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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. PURPOSE The European Organisation for Research and Treatment of Cancer 10981-22023 AMAROS trial evaluated axillary lymph node dissection (ALND) versus axillary radiotherapy (ART) in patients with cT1-2, node-negative breast cancer and a positive sentinel node (SN) biopsy. At 5 years, both modalities showed excellent and comparable axillary control, with significantly less morbidity after ART. We now report the preplanned 10-year analysis of the axillary recurrence rate (ARR), overall survival (OS), and disease-free survival (DFS), and an updated 5-year analysis of morbidity and quality of life. METHODS In this open-label multicenter phase III noninferiority trial, 4,806 patients underwent SN biopsy; 1,425 were node-positive and randomly assigned to either ALND (n = 744) or ART (n = 681). RESULTS Per intention-to-treat analysis, 10-year ARR cumulative incidence was 0.93% (95% CI, 0.18 to 1.68; seven events) after ALND and 1.82% (95% CI, 0.74 to 2.94; 11 events) after ART (hazard ratio [HR], 1.71; 95% CI, 0.67 to 4.39). There were no differences in OS (HR, 1.17; 95% CI, 0.89 to 1.52) or DFS (HR, 1.19; 95% CI, 0.97 to 1.46). ALND was associated with a higher lymphedema rate in updated 5-year analyses (24.5% v 11.9%; P < .001). Quality-of-life scales did not differ by treatment through 5 years. Exploratory analysis showed a 10-year cumulative incidence of second primary cancers of 12.1% (95% CI, 9.6 to 14.9) after ART and 8.3% (95% CI, 6.3 to 10.7) after ALND. CONCLUSION This 10-year analysis confirms a low ARR after both ART and ALND with no difference in OS, DFS, and locoregional control. Considering less arm morbidity, ART is preferred over ALND for patients with SN-positive cT1-2 breast cancer.

The phosphoinositide 3′-kinase (PI3K)–mediated signaling pathway plays a key role in fundamental cellular functions important in normal cellular homeostasis and malignant transformation. Deregulated signaling through this pathway contributes to development of gliomas and their resistance to radiation and chemotherapy. Targeting the PI3K signaling pathway has thus emerged as a promising approach to successful treatment of gliomas. We assessed the radiosensitizing potential of four small-molecule inhibitors that differ in their activities against specific isoforms of the PI3K 110-kDa catalytic subunit (p110). p110α inhibitors blocked phosphorylation of both protein kinase B/Akt and S6 in all cell lines examined, effectively decreased cellular proliferation, and produced additive cytotoxic effects in combination with radiation therapy. The p110β inhibitor exhibited limited biochemical effects and failed to decrease cellular proliferation or viability as either a single agent or in combination with radiation or rapamycin. In vivo studies examining the effects of the p110α inhibitor in combination with radiation indicated a significant reduction in tumor growth rate induced by the combined treatment compared with each treatment modality alone. This translated into a trend toward prolonged time-to-failure for mice in the combination treatment group. In conclusion, PI3K inhibitors are promising agents in the treatment of glioblastomas, especially when used in combination with ionizing radiation. [Mol Cancer Ther 2008;7(4):841–50]

To investigate whether axillary radiotherapy (ART) in patients with primary breast cancer and a tumour-positive sentinel node results in a similar axillary tumour recurrence rate compared with axillary lymph node dissection (ALND), and whether ART results in lower morbidity.Randomised, multicentre non-inferiority trial.Patients with breast cancer ≤ 5 cm without clinical signs of lymph node metastases but with a tumour-positive sentinel node were randomised between ALND or ART. The primary endpoint was the 5-year axillary recurrence rate. Secondary endpoints were disease-free survival, overall survival, morbidity (lymphoedema and shoulder function) and quality of life. (www.clinicaltrials.gov, study number NCT00014612.)Between 2001 and 2010, 1425 patients with a tumour-positive sentinel node were included, 744 of whom had been randomised to ALND and 681 to ART. After a median follow-up period of 6.1 years, the 5-year axillary recurrence rate was 0.43% after ALND and 1.19% after ART; the difference was not statistically significant. The primary analysis was underpowered due to the low number of axillary recurrences. At 5 years the disease-free survival rate was 86.9% after ALND and 82.7% after ART. Overall survival was 93.3% and 92.5% respectively. Lymphoedema was noted significantly more often after ALND than after ART at 1 year, 3 years and 5 years. There were no significant differences in shoulder function or quality of life.Both ART and ALND produce very low axillary recurrence rates in patients with breast cancer ≤ 5 cm and a tumour-positive sentinel node. ART results in significantly less lymphoedema than ALND.

