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Biomedical subjects

Padraig Warde

Publications and source records attributed to Padraig Warde.

At least 19 recordsLinked to original sources

Treatment options, prognostic factors and selection of treatment in stage I seminoma.

Treatment options in patients with stage I seminoma include radiotherapy (RT), surveillance, and adjuvant chemotherapy. This patient population has virtually a 100% cure rate whichever approach is taken. While adjuvant retroperitoneal RT has been the standard of care for the past 50-60 years, there is increasingly persuasive data that adjuvant RT in this setting is associated with a small but definite increased risk of second malignancy and cardiovascular death. The long-term data from surveillance series have documented the safety of this approach, and it is now accepted that a policy of surveillance is the optimal management approach. This gives a relapse rate of 15%, and most patients can be successfully salvaged with RT. Second relapse after salvage RT occurs in a small proportion of cases, and these patients are cured with chemotherapy. Adjuvant chemotherapy using carboplatin has been investigated as an alternative strategy but has not lived up to its initial promise. If used, then 2 courses of treatment should probably be given. It must be remembered that 80-85% of patients with testicular seminoma require no treatment after orchiectomy, and the long-term side effects of any adjuvant treatment approach must be carefully considered.

Chemotherapy, Adjuvant↗

Pain flare in patients with bone metastases after palliative radiotherapy--a nested randomized control trial.

BACKGROUND: Short-course radiotherapy is a common treatment for the palliation of painful osseous metastases. Pain flare can be problematic, but its incidence has previously not been well-documented. The objectives of this study were to determine (1) the incidence of pain flare after palliative radiation for painful osseous metastases, and (2) whether single-fraction radiotherapy increases the risk of pain flare. MATERIALS AND METHODS: Patients accrued to a prospective randomized control trial comparing 8 Gy in one fraction to 20 Gy in five fractions (the Canadian Bone Metastasis Study) were approached to fill out a daily pain and analgesia diary for the 7 days post-radiotherapy. Patients assessed their average pain at the index site using the Present Pain Intensity (PPI) scale of the McGill-Melzack pain questionnaire and recorded their daily analgesic medications, which were translated into an analgesic score. Pain flare was defined as a two-point increase in the PPI with no decrease in analgesic score or a 50% increase in analgesic score with no decrease in PPI on at least two consecutive days. RESULTS: Forty-seven patients agreed to fill out the diary and 44 (94%) completed it. Fifteen of 44 (34.1%) patients experienced a pain flare that lasted a median of 3 days. Ten of 23 (43.5%) and 5/21 (23.8%) of patients who received 8 Gy and 20 Gy had a pain flare, respectively. CONCLUSIONS: Pain flare is common after palliative radiotherapy for osseous metastases and patients receiving single fraction radiotherapy may be at higher risk. Further study is warranted to determine predictors and preventive interventions.

Adult↗

Testosterone and erectile function recovery after radiotherapy and long-term androgen deprivation with luteinizing hormone-releasing hormone agonists.

OBJECTIVE: To study the recovery of testosterone levels and erectile function in men who received radiotherapy plus long-term adjuvant androgen deprivation (LTAD) with luteinizing hormone-releasing hormone (LHRH) agonists. PATIENTS AND METHODS: From April 2000 to July 2001, men who had completed prostate radiotherapy with > or = 2 years of LTAD, and had their last LHRH agonist injection at least 6 months before, were invited to participate. At study entry, the men completed the International Index of Erectile Function (IIEF), and their serum total testosterone (TT), prostate-specific antigen, LH, follicle-stimulating hormone, haemoglobin, and body mass were measured. This assessment was repeated at 1 year. RESULTS: In all, 20 men were recruited, with a mean (range) age of 70 (55-81) years. Defining a normal TT level as > or = 8.0 nmol/L, the median time to a normal level was 2.3 years (95% confidence interval (CI), 1.9-4.2). The median duration of castrate TT levels was 8 months (95% CI, 6.2-14.9). LH recovered before TT, suggesting that the rate-limiting step in the recovery of TT may be at the testicular level. The median time to recovery of normal LH levels was 3.8 months, compared to 8.0 months to reach supracastrate TT levels, and 2.3 years to reach normal TT levels. Age and the LH/TT ratio were associated with the time to recovery of both supracastrate and normal levels of TT. The IIEF was completed by 17 men; there were no significant changes in the scores in any domain of the IIEF during the study. CONCLUSIONS: Most men recover supracastrate testosterone levels after LTAD and external beam radiotherapy, but recovery of 'normal' testosterone levels is slow. Few men recover potency and sexual desire. The patients age and LH/TT ratio may be predictive of the time to recovery of both supracastrate and normal testosterone levels.

