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Padraig Warde,
Malcolm Mason,
Keyue Ding,
Peter Kirkbride,
Michael Brundage,
Richard Cowan,
Mary Gospodarowicz,
Karen Sanders,
Edmund Kostashuk,
Greg Swanson,
Jim Barber,
Andrea Hiltz,
Mahesh K B Parmar, Jinka Sathya,
John Anderson,
Charles Hayter,
John Hetherington,
Matthew R Sydes,
Wendy Parulekar
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ABSTRACT: Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer.
Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65-69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633.
Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4-8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70-78 vs 66%, 60-70; hazard ratio [HR] 0·77, 95% CI 0·61-0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups).
The benefits of combined modality treatment--ADT and RT--should be discussed with all patients with locally advanced prostate cancer.
Canadian Cancer Society Research Institute, US National Cancer Institute, and UK Medical Research Council.
The Lancet 11/2011; 378(9809):2104-11. · 38.28 Impact Factor
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ABSTRACT: A framework for the introduction and evaluation of APN roles emphasizes the importance of a systematic approach to role development based on the assessment of patient health needs. This study determined the health-related quality of life (HRQL) of patients with prostate cancer. The most frequent and severe patient health problems and their perceptions of priority health problems were identified and compared across five patient groups as a strategy to inform the supportive care role of the advanced oncology nurse for patients with advanced prostate cancer. The study found that the majority of men with early stage and advanced hormone sensitive prostate cancer can expect to enjoy good quality of life for several years following diagnosis. These two patient groups have common priority needs for improving their health related to sexual function, urinary frequency, urinary incontinence, and physical activity. Both groups may benefit from an advanced practice nursing (APN) role that can provide episodic supportive care for health problems occurring at different treatment stages. Conversely, it was found that men with advanced hormone refractory prostate cancer experience significantly poorer HRQL and have multiple severe health problems. These patients also have different priority needs including problems related to pain, fatigue, and decreased physical activity. Because of this, the focus of supportive care programs and interventions in advanced prostate cancer will differ for those with hormone refractory disease. They may benefit more from an APN role that can provide ongoing rather than episodic supportive care to assess and manage the multiple, new, and worsening health problems associated with progressive disease.
Canadian oncology nursing journal = Revue canadienne de nursing oncologique 01/2010; 20(1):5-14.
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ABSTRACT: To examine a potential correlation between the in vitro apoptotic response of lymphocytes to radiation and the risk of developing late gastrointestinal (GI)/genitourinary (GU) toxicity from radiotherapy for prostate cancer.
Prostate cancer patients formerly enrolled in a randomized study were tested for radiosensitivity by using a radiation-induced lymphocyte apoptosis assay. Apoptosis was measured using flow cytometry-based Annexin-FITC/7AAD and DiOC(6)/7AAD assays in subpopulations of lymphocytes (total lymphocytes, CD4+, CD8+ and CD4-/CD8-) after exposure to an in vitro dose of 0, 2, 4, or 8 Gy.
Patients with late toxicity after radiotherapy showed lower lymphocyte apoptotic responses to 8 Gy than patients who had not developed late toxicity (p = 0.01). All patients with late toxicity had apoptosis levels that were at or below the group mean. The negative predictive value in both apoptosis assays ranged from 95% to 100%, with sensitivity values of 83% to 100%. Apoptosis at lower dose points and in lymphocyte subpopulations had a weaker correlation with the occurrence of late toxicity.
Lymphocyte apoptosis after 8 Gy of radiation has the potential to predict which patients will be spared late toxicity after radiation therapy. Further research should be performed to identify the specific subset of lymphocytes that correlates with late toxicity, followed by a corresponding prospective study.
