms is investigated on surface data of specially designed phantoms captured by the optical 3D sensor for predefined shifts of the treatment table. A rigid body transform is compared with the actual displacement to check registration reliability for predefined limits. The curvature type of investigated phantom bodies has a strong influence on registration result which is more critical for surfaces of low curvature. We investigated the registration accuracy of the optical 3D sensor for the chosen phantoms and compared the results with selected unconstrained ICP algorithms. Safe registration within the clinical limits is only possible for uniquely shaped surface regions, but error metrics based on surface normals improve translational registration. Large registration errors clearly hint at setup deviations, whereas small values do not guarantee correct positioning.

Radioablation of liver malignancies with interstitial high-dose-rate brachytherapy : Complications and risk factors.

BACKGROUND: To evaluate complications and identify risk factors for adverse events in patients undergoing high-dose-rate interstitial brachytherapy (iBT). MATERIAL AND METHODS: Data from 192 patients treated in 343 CT- or MRI-guided interventions from 2006-2009 at our institution were analyzed. In 41 %, the largest tumor treated was ≥ 5 cm, 6 % of the patients had tumors ≥ 10 cm. Prior to iBT, 60 % of the patients had chemotherapy, 22 % liver resection, 19 % thermoablation or transarterial chemoembolization (TACE). Safety was the primary endpoint; survival data were obtained as the secondary endpoints. During follow-up, MRI or CT imaging was performed and clinical and laboratory parameters were obtained. RESULTS: The rate of major complications was below 5 %. Five major bleedings (1.5 %) occurred. The frequency of severe bleeding was significantly higher in patients with advanced liver cirrhosis. One patient developed signs of a nonclassic radiation-induced liver disease. In 3 patients, symptomatic gastrointestinal (GI) ulcers were detected. A dose exposure to the GI wall above 14 Gy/ml was a reliable threshold to predict ulcer formation. A combination of C-reactive protein ≥ 165 mg/l and/or leukocyte count ≥ 12.7 Gpt/l on the second day after the intervention predicted infection (sensitivity 90.0 %; specificity 92.8 %.) Two patients (0.6 %) died within 30 days. Median overall survival after the first liver treatment was 20.1 months for all patients and the local recurrence-free surviving proportion was 89 % after 12 months. CONCLUSIONS: Image-guided iBT yields a low rate of major complications and is effective.

Prospective randomized trial of enoxaparin, pentoxifylline and ursodeoxycholic acid for prevention of radiation-induced liver toxicity.

BACKGROUND/AIM: Targeted radiotherapy of liver malignancies has found to be effective in selected patients. A key limiting factor of these therapies is the relatively low tolerance of the liver parenchyma to radiation. We sought to assess the preventive effects of a combined regimen of pentoxifylline (PTX), ursodeoxycholic acid (UDCA) and low-dose low molecular weight heparin (LMWH) on focal radiation-induced liver injury (fRILI). METHODS AND MATERIALS: Patients with liver metastases from colorectal carcinoma who were scheduled for local ablation by radiotherapy (image-guided high-dose-rate interstitial brachytherapy) were prospectively randomized to receive PTX, UDCA and LMWH for 8 weeks (treatment) or no medication (control). Focal RILI at follow-up was assessed using functional hepatobiliary magnetic resonance imaging (MRI). A minimal threshold dose, i.e. the dose to which the outer rim of the fRILI was formerly exposed to, was quantified by merging MRI and dosimetry data. RESULTS: Results from an intended interim-analysis made a premature termination necessary. Twenty-two patients were included in the per-protocol analysis. Minimal mean hepatic threshold dose 6 weeks after radiotherapy (primary endpoint) was significantly higher in the study treatment-group compared with the control (19.1 Gy versus 14.6 Gy, p = 0.011). Qualitative evidence of fRILI by MRI at 6 weeks was observed in 45.5% of patients in the treatment versus 90.9% of the control group. No significant differences between the groups were observed at the 12-week follow-up. CONCLUSIONS: The post-therapeutic application of PTX, UDCA and low-dose LMWH significantly reduced the extent and incidence fRILI at 6 weeks after radiotherapy. The development of subsequent fRILI at 12 weeks (4 weeks after cessation of PTX, UDCA and LMWH during weeks 1-8) in the treatment group was comparable to the control group thus supporting the observation that the agents mitigated fRILI. TRIAL REGISTRATION: EU clinical trials register 2008-002985-70 ClinicalTrials.gov NCT01149304.

