Heterogeneity in high-risk prostate cancer treated with high-dose radiation therapy and androgen deprivation therapy.

BACKGROUND: Our aim was to assess the heterogeneity of high-risk (HR) prostate cancer managed with high-dose external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT). METHODS: We identified 547 patients who were treated with modern EBRT from 1997 to 2013, of whom 98% received ADT. We analyzed biochemical relapse-free survival (bRFS) and distant metastases-free survival (DMFS). RESULTS: Median EBRT dose was 74 Gy, and median ADT duration was 8 months. At 5 years, the DMFS was 85%. On multivariate analysis, significant predictors of shorter bRFS were biopsy Gleason score (bGS) of 8 to 10, higher prostate-specific antigen (PSA) level, shorter duration of ADT and lower radiation dose while predictors of shorter DMFS were bGS of 8 to 10, higher PSA level, and lower radiation dose. We identified an unfavorable high-risk (UHR) group of with 2-3 HR factors based on 2015 National Comprehensive Cancer Network (NCCN) criteria and a favorable high-risk (FHR) group, with 1 HR feature. Comparing very-HR prostate cancer, UHR & FHR, 5 year bRFS rates were 58.2%, 66.2%, and 69.2%, and 5 year DMFS rates were 78.4%, 81.2%, and 88.0%. CONCLUSION: Patients with multiple HR factors have worse outcome than patients with 1 HR factor. Future studies should account for this heterogeneity in HR prostate cancer.

Discovery and Longitudinal Evaluation of Candidate Protein Biomarkers for Disease Recurrence in Prostate Cancer.

When compared with hormonal therapy alone, treatment with combined hormone and radiation therapy (CHRT) gives improved disease-specific survival outcomes for patients with prostate cancer; however, a significant number of CHRT patients still succumb to recurrent disease. The purpose of this study was to use longitudinal patient samples obtained as part of an ongoing noninterventional clinical trial (ICORG06-15) to identify and evaluate a potential serum protein signature of disease recurrence. Label-free LC-MS/MS based protein discovery was undertaken on depleted serum samples from CHRT patients who showed evidence of disease recurrence (n = 3) and time-matched patient controls (n = 3). A total of 104 proteins showed a significant change between these two groups. Multiple reaction monitoring (MRM) assays were designed for a subset of these proteins as part of a panel of putative prostate cancer biomarkers (41 proteins) for evaluation in longitudinal serum samples. These data revealed significant interpatient variability in individual protein expression between time of diagnosis, disease recurrence, and beyond and serve to highlight the importance of longitudinal patient samples for evaluating the use of candidate protein biomarkers in disease monitoring.

Temporal patterns of late bowel and bladder radiotherapy toxicity in a randomised controlled trial assessing duration of neo-adjuvant hormones in prostate cancer.

BACKGROUND: To assess the temporal patterns of late gastrointestinal (GI) and genitourinary (GU) radiotherapy toxicity and resolution rates in a randomised controlled trial (All-Ireland Cooperative Oncology Research Group 97-01) assessing duration of neo-adjuvant (NA) hormone therapy for localised prostate cancer. MATERIAL AND METHODS: Node negative patients with > 1 of: PSA > 20 ng/mL, Gleason score ≥ 7, and stage T3 or more, were included. Follow-up, including toxicity assessment, was three-monthly in the early stages and yearly thereafter. RESULTS: Median follow-up from the end of RT was 6.8 years. In the interval between 90 days following the end of RT and the last toxicity assessment, GI and GU toxicity (any grade) was found in 50% and 51% of 240 and 241 patients, respectively. For those who did develop toxicity, the median time from end of RT until the first development of any grade GI or GU toxicity was 1.2 years and 1.6 years, respectively, whilst median time to final resolution was 1.6 years and 2.2 years, respectively. Grade 2 (G2) or greater GI and GU toxicity occurred in 29 (12.1%) and 40 (16.6%) patients, respectively. The proportion with unresolved G2 + GI and GU toxicity was 89% and 79%, respectively, in year 1, 69% and 65% in year 2, 59% and 52% in year 3 and 27% and 32% in year 5. CONCLUSION: Long-term toxicities continue to occur many years after NA hormone therapy and RT. The rate of occurrence does not appear to reduce within the time frame during which our patients were followed. The percentage of patients suffering from G2 + toxicity at any time is however low. Resolution of these toxicities continues for the duration of the follow-up.