International journal of radiation oncology, biology, physics 02/2009; 74(5):1424-30. · 4.59 Impact Factor
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Journal of Clinical Oncology 01/2009; 27(4):644-6. · 18.37 Impact Factor
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ABSTRACT: Radiation protection regulations have been established to reduce exposure of individuals to acceptable safe levels. These limits assume that people have similar responses to ionizing radiation and that there is no variation in individual radiation risk. The purpose of this research was to determine if apoptosis in lymphocytes can be used to assess individual sensitivity to ionizing radiation. Blood samples were taken from 54 males ranging in age from 19-85 years. Apoptosis was measured using modified flow cytometry based Annexin-FITC/7AAD and DiOC(6)/7AAD assays in different populations of lymphocytes (total mixed lymphocyte population, subset CD4+ or CD8+ lymphocytes) after exposure to in vitro doses of 0, 2, 4 or 8Gy (dose rate 0.1Gy/min). The variation in individual responses to radiation was large. The variation was the largest in the CD4+ lymphocyte sub-population. Radiation-induced apoptosis decreased with age of donor demonstrating that as people age their lymphocytes may become relatively more resistant to radiation. This research shows that individuals have marked differences in their sensitivity to radiation and protection policies may someday need to be tailored for some individuals.
Dose-Response 01/2007; 5(4):333-48. · 1.91 Impact Factor
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Himu Lukka,
Charles Hayter,
Jim A Julian,
Padraig Warde,
W James Morris,
Mary Gospodarowicz,
Mark Levine, Jinka Sathya,
Richard Choo,
Hugh Prichard,
Michael Brundage,
Winkle Kwan
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ABSTRACT: The optimal radiation dose fractionation schedule for localized prostate cancer is unclear. This study was designed to compare two dose fractionation schemes (a shorter 4-week radiation schedule v a longer 6.5-week schedule).
Patients with early-stage (T1 or T2) prostate cancer were randomly assigned to 66 Gy in 33 fractions over 45 days (long arm) or 52.5 Gy in 20 fractions over 28 days (short arm). The study was designed as a noninferiority investigation with a predefined tolerance of -7.5%. The primary outcome was a composite of biochemical or clinical failure (BCF). Secondary outcomes included presence of tumor on prostate biopsy at 2 years, survival, and toxicity.
From March 1995 to December 1998, 936 men were randomly assigned to treatment; 470 were assigned to the long arm, and 466 were assigned to the short arm. The median follow-up time was 5.7 years. At 5 years, the BCF probability was 52.95% in the long arm and 59.95% in the short arm (difference = -7.0%; 90% CI, -12.6% to -1.4%), favoring the long arm. No difference in 2-year postradiotherapy biopsy or in overall survival was detected between the arms. Acute toxicity was found to be slightly higher in the short arm (11.4%) compared with the long arm (7%; difference = -4.4%; 95% CI, -8.1% to -0.6%); however, late toxicity was similarly low in both arms (3.2%).
Given the results, we cannot exclude the possibility that the chosen hypofractionated radiation regimen may be inferior to the standard regimen. Further evaluation involving higher dose hypofractionated radiation regimens in contemporary radiation settings is necessary.
Journal of Clinical Oncology 10/2005; 23(25):6132-8. · 18.37 Impact Factor
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ABSTRACT: The purpose was to develop a systematic review that would address the following question: what is the role of radiopharmaceuticals in the palliation of metastatic bone pain in adults with uncomplicated, multifocal painful bone metastases whose pain is not controlled with conventional analgesic regimens? The outcomes of interest are pain response, analgesic consumption, overall survival, adverse effects and quality of life.
A systematic review of the English published literature was undertaken to provide evidence relevant to the above outcomes.
