BRCA1 Protein Expression Predicts Survival in Glioblastoma Patients from an NRG Oncology RTOG Cohort.

PURPOSE: Glioblastoma, the most common malignant brain tumor, was associated with a median survival of <1 year in the pre-temozolomide (TMZ) era. Despite advances in molecular and genetic profiling studies identifying several predictive biomarkers, none has been translated into routine clinical use. Our aim was to investigate the prognostic significance of a panel of diverse cellular molecular markers of tumor formation and growth in an annotated glioblastoma tissue microarray (TMA). METHODS AND MATERIALS: A TMA composed of archived glioblastoma tumors from patients treated with surgery, radiation, and non-TMZ chemother-apy, was provided by RTOG. RAD51, BRCA-1, phosphatase and tensin homolog tumor suppressor gene (PTEN), and miRNA-210 expression levels were assessed using quantitative in situ hybridization and automated quantitative protein analysis. The objectives of this analysis were to determine the association of each biomarker with overall survival (OS), using the Cox proportional hazard model. Event-time distributions were estimated using the Kaplan-Meier method and compared by the log-rank test. RESULTS: A cohort of 66 patients was included in this study. Among the 4 biomarkers assessed, only BRCA1 expression had a statistically significant correlation with survival. From univariate analysis, patients with low BRCA1 protein expression showed a favorable outcome for OS (p = 0.04; hazard ratio = 0.56) in comparison with high expressors, with a median survival time of 18.9 versus 4.8 months. CONCLUSIONS: BRCA1 protein expression was an important survival predictor in our cohort of glioblastoma patients. This result may imply that low BRCA1 in the tumor and the consequent low level of DNA repair cause vulnerability of the cancer cells to treatment.

A 10-year follow-up of treatment outcomes in patients with early stage breast cancer and clinically negative axillary nodes treated with tangential breast irradiation following sentinel lymph node dissection or axillary clearance.

We compare long-term outcomes in patients with node negative early stage breast cancer treated with breast radiotherapy (RT) without the axillary RT field after sentinel lymph node dissection (SLND) or axillary lymph node dissection (ALND). We hypothesize that though tangential RT was delivered to the breast tissue, it at least partially sterilized occult axillary nodal metastases thus providing low nodal failure rates. Between 1995 and 2001, 265 patients with AJCC stages I-II breast cancer were treated with lumpectomy and either SLND (cohort SLND) or SLND and ALND (cohort ALND). Median follow-up was 9.9 years (range 8.3-15.3 years). RT was administered to the whole breast to the median dose of 48.2 Gy (range 46.0-50.4 Gy) plus boost without axillary RT. Chi-square tests were employed in comparing outcomes of two groups for axillary and supraclavicular failure rates, ipsilateral in-breast tumor recurrence (IBTR), distant metastases (DM), and chronic complications. Progression-free survival (PFS) was compared using log-rank test. There were 136/265 (51%) and 129/265 (49%) patients in the SLND and ALND cohorts, respectively. The median number of axillary lymph nodes assessed was 2 (range 1-5) in cohort SLND and 18 (range 7-36) in cohort ALND (P < 0.0001). Incidence of AFR and SFR in both cohorts was 0%. The rates of IBTR and DM in both cohorts were not significantly different. Median PFS in the SLND cohort is 14.6 years and 10-year PFS is 88.2%. Median PFS in the ALND group is 15.0 years and 10-year PFS is 85.7%. At a 10-year follow-up chronic lymphedema occurred in 5/108 (4.6%) and 40/115 (34.8%) in cohorts SLND and ALND, respectively (P = 0.0001). This study provides mature evidence that patients with negative nodes, treated with tangential breast RT and SLND alone, experience low AFR or SFR. Our findings, while awaiting mature long-term data from NSABP B-32, support that in patients with negative axillary nodal status such treatment provides excellent long-term cure rates while avoiding morbidities associated with ALND or addition of axillary RT field.

Influence of radiation dose on positive surgical margins in women undergoing breast conservation therapy.

