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RTOG 0518: Randomized Phase III Trial to Evaluate Zoledronic Acid for Prevention of Osteoporosis and Associated Fractures in Prostate Cancer Patients
Background: RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT). Methods: Eligible patients with T-scores of the hip ( β2.5 vs. > β1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years. Results: Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm I and 34.8 months for Arm 2. Only two patients experienced a bone fracture (1 in each arm) resulting in no difference in freedom from any bone fracture (p=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs. β5%, p<0.0001), left total hip (1% vs. β8%, p=0.0002), and left femoral neck (3% vs. β8%, p=0.0007). Conclusions: For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL
Adjuvant gemcitabine and concurrent radiation for patients with resected pancreatic cancer: a phase II study
The safety and efficacy of gemcitabine and concurrent radiation to the upper abdomen followed by weekly gemcitabine in patients with resected pancreatic cancer was determined. Patients with resected adenocarcinoma of the pancreas were treated with intravenous gemcitabine administered twice-weekly (40βmgβmβ2) for 5 weeks concurrent with upper abdominal radiation (50.4βGy in 5Β½ weeks). At the completion of the chemoradiation, patients without disease progression were given gemcitabine (1000βmgβmβ2) weekly for two cycles. Each cycle consisted of 3 weeks of treatment followed by 1 week without treatment. Forty-seven patients were entered, 46 of whom are included in this analysis. Characteristics: median age 61 years (range 35β79); 24 females (58%); 73% stage T3/T4; and 70% lymph node positive. Grade III/IV gastrointestinal or haematologic toxicities were infrequent. The median survival was 18.3 months, while the median time to disease recurrence was 10.3 months. Twenty-four percent of patients were alive at 3 years. Only six of 34 patients with progression experienced local regional relapse as a component of the first site of failure. These results confirm the feasibility of delivering adjuvant concurrent gemcitabine and radiation to the upper abdomen. This strategy produced good local regional tumour control
Association of pretreatment hippocampal volume with neurocognitive function in patients treated with hippocampal avoidance whole brain radiation therapy for brain metastases: Secondary analysis of NRG Oncology/RTOG 0933
PURPOSE: Hippocampal volume (HV) is an established predicting factor for neurocognitive function (NCF) in neurodegenerative disease. Whether the same phenomenon exists with hippocampal-avoidant whole brain radiation therapy is not known; therefore, we assessed the association of baseline HV with NCF among patients enrolled on RTOG 0933.
METHODS AND MATERIALS: Hippocampal volume and total brain volume were calculated from the radiation therapy plan. Hippocampal volume was correlated with baseline and 4-month NCF scores (Hopkins Verbal Learning Test-Revised [HVLT-R] Total Recall [TR], Immediate Recognition, and Delayed Recall [DR]) using Pearson correlation. Deterioration in NCF was defined per the primary endpoint of RTOG 0933(mean 4-month relative decline in HVLT-R DR). Comparisons between patients with deteriorated and nondeteriorated NCF were made using the Wilcoxon test.
RESULTS: Forty-two patients were evaluable. The median age was 56.5 years (range, 28-83 years), and 81% had a class II recursive partitioning analysis. The median total, right, and left HVs were 5.4 cm
CONCLUSIONS: Larger HV was positively associated with improved performance on baseline and 4-month HVLT-R TR and DR scores in patients with brain metastases undergoing hippocampal-avoidant whole brain radiation therapy but was not associated with a change in NCF
Patient-Reported Outcomes (PROs) in NRG Oncology RTOG 1010: Phase III Trial Evaluating the Addition of Trastuzumab to Trimodality Treatment of HER2 Overexpressing (HER2+) Esophageal Adenocarcinoma (EAC)
Purpose/Objective(s): NRG/RTOG 1010 evaluated the benefit of trastuzumab for patients (pts) with HER2+ localized EAC receiving trimodality therapy. Adding trastuzumab did not improve disease-free (primary endpoint) or overall survival, nor treatment toxicity (Lancet Oncology 2022). The primary PRO objective was improvement (impr) in the FACT-Esophageal Cancer Subscale (ECS) score with trastuzumab at restaging prior to surgery. A secondary objective was to assess if impr in ECS score is associated with pathologic complete response (pCR).
Materials/Methods: Pts with HER2+ EAC (T1N1-2; T2-3N0-2) were stratified by presence of adenopathy & randomized 1:1 to weekly paclitaxel, carboplatin with 50.4 Gy radiation (CRT) followed by surgery Β± trastuzumab (CRT+T), 4mg/kg week 1, 2mg/kg/weekly x 5 during CRT, 6 mg/kg x1 prior to surgery, and then 6mg/kg every 3 weeks (wks) x 13. The ECS, v4, was done at baseline, 6-8 wks post-CRT and at 1 & 2 years. Impr in ECS and its Swallowing Index (SI) & Eating Index (EI) were defined as increases of 5, 2 & 2 points, respectively, from baseline. PRO sample size provided β₯ 80% power with 1-sided 0.05 alpha & a chi-squared test to determine if the proportion of pts categorized as improved at 6-8 wks is β₯ 25% higher for the CRT+T arm. Correlation between pCR & impr in ECS score was evaluated via chi-squared test.