Six randomized phase III trials, two randomized phase II trials and one randomized crossover trial of strontium-89 were reviewed. A randomized phase III trial comparing strontium-89 plus cisplatin with strontium-89 plus placebo reported a significantly higher proportion of patients experiencing pain relief for a significantly longer duration with strontium-89 plus cisplatin. A randomized phase III trial comparing adjuvant strontium-89 with placebo following radiotherapy reported a higher proportion of pain-free patients with strontium-89. Patients who received strontium-89 also experienced fewer new sites of bone pain. A second, but underpowered study failed to confirm these results. In one randomized trial of strontium-89 versus radiotherapy (hemibody or local), patients treated with strontium-89 developed fewer new sites of pain. In a second trial comparing strontium-89 versus local radiotherapy, median overall survival was improved with radiotherapy, while pain response and time-to-progression were similar in the two groups. One randomized phase III trial reported no difference in pain relief between strontium-89 and placebo. Three randomized phase III trials and two randomized phase II trials investigating samarium-153 were reviewed. In a randomized phase III trial of three different doses of samarium-153, the pain responses were similar for all three doses. In a randomized phase III trial of two different doses of samarium-153 versus placebo, the complete pain response rate was significantly higher with the higher dose of samarium-153 compared with placebo. In a randomized phase III trial comparing samarium-153 with placebo, significant differences favouring samarium-153 were reported for pain and opiate use. In addition, one randomized phase III trial, two randomized phase II trials, one randomized crossover trial and 13 phase II or phase I trials of rhenium, one phase I trial of tin-117 m and one phase II trial of phosphorus-32 were reviewed. The majority of patients treated in trials of radiopharmaceuticals where histology was specified had metastatic breast cancer (approximately 5-10% of patients reported), metastatic hormone-refractory prostate cancer (80-90% of patients reported) or metastatic lung cancer (5-10% of patients reported). Information on histologic subtype was not available for a significant proportion of patients treated on trials (30-40% of patients reported).
Use of single-agent radiopharmaceuticals (strontium-89 and samarium-153) should be considered as a possible option for the palliation of multiple sites of bone pain from metastatic cancer where pain control with conventional analgesic regimens is unsatisfactory and where activity on a bone scan of the painful lesions is demonstrated. Ongoing clinical research should seek to establish the benefit of newer radiopharmaceuticals and radiopharmaceuticals in combination with other systemic therapies.
Radiotherapy and Oncology 07/2005; 75(3):258-70. · 5.58 Impact Factor
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ABSTRACT: To survey radiation oncology practice in the utilization of hormonal and radiation therapy in the primary, adjuvant and salvage treatment of localized prostate cancer.
Genitourinary radiation oncologists practicing in Ontario were invited to participate in a practice survey examining staging, hormonal and radiation management, and radiation technique for a variety of common clinical scenarios. Background demographic information was collected on all respondents. The survey consisted of three cases relating to the hormonal/radiation management of low-, intermediate-, and high-risk prostate cancer as well as two adjuvant and one salvage post-prostatectomy scenarios. The survey response rate was 70% (26/37).
Clinicians were more likely to utilize laboratory and imaging studies for staging as the risk categorization increased. Low-risk disease was managed with radiation alone in 26/26 (70 Gy in 65%, 74-79.8 Gy in 35%). Intermediate-risk disease was managed with radiation (70 Gy in 46%, 74-79.8 Gy in 54%) with neoadjuvant hormones in 58%. All respondents managed high-risk disease with adjuvant hormones in addition to radiation therapy (70-71 Gy in 85%, and 76 Gy in 15%). In the pT3a, margin negative (PSA undetectable) scenario, most individuals would not recommend adjuvant radiation (73%). If margins were positive, 30% would still not recommend adjuvant radiation. In the salvage scenario (slowly rising PSA 4 years post-prostatectomy for pT2a close margin disease), all respondents would manage with radiation therapy. Hormones were not routinely recommended in the initial management of the adjuvant and salvage scenarios. Radiation doses utilized for both adjuvant and salvage treatment ranged from 60-70 Gy (median 66 Gy).
General agreement exists for the management of low- and high-risk disease and in the post-prostatectomy salvage setting. Use of dose-escalation and neoadjuvant hormones in the intermediate-risk setting and use of post-prostatectomy adjuvant radiation in the pT3a scenarios varied among radiation oncologists. Current clinical practice in localized prostate cancer reflects the evolving information in the published medical literature.
Radiotherapy and Oncology 11/2003; 69(1):63-72. · 5.58 Impact Factor