Multimodal treatment, including interferon beta, of nasopharyngeal carcinoma in children and young adults: preliminary results from the prospective, multicenter study NPC-2003-GPOH/DCOG.

BACKGROUND: The authors report preliminary results from a prospective multicenter study (Nasopharyngeal Carcinoma [NPC] 2003 German Society of Pediatric Oncology and Hematology/German Children's Oncology Group [NPC-2003-GPOH/DCOG]). METHODS: From 2003 to 2010, 45 patients (ages 8-20 years), including 1 patient with stage II NPC and 44 patients with stage III/IV NPC, were recruited to the study. The patient with stage II disease received radiotherapy (59.4 grays [Gy]). The patients with stage III/IV disease received 3 courses of neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and folinic acid. The cumulative irradiation dose was 54 Gy in 5 patients, who achieved complete remission after neoadjuvant chemotherapy, and 59.4 Gy in the remaining 40 patients. All patients received concomitant cisplatin during the first week and last week of irradiation. After irradiation, all patients received interferon beta for 6 months. Tumor response was evaluated by magnetic resonance imaging studies and positron emission tomography scans. RESULTS: After the completion of treatment, 43 of 45 patients were in complete remission. In 2 patients, only a partial response was achieved, followed by distant metastases (1 patient) or local progression and distant metastases (1 patient), 6 months and 10 months after diagnosis, respectively. Another patient developed a solitary pelvic bone metastasis 21 months after diagnosis. After a median follow-up of 30 months (range, 6-95 months), the event-free survival rate was 92.4%, and the overall survival was 97.1%. Acute toxicity consisted mainly of leucopenia, mucositis, and nausea; and late toxicity consisted of hearing loss and hypothyroidism. CONCLUSIONS: Combined therapy with neoadjuvant chemotherapy, radiochemotherapy, and interferon beta was well tolerated and resulted in a very good outcome that was superior to the outcomes of published results from all other pediatric NPC study groups.

Treatment of hepatic metastases of breast cancer with CT-guided interstitial brachytherapy - a phase II-study.

PURPOSE: The aim of the study was the evaluation of feasibility, safety and effectiveness of interstitial brachytherapy for the treatment of hepatic metastases of breast cancer. MATERIALS AND METHODS: Forty-one consecutive patients with 115 unresectable hepatic metastases of breast cancer were included in this phase-II-trial. They were treated in 69 interventions of CT-guided-interstitial-brachytherapy of the liver. Brachytherapy was applied as a single fraction high-dose-irradiation (15-25Gy (Gray)) using a (192)Ir-source of 10Ci. Nineteen patients presented systemically pretreated extrahepatic tumors. Primary endpoints were complications, local tumor control and progression-free survival. RESULTS: The median tumor diameter was 4.6 cm (1.5-11 cm). The median irradiation time per intervention was 26.5 min (range: 7-47 min). The applied median minimal dose at the CTV (clinical target volume) margin was 18.5 Gy (12-25 Gy). In 69 interventions and during the postinterventional period, one major complication (symptomatic post-interventional bleeding) (1.5%) and six minor complications occurred (8.7%). The median follow-up time was 18 months (range: 1-56). After 6, 12 and 18 months, local tumor control was 97%, 93.5% and 93.5%, intra- and extrahepatic progression free survival was 53%, 40% and 27%, and overall survival was 97%, 79% and 60%, respectively. CONCLUSION: CT-guided-brachytherapy is safe and effective for the treatment of liver metastases of breast cancer.

Value of diffusion weighted MR imaging as an early surrogate parameter for evaluation of tumor response to high-dose-rate brachytherapy of colorectal liver metastases.