Cancer Trials Ireland (ICORG) 06-34: A multi-centre clinical trial using three-dimensional conformal radiation therapy to reduce the toxicity of palliative radiation for lung cancer.

TITLE: Cancer Trials Ireland (ICORG) 06-34: A multi-centre clinical trial using three-dimensional conformal radiation therapy to reduce the toxicity of palliative radiation for lung cancer. NCT01176487. BACKGROUND & PURPOSE: Trials of radiation therapy for the palliation of intra-thoracic symptoms from locally advanced non-small cell lung cancer (NSCLC) have concentrated on optimising fractionation and dose schedules. In these trials, the rates of oesophagitis induced by this "palliative" therapy have been unacceptably high. In contrast, this non-randomised, single-arm trial was designed to assess if more technically advanced treatment techniques would result in equivalent symptom relief and reduce the side-effect of symptomatic oesophagitis. MATERIALS & METHODS: Thirty-five evaluable patients with symptomatic locally advanced or metastatic NSCLC were treated using a three-dimensional conformal technique (3-DCRT) and standardised dose regimens of 39 Gy in 13 fractions, 20 Gy in 5 fractions or 17 Gy in 2 fractions. Treatment plans sought to minimise oesophageal dose. Oesophagitis was recorded during treatment, at two weeks, one month and three months following radiation therapy and 3-6 monthly thereafter. Mean dose to the irradiated oesophagus was calculated for all treatment plans. RESULTS: Five patients (14%) had experienced grade 2 oesophagitis or dysphagia or both during treatment and 2 other patients had these side effects at the 2-week follow-up. At follow-up of one month after therapy, there was no grade two or higher oesophagitis or dysphagia reported. 22 patients were eligible for assessment of late toxicity. Five of these patients reported oesophagitis or dysphagia (one had grade 3 dysphagia, two had grade 2 oesophagitis, one of whom also had grade 2 dysphagia). Quality of Life (QoL) data at baseline and at 1-month follow up were available for 20 patients. At 1-month post radiation therapy, these patients had slightly less trouble taking a short walk, less shortness of breath, did not feel as weak, had better appetite and generally had a better overall quality of life than they did at baseline. They did report being slightly more tired. CONCLUSIONS: This trial is the first of its kind showing that 3-DCRT provides patients with lower rates of oesophageal toxicity whilst yielding acceptable rates of symptom control. (Sponsored by Cancer Trials Ireland (ICORG) Study number 06-34, the Friends of St. Luke's and the St. Luke's Institute of Cancer Research.).

Escalated dose for non-small-cell lung cancer with accelerated hypofractionated three-dimensional conformal radiation therapy.

BACKGROUND AND PURPOSE: To prospectively assess the feasibility and efficacy of a hypofractionated accelerated radiotherapy regimen (72 Gy in 24 daily fractions, 3 Gy per fraction) in patients (pts) with non-resectable non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS: We included 25 pts with a histologically or cytologically proven NSCLC, with KPS > or = 70 and < or =10% weight loss over prior three months, and with tumour stage I/II medically inoperable (9 pts) or non-resectable stage III a/b without pleural effusion (16 pts). Eleven pts received induction chemotherapy. No more than 30% of the combined lung volume could receive more than 25 Gy and the maximal biological effective dose to the spinal cord was maintained below 44 Gy. RESULTS: No grade-4 acute toxicity event was reported. Two pts had a treatment break because of grade-3 acute oesophagitis. Twenty-two pts were evaluable for long-term toxicity (median follow-up=9.7 months, range 4 to 30.2 months). There were 4 Grade-1 pulmonary and 2 Grade-1 oesophageal long-term toxicity events. Twenty-two pts were evaluable for tumour response with 7 complete and 8 partial responses, 5 stable diseases and 2 progressive diseases. The actuarial 1-year overall and thoracic-progression-free survival rates were 68% and 72% respectively. CONCLUSIONS: This study demonstrates the feasibility of the experimental radiotherapy schedule, however more data are needed to confirm its efficacy.

Development of a label-free LC-MS/MS strategy to approach the identification of candidate protein biomarkers of disease recurrence in prostate cancer patients in a clinical trial of combined hormone and radiation therapy.