PURPOSE: Positive surgical margins adversely influence local tumor control in breast conservation therapy (BCT). However, reports have conflicted regarding whether an increased radiation dose can overcome this poor prognostic factor. In this study, we evaluated the influence of an increased radiation dose on tumor control in women with positive surgical margins undergoing BCT. METHODS AND MATERIALS: Between 1978 and 1994, 733 women with pathologic Stage I-II breast cancer and known surgical margin status were treated at Thomas Jefferson University Hospital with BCT. Of these 733 patients, 641 women had a minimal tumor bed dose of 60 Gy and had documentation of their margin status; 509 had negative surgical margins, and 132 had positive surgical margins before definitive radiotherapy. Complete gross excision of the tumor and axillary lymph node sampling was obtained in all patients. The median radiation dose to the primary site was 65.0 Gy (range 60-76). Of the women with positive margins (n = 132), the influence of higher doses of radiotherapy was evaluated. The median follow-up time was 52 months. RESULTS: The local tumor control rate for patients with negative margins at 5 and 10 years was 94% and 88%, respectively, compared with 85% and 67%, respectively, for those women with positive margins (p = 0.001). The disease-free survival rate for the negative margin group at 5 and 10 years was 91% and 82%, respectively, compared with 76% and 71%, respectively, for the positive margin group (p = 0.001). The overall survival rate of women with negative margins at 5 and 10 years was 95% and 90%, respectively. By comparison, for women with positive surgical margins, the overall survival rate at 5 and 10 years was 86% and 79%, respectively (p = 0.008). A comparison of the positive and negative margin groups revealed that an increased radiation dose (whether entered as a dichotomous or a continuous variable) >65.0 Gy did not improve local tumor control (p = 0.776). On Cox multivariate analysis, margin status and menopausal status had prognostic significance for local tumor control and DFS. CONCLUSION: Patients with positive surgical margins have a higher risk of local tumor recurrence and worse survival when undergoing BCT. Higher doses of radiation are unable to provide an adequate level of local control in patients with positive margins.

Hyperbaric oxygen therapy for radiation-induced cystitis and proctitis.

PURPOSE: To provide a retrospective analysis of the efficacy of hyperbaric oxygen therapy (HBOT) for treating hemorrhagic cystitis (HC) and proctitis secondary to pelvic- and prostate-only radiotherapy. METHODS AND MATERIALS: Nineteen patients were treated with HBOT for radiation-induced HC and proctitis. The median age at treatment was 66 years (range, 15-84 years). The range of external-beam radiation delivered was 50.0-75.6 Gy. Bleeding must have been refractory to other therapies. Patients received 100% oxygen at 2.0 atmospheres absolute pressure for 90-120 min per treatment in a monoplace chamber. Symptoms were retrospectively scored according to the Late Effects of Normal Tissues-Subjective, Objective, Management, Analytic (LENT-SOMA) scale to evaluate short-term efficacy. Recurrence of hematuria/hematochezia was used to assess long-term efficacy. RESULTS: Four of the 19 patients were lost to follow-up. Fifteen patients were evaluated and received a mean of 29.8 dives: 11 developed HC and 4 proctitis. All patients experienced a reduction in their LENT-SOMA score. After completion of HBOT, the mean LENT-SOMA score was reduced from 0.78 to 0.20 in patients with HC and from 0.66 to 0.26 in patients with proctitis. Median follow-up was 39 months (range, 7-70 months). No cases of hematuria were refractory to HBOT. Complete resolution of hematuria was seen in 81% (n = 9) and partial response in 18% (n = 2). Recurrence of hematuria occurred in 36% (n = 4) after a median of 10 months. Complete resolution of hematochezia was seen in 50% (n = 2), partial response in 25% (n = 1), and refractory bleeding in 25% (n = 1). CONCLUSIONS: Hyperbaric oxygen therapy is appropriate for radiation-induced HC once less time-consuming therapies have failed to resolve the bleeding. In these conditions, HBOT is efficacious in the short and long term, with minimal side effects.