BACKGROUND: To assess the value of diffusion weighted imaging (DWI) as an early surrogate parameter for treatment response of colorectal liver metastases to image-guided single-fraction ¹9²Ir-high-dose-rate brachytherapy (HDR-BT). METHODS: Thirty patients with a total of 43 metastases underwent CT- or MRI-guided HDR-BT. In 13 of these patients a total of 15 additional lesions were identified, which were not treated at the initial session and served for comparison. Magnetic resonance imaging (MRI) including breathhold echoplanar DWI sequences was performed prior to therapy (baseline MRI), 2 days after HDR-BT (early MRI) as well as after 3 months (follow-up MRI). Tumor volume (TV) and intratumoral apparent diffusion coefficient (ADC) were measured independently by two radiologists. Statistical analysis was performed using univariate comparison, ANOVA and paired t test as well as Pearson's correlation. RESULTS: At early MRI no changes of TV and ADC were found for non-treated colorectal liver metastases. In contrast, mean TV of liver lesions treated with HDR-BT increased by 8.8% (p = 0.054) while mean tumor ADC decreased significantly by 11.4% (p < 0.001). At follow-up MRI mean TV of non-treated metastases increased by 50.8% (p = 0.027) without significant change of mean ADC values. In contrast, mean TV of treated lesions decreased by 47.0% (p = 0.026) while the mean ADC increased inversely by 28.6% compared to baseline values (p < 0.001; Pearson's correlation coefficient of r = -0.257; p < 0.001). CONCLUSIONS: DWI is a promising imaging biomarker for early prediction of tumor response in patients with colorectal liver metastases treated with HDR-BT, yet the optimal interval between therapy and early follow-up needs to be elucidated.

Safety margin in irradiation of colorectal liver metastases: assessment of the control dose of micrometastases.

BACKGROUND: Micrometastases of colorectal liver metastases are present in up to 50% of lesions. In this study we sought to determine the threshold dose for local control of occult micrometastases in patients undergoing CT (computed tomography)-guided brachytherapy of colorectal liver metastases. MATERIALS AND METHODS: Nineteen patients demonstrated 34 local tumor recurrences originating from micrometastases after CT-guided brachytherapy of 27 colorectal liver metastases. We considered a local tumor recurrence as originating from a micrometastasis if tumor regrowth occurred adjacent to a formerly irradiated lesion and the distance of the 3D isocenter of the new lesion was 9-15 mm and > 15 mm. The median dose in the according isocenters was 13.18, 11.6 and 11.85 Gy. The threshold dose failing to prevent micrometastasis growth was sigificantly higher in a subgroup of lesions with 15 mm (13.18 vs 11.85 Gy). Adjuvant chemotherapy correlated with greater distance of micrometastasis growth to the tumor but not with the threshold dose. CONCLUSION: To prevent loss of local tumor control by continuous growth of micrometastases a threshold dose of 15,4 Gy (single fraction) should be delivered at a distance of 21 mm to the gross tumor margin.

Computed tomography-guided high-dose-rate brachytherapy in hepatocellular carcinoma: safety, efficacy, and effect on survival.

PURPOSE: To determine the safety and efficacy of computed tomography (CT)-guided brachytherapy in hepatocellular carcinoma (HCC). METHODS AND MATERIALS: A total of 83 patients were recruited, presenting with 140 HCC- lesions. Treatment was performed by CT-guided high-dose-rate (HDR) brachytherapy with an iridium-192 source. The primary endpoint was time to progression; secondary endpoints included local tumor control and overall survival (OS). A matched-pair analysis with patients not receiving brachytherapy was performed. Match criteria included the Cancer of the Liver Italian Program (CLIP) score, alpha-fetoprotein, presence, and extent of multifocal disease. For statistical analysis, Kaplan-Meier and Cox regression were performed. RESULTS: Mean and median cumulative TTP for all patients (n = 75) were 17.7 and 10.4 months. Five local recurrences were observed. The OS after inclusion reached median times of 19.4 months (all patients), 46.3 months (CLIP score, 0), 20.6 months (CLIP score, 1) 12.7 months, (CLIP score, 2), and 8.3 months (CLIP score, >or=3). The 1- and 3-year OS were 94% and 65% (CLIP score, 0), 69% and 12% (CLIP score, 1), and 48% and 19% (CLIP score, 2), respectively. Nine complications requiring intervention were encountered in 124 interventions. Matched-pair analysis revealed a significantly longer OS for patients undergoing CT-guided brachytherapy. CONCLUSION: Based on our results the study treatment could be safely performed. The study treatment had a beneficial effect on OS in patients with advanced HCC, with respect to (and depending on) the CLIP score and compared with OS in a historical control group. A high rate of local control was also observed, regardless of applied dose in a range of 15 to 25 Gy.