PURPOSE: Combined hormone and radiation therapy (CHRT) is one of the principle curative regimes for localised prostate cancer (PCa). Following treatment, many patients subsequently experience disease recurrence however; current diagnostics tests fail to predict the onset of disease recurrence. Biomarkers that address this issue would be of significant advantage. EXPERIMENTAL DESIGN: Label-free LC-MS/MS for protein biomarker discovery and MRM for targeted confirmation were applied to patient serum samples accrued in a non-interventional clinical trial of CHRT. RESULTS: Analysis of time-matched patient samples from a patient with disease recurrence compared with a time match disease-free individual supported the identification of 287 proteins. Of these, 141 proteins were quantified, 95 proteins changed in their expression (P ≤ 0.05 and ≥1.5-fold change) and of these 16 were selected for MRM confirmation. The protein expression changes observed in the label-free LC-MS/MS and MRM analysis were found to be highly correlated (R(2) = 0.85). CONCLUSIONS AND CLINICAL RELEVANCE: The establishment of a clinical trial to support the acquisition of samples and development of a pipeline for MS-based biomarker discovery and validation should contribute to the identification of a serum protein signature to predict or monitor the outcome of treatment of patients with PCa.

The effect of short term neo-adjuvant androgen deprivation on erectile function in patients treated with external beam radiotherapy for localised prostate cancer: an analysis of the 4- versus 8-month randomised trial (Irish Clinical Oncology Research Group 97-01).

BACKGROUND AND PURPOSE: Erectile dysfunction is a common consequence of external beam radiotherapy (EBRT) for prostate cancer. The addition of neo-adjuvant androgen deprivation (NAD) has an indeterminate additive effect. We examined the long-term effect on erectile function (EF) of two durations (4 months: arm 1 and 8 months: arm 2) of NAD prior to radiation (RT) for patients with localised prostate cancer from the Irish Clinical Oncology Research Group (ICORG 97-01) 4- versus 8-month trial. In this study we aimed to (1) analyse the overall effect on EF of NAD in an EBRT population, (2) compare the probability of retained EF over time in an EBRT population treated with either 4 or 8 months of NAD and (3) identify any variables such as risk group and age which may have an additive detrimental effect. This analysis provides unique long term follow up data. MATERIALS AND METHODS: From 1997 to 2001, 276 patients with adenocarcinoma of the prostate were randomised to 4 or 8 months of NAD before RT. EF data were recorded at baseline and at each follow-up visit by physician directed questions, using a 4-point grading system. RESULTS: Two hundred and thirty patients were included in the analysis of EF and were followed for a median of 80 months. One hundred and forty-one patients had EF at baseline. Neo-adjuvant androgen deprivation in addition to radiation therapy caused a significant reduction in EF. The most significant reduction in EF happens within the first year. The median time to grade 3-4 EF toxicity was 14.6 months, 17.6 months in arm 1 and 13.7 in arm 2. Freedom from late EF toxicity did not differ significantly between arms, overall or at 5 years (n=141). The cumulative probability of EF preservation at 5 years was 28% (22-34) in arm 1 and 24% (19-30) in arm 2. Age was a significant predictor of post-treatment EF. CONCLUSIONS: The first year post ADT and EBRT poses the greatest risk to sexual function and a continued decline may be expected. However, 26% of men can expect to retain sexual function at 5 years.

A randomized trial (Irish clinical oncology research group 97-01) comparing short versus protracted neoadjuvant hormonal therapy before radiotherapy for localized prostate cancer.

PURPOSE: To examine the long-term outcomes of a randomized trial comparing short (4 months; Arm 1) and long (8 months; Arm 2) neoadjuvant hormonal therapy before radiotherapy for localized prostate cancer. METHODS AND MATERIALS: Between 1997 and 2001, 276 patients were enrolled and the data from 261 were analyzed. The stratification risk factors were prostate-specific antigen level >20 ng/mL, Gleason score≥7, and Stage T3 or more. The intermediate-risk stratum had one factor and the high-risk stratum had two or more. Staging was done from the bone scan and computed tomography findings. The primary endpoint was biochemical failure-free survival. RESULTS: The median follow-up was 102 months. The overall survival, biochemical failure-free survival. and prostate cancer-specific survival did not differ significantly between the two treatment arms, overall or at 5 years. The cumulative probability of overall survival at 5 years was 90% (range, 87-92%) in Arm 1 and 83% (range, 80-86%) in Arm 2. The biochemical failure-free survival rate at 5 years was 66% (range, 62-71%) in Arm 1 and 63% (range, 58-67%) in Arm 2. CONCLUSION: No statistically significant difference was found in biochemical failure-free survival between 4 months and 8 months of neoadjuvant hormonal therapy before radiotherapy for localized prostate cancer.