Aged↗

GU radiation oncologists consensus on bone loss from androgen deprivation.

The majority of GU radiation oncologists in Canada attended a consensus meeting in November 2004. The topic of osteoporosis in men receiving androgen deprivation therapy (ADT) for prostate cancer was identified as a key theme. A chaired session with keynote speakers and review of the evidence took place followed by open debate. Participants were provided with background information. Osteoporosis was defined as a T-score < or = -2.5, but the importance of risk factors and clinical findings is noted. Dual DEXA is the current standard for assessment of bone density and relates well to fracture risk. The lifetime risk of fracture is 13% for men over the age of 50 years even without the influence of ADT. Lifestyle, dietary and supplementation advice are provided both to prevent and to manage osteoporosis. The role for prophylactic bisphosphonate therapy in men on ADT without osteoporosis has not been established. Follow-up DEXA scans are required to monitor density, risk and response to interventions. Fracture incidence and BMD should be considered in the trial design of studies involving prolonged ADT. Osteoporosis is a treatable condition and the oncologist should employ ADT with this knowledge. A follow-up e-mail survey was carried out regarding the consensus statement. Responses were received from 49 of the 69 attendees (71%), and overall there was an 89% agreement with the consensus statement. This is now adopted as national practice guidelines for radiation oncologists employed prolonged ADT in prostate cancer patients.

Androgen Antagonists↗

Low and intermediate risk prostate cancer-- role of hormonal therapy with external beam radiation therapy.

Risk categorization based on pre-treatment PSA, clinical stage and Gleason score is now widely used in the management of patients with localized prostate cancer. In patients with low-risk disease (cT1-T2a, PSA < 10 ng/ml and Gleason score < 6) there is no role for the routine use of adjunctive hormonal therapy. In intermediate-risk patients (T1-T2, PSA < 20 ng/ml and Gleason <or= 7) there is some evidence to suggest improved outcomes with neo-adjuvant hormonal therapy when low-dose external beam radiation therapy (EBRT) is used. However, with appropriate modern dose EBRT there is little data to support the use of routine adjunctive hormonal therapy and this should be done only in the context of a clinical trial.

Androgen Antagonists↗

A phase II trial of palliative radiotherapy for metastatic renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) has previously been described as being less responsive to radiotherapy (RT) than other tumor types. The authors conducted a prospective study to assess the effect of RT on symptoms and quality of life (QOL) in patients with metastatic RCC. METHODS: Between 1996 and 2002, patients with symptomatic metastatic RCC were entered into a prospective study in two cancer centers. Symptomatic sites of disease were treated with 30 grays (Gy) in 10 fractions. Patients reported pain, analgesic use, symptoms, and QOL using validated questionnaires before RT, 1 month and 3 months after treatment, and every 3 months to 1 year thereafter. RESULTS: Thirty-one patients (19 males and 12 females) were entered into the trial. The median age of the patients was 61 years (range, 35-81 yrs). The most common indication for RT was bone pain (n = 24). The median duration of follow-up was 4.3 months (range, 1-15 mos). Of 23 evaluable patients treated for pain, 83% (n = 19) experienced site-specific pain relief after RT, and 48% (n = 11) did not have an associated increase in analgesic medication use. The median duration of site-specific pain response was 3 months (range, 1-15 mos). The global pain response rate was only 15% (n = 3) because many patients developed other painful metastases. Global QOL was found to improve in 33% (n = 8) of the evaluable patients. CONCLUSIONS: A palliative radiotherapy dose of 30 Gy in 10 fractions can result in a significant response rate and the relief of local symptoms in patients with bone metastases from RCC. Improvements in global pain and QOL appear to be limited by the effects of progressive systemic disease.