CT-guided brachytherapy (CTGB) versus interstitial laser ablation (ILT) of colorectal liver metastases: an intraindividual matched-pair analysis.

PURPOSE: To compare local tumor control after percutaneous tumor ablation by interstitial laser therapy (ILT) or CT-guided brachytherapy (CTGB). PATIENTS AND METHODS: In a matched pair analysis including 18 patients with 36 liver metastases of colorectal primary, both ILT and CTGB were performed in different lesions. The following matching factors were considered: (i) tumor size < or = 5 cm, and (ii) execution of chemotherapy after tumor ablation. Primary endpoint was local tumor control. RESULTS: Treated lesions were identical in terms of tumor size and all matching criteria were fulfilled in all patients except for the performance of adjuvant chemotherapy. Median follow-up was 14 months (3-24 months) for both groups. Only five of 18 patients (28%) demonstrated local tumor progression after CTGB, whereas in ten of 18 patients (56%) tumor progression was found after ILT. Differences encountered were significant for all patients (p = 0.04), whereas in those who fulfilled all matching criteria (n = 14) the level of statistical significance was not reached (p = 0.23). CONCLUSION: CTGB demonstrated superior local tumor control compared to ILT in long-term follow-up.

Radiotherapy of liver metastases. Comparison of target volumes and dose-volume histograms employing CT- or MRI-based treatment planning.

PURPOSE: To assess differences in delineated target volumes of liver metastases using contrast-enhanced CT and different MRI sequences for radiation treatment planning. PATIENTS AND METHODS: 25 patients with 43 colorectal liver metastases were recruited. Tumor margins were defined by two experienced radiologists. The resulting D90 was assessed and the CT-based 3-D dose distribution merged with the according MRI dataset by employing image fusion. A theoretical D90 as a result of MRI-based treatment planning was assessed for various MRI sequences individually. RESULTS: In venous phase contrast-enhanced CT, the mean tumor volume was 20 ml; T1-weighted (T1w) MRI, 27 ml; contrast-enhanced T1w 42 ml; T2w 65 ml. The difference between the target volumes as assessed by either CT or MRI was 181% for T1w images, 178% for contrast-enhanced T1w, and 246% for T2w sequences. All differences were statistically significant (p < 0.05). The analysis of the dose-volume histograms revealed statistically significant differences (i.e., for the D90) for the different target volumes specified by CT and MRI: mean D90 on CT, 18 Gy; plain T1w, 16 Gy; contrast-enhanced T1w, 15.5 Gy; T2w, 12 Gy. Hence, delineation of a larger target volume in T2w MRI compared to contrast-enhanced CT resulted in a smaller D90. The mean differences of tumor volumes assessed by CT and plain T1w were significantly higher in the group of patients showing local tumor recurrences as compared to patients with long-term local tumor control (p = 0.002). CONCLUSION: For treatment planning of liver metastases, the use of either plain T1w or T2w sequences is recommended to delineate the clinical target volume as completely as possible and not to miss potential tumor cell congregations in the surroundings as in CT.

A randomised trial of goserelin versus control after adjuvant, risk-adapted chemotherapy in premenopausal patients with primary breast cancer - GABG-IV B-93.

GABG-IV B-93 is a prospective, randomised study comparing goserelin (n=384) with no further treatment (n=392) in hormone receptor (HR)-negative breast cancer patients (n=465) after 3 cycles cyclophosphamide, methotrexate, 5-fluorouracil (CMF) for patients with 0-3 positive lymph nodes (LN) or 4 cycles epirubicin, cyclophosphamide (EC) followed by 3 cycles CMF for patients with 4-9 positive LN. After completion of the ZEBRA trial the study was amended to enrol also HR-positive patients with 1-9+LN (n=311). After a median follow-up of 4.7 years neither HR-negative nor HR-positive patients showed a benefit for goserelin. The adjusted estimated hazard ratio for event-free survival in HR-negative patients was 1.01 (goserelin versus control, 95% confidence interval [CI] 0.72-1.42, P=0.97) and 0.77 in HR-positive patients (95% CI 0.47-1.24, P=0.27). These results do not support the general use of goserelin after adjuvant chemotherapy in this group of premenopausal patients.

Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study.

PURPOSE: In postmenopausal women with estrogen receptor-positive early breast cancer, surgery is usually followed by a 5-year course of tamoxifen. This report presents results of a prospective, open-label, randomized study, designed to evaluate the benefits of switching to anastrozole after 2 years of tamoxifen treatment, compared with continuing on tamoxifen for 5 years. PATIENTS AND METHODS: After receiving tamoxifen treatment for 2 years, eligible patients (n = 979) were randomly assigned to switch to anastrozole (1 mg/d) or continue tamoxifen (20 or 30 mg/d) for an additional 3 years. Patients were monitored every 6 months during years 1 to 3 and annually thereafter. The primary efficacy variable was disease-free survival, including local or distant recurrence, new contralateral breast cancer, or death. Secondary variables were overall survival and assessment of safety. RESULTS: Switching to anastrozole resulted in a significant reduction in the risk of disease recurrence (hazard ratio [HR], 0.66; 95% CI, 0.44 to 1.00; P = .049), and improved overall survival (HR, 0.53; 95% CI, 0.28 to 0.99; P = .045) compared with continuing on tamoxifen. Fewer patients who switched to anastrozole reported serious adverse events (22.7% v 30.8%) compared with those who continued on tamoxifen, mainly due to more patients in the tamoxifen group with endometrial events. The overall safety profile for anastrozole was consistent with previous reports and no new safety issues were identified. CONCLUSION: Postmenopausal women who have taken tamoxifen for 2 years as adjuvant therapy are less likely to experience a recurrence of breast cancer and have improved overall survival if they switch to anastrozole compared with continuing to receive tamoxifen.

In vitro combined modality treatment of prostate carcinoma cells with 17-(allylamino)-17-demethoxygeldanamycin and ionizing radiation.

BACKGROUND: The effect of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a benzoquinone-ansamycin-type Hsp90-inhibitor, on the expression of focal adhesion kinase (FAK) and, when combined with ionizing radiation, on the clonogenicity of prostate cancer cells were determined. MATERIALS AND METHODS: FAK was analyzed by Western immunoblot. Prostate carcinoma cells were exposed either to 17-AAG alone or combined with a single radiation fraction of 3 Gy. RESULTS: FAK concentrations were reduced by 17-AAG in a time-dependent manner. Treatment with 100 nM 17-AAG for 24 h reduced clonogenicity by 90%. The plot of surviving fraction versus radiation energy dose yielded roughly parallel graphs for solvent- and 17-AAG-treated cells. CONCLUSION: 17-AAG induced rapid degradation of FAK A single radiation fraction of 3 Gy did not enhance the dose-dependent drug-effect on survival. In this sequence, the combined effect of both modalities towards clonogenicity was largely additive.

Tamoxifen versus control after adjuvant, risk-adapted chemotherapy in postmenopausal, receptor-negative patients with breast cancer: a randomized trial (GABG-IV D-93)--the German Adjuvant Breast Cancer Group.

PURPOSE: To investigate the effect of adjuvant sequential tamoxifen after chemotherapy in postmenopausal patients with hormone receptor-negative breast cancer. METHODS: Patients were randomly assigned to oral tamoxifen (30 mg daily for 5 years; n = 421) or no additional treatment (n = 408) after risk-adapted polychemotherapy consisting of three 28-day cycles of CMF (cyclophosphamide, 500 mg/m(2), methotrexate, 40 mg/m(2), and fluorouracil, 600 mg/m(2)) in patients with negative or one to three positive lymph nodes and four 21-day cycles of epirubicin 90 mg/m(2), cyclophosphamide 600 mg/m(2) followed by three cycles of CMF in patients with four to nine positive lymph nodes. RESULTS: Thirty-six percent of the patients included were older than 60 years, 63% were node negative, 13% had four to nine positive nodes, 55% had tumor grade 3, and 41% received breast-preserving surgery. At 5.3 years' median follow-up, the first event of failure (recurrence, secondary tumor, or death) had occurred in 123 patients in the tamoxifen group and 107 patients of the control group. Event-free survival rates after 5 years were 70.3% (95% CI, 65.5% to 75.0%) and 72.8% (95% CI, 68.2% to 77.5%) for the tamoxifen and control groups, respectively. The estimated hazard ratio of tamoxifen versus control was 1.13 (95% CI, 0.87 to 1.48; P = .34), which gives no indication of an additional benefit of tamoxifen in these patients. CONCLUSION: This study contributes substantially to finalization of the presently emerging evidence that tamoxifen does not benefit women with receptor-negative breast cancer after chemotherapy.