Purpose Adjuvant radiotherapy (RT) after a local excision (LE) for ductal carcinoma in situ (DCIS) aims at reduction of the incidence of a local recurrence (LR). We analyzed the long-term risk on developing LR and its impact on survival after local treatment for DCIS. Patients and Methods Between 1986 and 1996, 1,010 women with complete LE of DCIS less than 5 cm were randomly assigned to no further treatment (LE group, n = 503) or RT (LE+RT group, n = 507). The median follow-up time was 15.8 years. Results Radiotherapy reduced the risk of any LR by 48% (hazard ratio [HR], 0.52; 95% CI, 0.40 to 0.68; P < .001). The 15-year LR-free rate was 69% in the LE group, which was increased to 82% in the LE+RT group. The 15-year invasive LR-free rate was 84% in the LE group and 90% in the LE+RT group (HR, 0.61; 95% CI, 0.42 to 0.87). The differences in LR in both arms did not lead to differences in breast cancer–specific survival (BCSS; HR, 1.07; 95% CI, 0.60 to 1.91) or overall survival (OS; HR, 1.02; 95% CI, 0.71 to 1.44). Patients with invasive LR had a significantly worse BCSS (HR, 17.66; 95% CI, 8.86 to 35.18) and OS (HR, 5.17; 95% CI, 3.09 to 8.66) compared with those who did not experience recurrence. A lower overall salvage mastectomy rate after LR was observed in the LE+RT group than in the LE group (13% v 19%, respectively). Conclusion At 15 years, almost one in three nonirradiated women developed an LR after LE for DCIS. RT reduced this risk by a factor of 2. Although women who developed an invasive recurrence had worse survival, the long-term prognosis was good and independent of the given treatment.

On average, 250 skin-sparing mastectomies with immediate prosthetic reconstruction are performed in the Dutch Antoni van Leeuwenhoek Hospital each year. We report on two breast cancer patients (46 and 53 years old) who each developed a local recurrence at the entry site of the core needle biopsy after skin-sparing mastectomy with immediate prosthetic reconstruction. In hindsight, the most likely cause for these recurrences was the fact that one of the entry sites for the core needle biopsies was not marked preoperatively, and thus not excised during surgery. These examples emphasise the need for accurate documentation of the locations of these entry sites, followed by their excision, in patients undergoing skin-sparing mastectomy for invasive breast cancer.

The combination of irradiation with angiogenic inhibition is increasingly being investigated for treatment of glioblastoma multiforme (GBM). We investigated whether vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor DC101 affects morbidity and tumor growth in irradiated and non-irradiated intracerebral GBM-bearing mice, controlled with sham treatments. End-points were toxicity, morbidity and histology. Irradiation either or not combined, reduced tumor size strongly, whereas DC101 mono-treatment reduced tumor size by 64%. Irradiation delayed morbidity from 5.8 weeks in sham-treated mice to 10.3 weeks. Morbidity after combined treatment occurred after 5.9 weeks. Treatment with angiogenesis inhibitor DC101 delays tumor growth but it induces morbidity, by itself or combined with irradiation. (C) 2009 Elsevier Ireland Ltd. All rights reserved

Glioblastoma multiforme (GBM) is a radioresistant tumor. Tumor neoangiogenesis is an important mechanism for tumor sustenance. Angiogenesis is primarily mediated by vascular endothelial growth factor (VEGF), and earlier studies have suggested that VEGF protects human umbilical vein endothelial cells (HUVECs) against high doses of radiation. We tried to extend these findings to other endothelial cell lines and clinically relevant irradiation doses. Therefore, four different endothelial cell lines (HUVEC-C, primary HUVEC-P, an immortalized HUVEC cell line: EC-RF24, and bovine retina endothelial cells: BREC) were cultured without or with recombinant human VEGF165 (rhVEGF165). Cells were irradiated with gamma-rays from a 137Cs-source. Radiosensitivity was determined by proliferation or clonogenic assay. Apoptosis was assayed by flow cytometric determination of the sub-G1 population or by counting nuclear fragmentation. We found that the biologically active rhVEGF165 was able to improve clonogenic survival of HUVEC-C after 2 and 5 Gy. However, rhVEGF165 could not significantly alter the radiosensitivity of all cell lines studied in proliferation assays. rhVEGF165 only slightly reduced apoptosis in HUVEC-C after 3 Gy. In conclusion, the radioprotective effect from rhVEGF165 was found on different endothelial cell lines after clinically relevant radiation doses was negligible. We therefore hypothesize that the high VEGF-levels found in GBM in vivo do not reduce the radiosensitivity of endothelial cells, which is thought to contribute to the strong radioresistance of the tumor vasculature.

Objective: Postoperative radiotherapy is standard treatment for patients with a glioblastoma multiforme (GBM). However, a GBM is radioresistant and almost always recurs, even after a high dose of radiation. A GBM is characterized by its extensive neo-angiogenesis, which can be attributed to the high levels of vascular endothelial growth factor (VEGF). The scope of this study is to investigate the VEGF secretion by GBM cells with different radiosensitivity after irradiation. Methods:Three human GBM cell lines (U251, U251-NG2 and U87) were irradiated with single doses of 0, 5, 10 and 20 Gy of gamma(3)-rays from a Cs-137 source. VEGF levels in medium were measured by ELISA at 24, 48 and 72 h after radiation. Cell survival was measured by the XTT assay 7 days after irradiation. Results:Following single dose radiation, the VEGF levels showed a dose dependent increase in U251, U251-NG2 and U87 glioma cells. Both base-line and radiation-enhanced VEGF levels were about 10-fold higher in U87 compared to U251 and U251-NG2 cells. In addition, in the XTT assay, the U87 was more radioresistant than both U251 and U251-NG2 cell lines (dose modifying factor (DMF) = 1.6 and 1.7 resp). Conclusion:Irradiation enhanced VEGF secretion in all three tested glioma cell lines (up to eight times basal levels). It is tempting to associate the radiation-enhanced VEGF secretion with an increased angiogenic potential of the tumor, which may be a factor in radioresistance