Adult↗

Optimal treatment of intermediate-risk prostate carcinoma with radiotherapy: clinical and translational issues.

The clinical heterogeneity of intermediate-risk prostate carcinoma presents a challenge to urologic oncology in terms of prognosis and management. There is controversy regarding whether patients with intermediate-risk prostate carcinoma should be treated with dose-escalated external beam radiotherapy (EBRT) (e.g., doses > 74 gray [Gy]), or conventional-dose EBRT (e.g., doses < 74 Gy) combined with androgen deprivation (AD). Data for this review were identified through searches for articles in MEDLINE and in conference proceedings, indexed from 1966 to 2004. Currently, the intermediate-risk prostate carcinoma grouping is defined on the basis of prostate-specific antigen (PSA), tumor classification (T classification), and Gleason score. Emerging evidence suggests that additional prognostic information may be derived from the percentage of positive core needle biopsies at the time of diagnosis and/or from the pretreatment PSA doubling time. Novel prognostic biomarkers include protein expression relating to cell cycle control, cell death, DNA repair, and intracellular signal transduction. Preclinical data support dose escalation or combined AD with radiation as a means to increase prostate carcinoma cell kill. There is Level I evidence that patients with intermediate-risk prostate carcinoma benefit from dose-escalated EBRT or AD plus conventional-dose EBRT. However, clinical evidence is lacking to support the uniform use of AD plus dose-escalated EBRT. Patients in the intermediate-risk group should be entered into well designed, randomized clinical trials of dose-escalated EBRT and AD with sufficient power to address biochemical failure and cause-specific survival endpoints. These studies should be stratified by novel prognostic markers and accompanied by strong translational endpoints to address clinical heterogeneity and to allow for individualized treatment.

Clinical Trials as Topic↗

Randomized trial comparing two fractionation schedules for patients with localized prostate cancer.

PURPOSE: 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 AND METHODS: 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. RESULTS: 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%). CONCLUSION: 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.

Adenocarcinoma↗

Postradiotherapy quality of life for head-and-neck cancer patients is independent of xerostomia.

PURPOSE: To determine the relationship between quality of life (QOL) and xerostomia over time for patients undergoing radiotherapy (RT) for head-and-neck cancer in a prospective clinical trial. METHODS AND MATERIALS: Patients with head-and-neck cancer were randomized to pilocarpine (n = 65) vs. placebo (n = 65) during RT. QOL was measured using the McMaster Head and Neck Radiotherapy Questionnaire (HNRQ). Xerostomia was measured on a linear analog scale. No statistically significant differences were observed between arms; all 130 patients were analyzed together. RESULTS: Baseline QOL data were obtained for 98.5% of participants. The baseline HNRQ score of 5.7 declined significantly to 4.0 (p <0.0001) by RT Week 6 and returned to baseline (5.8) by 6 months after treatment. This represents a large, clinically important change of 1.7 of 7 (24%; effect size 1.34). The decline in HNRQ score during RT paralleled the onset of xerostomia on the linear analog scale (r = 0.36 at 1 month). After treatment, the QOL scores recovered without improvement in xerostomia. The trajectory of the linear analog scale score resembled that of the HNRQ's single xerostomia question (r = 0.75 at 1 month). CONCLUSION: Quality of life recovers to baseline after RT, despite persistent xerostomia. Either a response shift occurs or xerostomia in the absence of acute mucositis has a relatively small influence on overall QOL.