Effects of imatinib mesylate on adenoid cystic carcinomas.

BACKGROUND: Adenoid cystic carcinomas (ACCs) are rare tumors which most often arise in the salivary glands. They have a propensity for local relapse and tend to metastasize, frequently with a protracted clinical course. A substantial fraction of the tumors expresses c-Kit or the platelet-derived growth factor receptor beta (PDGFRbeta), both targets for imatinib mesylate. No standard systemic therapy is known for these neoplasms. PATIENTS AND METHODS: c-kit and PDGFRbeta-expression were determined by immunohistochemistry. Four patients with distant metastases and with at least one positive result were treated with 400 mg imatinib mesylate once daily and their response assessed. RESULTS: c-Kit and PDGFRbeta expressions were variable among the tumor samples. Toxicity was mild. No remissions were observed. CONCLUSION: These data support that c-Kit or PDGFRbeta expression per se are not prognostic for the therapeutic response of metastasized ACCs to imatinib mesylate.

Treatment of nasopharyngeal carcinoma in children and adolescents: definitive results of a multicenter study (NPC-91-GPOH).

BACKGROUND: Preliminary results of combined neoadjuvant chemotherapy, radiotherapy, and postradiation interferon beta (IFN-beta) in children and adolescents with nasopharyngeal carcinoma, especially in high-risk patients, have been promising. METHODS: From 1992 to 2003, 59 patients (58 high-risk patients and 1 low-risk patient, median age 13 yrs; range, 8-25 yrs) were treated in the GPOH-NPC-91 study. The Stage II patient received irradiation as initial therapy. Fifty-eight patients received preradiation chemotherapy with methotrexate, cisplatin, and 5-fluorouracil. The cumulative radiation dose to primary sites was 59.4 Gy, a total dose of 45 Gy was delivered to the neck area. After irradiation, all patients were treated with 10(5) U recombinant IFN-beta/kg body weight 3 times a week for 6 months. RESULTS: After combination therapy, complete response was accomplished in 58 patients. In one patient, there was tumor progression during chemotherapy. In 3 patients, distant metastases were observed 14, 15, and 18 months after diagnosis, respectively. One patient had a local relapse 12 months after diagnosis. Fifty-four patients are still in first remission with a median follow-up of 48 months (range, 10-110 mos). Chemotherapy-related toxicity was mucositis Grade II, III, or IV in all patients and acute cardiotoxicity in 2 (3.5%) of the patients. Nephrotoxicity Grade I-II occurred in 8.8% of patients. CONCLUSIONS: The combination of initial chemotherapy, radiotherapy, and IFN-beta results in an excellent outcome. These results strongly support the development of a future treatment strategy along this line.

Dosimetric characteristics of a new unshielded silicon diode and its application in clinical photon and electron beams.

Shielded p-silicon diodes, frequently applied in general photon-beam dosimetry, show certain imperfections when applied in the small photon fields occurring in stereotactic or intensity modulated radiotherapy (IMRT), in electron beams and in the buildup region of photon beam dose distributions. Using as a study object the shielded p-silicon diode PTW 60008, well known for its reliable performance in general photon dosimetry, we have identified these imperfections as effects of electron scattering at the metallic parts of the shielding. In order to overcome these difficulties a new, unshielded diode PTW 60012 has been designed and manufactured by PTW Freiburg. By comparison with reference detectors, such as thimble and plane-parallel ionization chambers and a diamond detector, we could show the absence of these imperfections. An excellent performance of the new unshielded diode for the special dosimetric tasks in small photon fields, electron beams and build-up regions of photon beams has been observed. The new diode also has an improved angular response. However, due to its over-response to low-energy scattered photons, its recommended range of use does not include output factor measurements in large photon fields, although this effect can be compensated by a thin auxiliary lead shield.