Results: From 2010-2015, 203 HER2+ pts were randomized; 194 eligible. Of 171 PRO consenting pts, the ECS was completed by 162 (95%) at baseline, 108 (64%) 6-8 wks, 82 (49%) 1 year & 55 (33%) at 2 years. The main reason for FACT-E noncompliance was pt death. Patient & tumor characteristics were similar between arms. Median age was 63 years; 86% male; 96% white; 65% Zubrod 0, 80% cT3 & 71% cN1-2 (AJCC 7th ed). For ECS scores at 6-8 wks, the mean change (Ξ) was higher (better) from baseline at 4.6 (95% CI: 1.3, 7.8) for the CRT+T arm vs 0.9 (95% CI: -2.7, 4.6) for the CRT arm; the proportion of pts with an impr in 6-8 wks ECS was higher on the CRT+T arm (46% vs 38% on the CRT arm) although not significantly different (p=0.39). Table 1 shows ECS, SI & EI scores for all timepoints. At 6-8 wks, 30% with a pCR had an impr in ECS vs 45% of nonpCR pts (p=0.18). There were no significant correlations between pCR and ECS, SI & EI impr at any time points.
Conclusion: The addition of trastuzumab to trimodality therapy for localized HER2+ EAC did not significantly improve survival or PROs. ECS score improvement following therapy was not associated with a pCR. The higher proportion of pts with improved ECS at 6-8 weeks and 2 years in the CRT+T arm is interesting and suggests that HER2 may still be an important target to explore
Adjuvant gemcitabine and concurrent radiation for patients with resected pancreatic cancer: a phase II study
The safety and efficacy of gemcitabine and concurrent radiation to the upper abdomen followed by weekly gemcitabine in patients with resected pancreatic cancer was determined. Patients with resected adenocarcinoma of the pancreas were treated with intravenous gemcitabine administered twice-weekly (40βmgβmβ2) for 5 weeks concurrent with upper abdominal radiation (50.4βGy in 5Β½ weeks). At the completion of the chemoradiation, patients without disease progression were given gemcitabine (1000βmgβmβ2) weekly for two cycles. Each cycle consisted of 3 weeks of treatment followed by 1 week without treatment. Forty-seven patients were entered, 46 of whom are included in this analysis. Characteristics: median age 61 years (range 35β79); 24 females (58%); 73% stage T3/T4; and 70% lymph node positive. Grade III/IV gastrointestinal or haematologic toxicities were infrequent. The median survival was 18.3 months, while the median time to disease recurrence was 10.3 months. Twenty-four percent of patients were alive at 3 years. Only six of 34 patients with progression experienced local regional relapse as a component of the first site of failure. These results confirm the feasibility of delivering adjuvant concurrent gemcitabine and radiation to the upper abdomen. This strategy produced good local regional tumour control
Allelic imbalance at 1p36 may predict prognosis of chemoradiation therapy for bladder preservation in patients with invasive bladder cancer
Invasive bladder cancers have been treated by irradiation combined with cis- platinum (CDDP) as a bladder preservative option. The aim of this study was to find a marker for predicting patient outcome as well as clinical response after chemoradiation therapy (CRT) by investigating allelic loss of apoptosis-related genes. A total of 67 transitional cell carcinomas of the bladder treated by CRT (median dose: 32.4βGy of radiation and 232βmg of CDDP) were studied. We investigated allelic imbalances at 14 loci on chromosomes 17p13 and 1p36 including the p53 and p73 gene regions by fluorescent multiplex PCR based on DNA from paraffin-embedded tumour specimens and peripheral blood. The response to CRT was clinical response (CR) in 21 patients (31%), partial response (PR) in 31 (46%), and no change(NC) in 15 (22%). There was no statistical correlation between treatment response and clinical parameters, such as tumour grade, stage, radiation dose, or CDDP dose. The frequencies of allelic imbalance for TP53 and TP73 were 21 and 56%, respectively; neither was correlated with clinical treatment response and tumour stage or grade. There was no statistical correlation between treatment response and allelic imbalance at the other 12 loci. We found a significant correlation between cancer-specific survival and an imbalance of D1S243 (P=0.0482) or TP73 (P=0.0013) using a Log-rank test, although other loci including TP53 did not correlate with survival (P=0.4529 Multivariate analysis showed performance status (P=0.0047), recurrence (P=0.0017), and radiation doses (P=0.0468) were independent predictive factors for cancer-specific survival. However, an allelic imbalance of TP73 was the most remarkable independent predictive factor of poor patient survival (P=0.0002, risk ratio: 3382). Our results suggest that the allelic loss of the p73 gene predicts a clinical outcome of locally advanced bladder cancer when treated by CRT
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