Carcinoma, Squamous Cell↗

A reliable coding system to define screening prostate-specific antigen tests was developed in a case-control study.

OBJECTIVE: To establish the reliability of a coding system for screening and diagnostic prostate-specific antigen (PSA) testing from patient charts. STUDY DESIGN AND SETTING: Two investigators reviewed 448 chart abstractions from a population-based case-control study of PSA screening in the Toronto area. The tests evaluated for reliability were transrectal ultrasound (TRUS), digital rectal examination (DRE), and prostate-specific antigen (PSA). RESULTS: DRE results were found in 87%, PSA results in 65%, and TRUS results in 12% of the 749 charts. Interobserver agreement was 94% for DRE texture (kappa =.885), 95% for DRE asymmetry (kappa = .868), 85% for DRE physician interpretation (kappa = .698), 97% for final DRE result (kappa = .856), and 87% for TRUS (kappa = .769). Physician interpretation modified the final result in only 6.2% of DREs. Interobserver agreement for PSA coding was 91% (kappa = .787). Of PSA results, pure PSA screening with no symptoms of obstructive urination was found in 19%, symptomatic PSA screening in 46%, and diagnostic PSA testing in 35%. CONCLUSION: We have developed a practical and reliable coding system for TRUS, DRE, and PSA in the context of a case-control study of PSA screening.

Biomarkers, Tumor↗

A phase II study of localized prostate cancer treated to 75.6 Gy with 3D conformal radiotherapy.

BACKGROUND AND PURPOSE: To prospectively evaluate toxicity, biochemical failure-free survival (bFFS) and biopsy-proven local control for prostate cancer patients treated with 75.6 Gy in 42 fractions using 6-field conformal radiotherapy to prostate alone. PATIENTS AND METHODS: From 1997 to 1999, 140 patients with T1-2NxM0, Gleason score or=grade 2: 2%, and GU>or=grade 2: 1%. The 3-year bFFS of patients failure-free before biopsy was 93% (95% CI: 83-100) from a negative biopsy and 22% (95% CI: 0-56) from a positive biopsy (P=0.001). Patients reported significantly more late toxicity than physicians (GI: P=0.003, GU: P<0.001). At 5.0 years median follow-up, cause-specific survival was 98% (95% CI: 96-100), overall survival was 91% (95% CI: 86-97), and bFFS was 55% (95% CI: 45-64). CONCLUSIONS: 75.6 Gy caused modest levels of acute and late toxicity. Three-year biopsies predicted subsequent biochemical outcome.

Adenocarcinoma↗

Screening with prostate specific antigen and metastatic prostate cancer risk: a population based case-control study.

PURPOSE: Screening of asymptomatic men with prostate specific antigen (PSA) remains a controversial issue. There is limited evidence that screening is effective in reducing mortality from prostate cancer. In the current study we determined if screening with PSA reduces the risk of metastatic prostate cancer. MATERIALS AND METHODS: We conducted a population based case-control study among the residents of Metropolitan Toronto and 5 surrounding counties in Ontario, Canada. Data were obtained from 236 cases of metastatic prostate cancer and 462 controls randomly sampled from the source population and frequency matched to cases for age and area of residence. History of PSA testing, digital rectal examination, symptoms and other data were obtained from medical records and a self-administered questionnaire. The association between PSA screening and metastatic prostate cancer was measured by the Mantel-Haenszel odds ratio stratified by exposure observation time and other potential confounding factors. RESULTS: In asymptomatic men, the frequency of PSA screening as determined from medical records was significantly lower among the cases compared with the controls (odds ratio 0.65, 95% confidence interval 0.45 to 0.93). The odds ratio was 0.52 (0.28 to 0.98) in men 45 to 59 years old and 0.67 (0.41 to 1.09) in those 60 to 84 years old. CONCLUSIONS: In this case-control study screening of asymptomatic men with PSA was associated with a significantly reduced risk of metastatic prostate cancer. The results need to be confirmed in randomized controlled trials.

Aged↗

Prostate cancer radiotherapy 2002: the way forward.

In November 2000, the GU Radiation Oncologists of Canada had their first meeting, "Controversies in prostate cancer radiotherapy: consensus development". The success of this meeting prompted a second meeting, held in December 2002 to discuss "The Way Forward" in prostate radiotherapy. Radiation oncologists from across Canada were brought together and integrated with key opinion leaders in prostate cancer treatment from throughout North America. The group debated current controversies including: intensity modulated radiotherapy (IMRT), external beam hypofractionation, high dose-rate brachytherapy, and hormone therapy in the management of prostate cancer. The meeting also sought to identify and prioritize clinical trial opportunities and to highlight steps required to achieve these research goals. In summary, advances involving IMRT have enabled the use of higher radiation doses without increasing morbidity. With renewed interest in hypofractionated radiation schedules, the value of hypofractionation using IMRT was discussed and initial results from ongoing clinical trials were presented. The emerging role for high dose-rate brachytherapy in higher risk patients was also discussed. Based on existing preliminary evidence the group expressed enthusiasm for further investigation of the role for brachytherapy in intermediate to high-risk patients. Despite significant advances in radiotherapy, hormone therapy continues to play an important role in prostate cancer treatment for patients with intermediate and high-risk disease. Although evidence supports the effectiveness of hormone therapy, the optimal timing, and duration of hormonal treatment are unclear. Results from ongoing clinical trials will provide insight into these questions and will assist in the design of future clinical trials.

Clinical Trials as Topic↗

Polarographic electrode study of tumor oxygenation in clinically localized prostate cancer.

PURPOSE: To describe the oxygenation of clinically localized prostate cancer. METHODS AND MATERIALS: Intraprostatic oxygen tension was measured using the Eppendorf electrode in 55 unanesthetized men with localized prostate cancer before radiotherapy. Measurements were made along two tracks through regions of suspected tumor in the prostate, and core needle biopsies were then obtained from the same regions. RESULTS: The median pO(2) ranged from 0.2 to 57.3 mm Hg, and the grand median pO(2) was 4.5 mm Hg. The percentage of oxygen readings <5 mm Hg (HP(5)) ranged from 0% to 100% (median 60%). The track 1 oxygen readings were greater than those from track 2. Statistically significant heterogeneity was found in the individual oxygen readings: the between- and within-tumor components accounted for 32% and 68% of the total variability, respectively. However, the between-tumor variability in HP(5) significantly exceeded the within-tumor variability (61% vs. 39%). No association was found between oxygen values and clinical factors, including age, T stage, Gleason score, prostate-specific antigen level, hemoglobin concentration, or prior hormonal treatment. No difference was noted in the oxygenation between regions of tumor and normal prostate tissue, as determined from the core biopsies. CONCLUSION: Localized prostate cancer is characterized by marked hypoxia and significant heterogeneity in oxygenation, similar to other human tumors. The normal prostate may contain regions of low oxygen concentration. HP(5), as determined in this study, should adequately discriminate among patients with prostate cancer and allow the independent prognostic significance of oxygenation to be evaluated once the study matures.

Aged↗

A multinational, randomized phase III trial of iseganan HCl oral solution for reducing the severity of oral mucositis in patients receiving radiotherapy for head-and-neck malignancy.

PURPOSE: Oral mucositis (OM) causes significant morbidity during the course of radiotherapy (RT) treatment of head-and-neck cancer. It is hypothesized that infection plays a role in the development of OM. We tested the efficacy of iseganan HCl (iseganan), a synthetic peptide with broad-spectrum antimicrobial activity, for preventing RT-associated OM. METHODS: A multinational, randomized, double-blind, controlled trial was performed on patients receiving primary RT, primary chemoradiotherapy or postoperative RT. Patients were randomized to receive iseganan oral solution plus standard-of-care oral hygiene (SOC), placebo plus SOC, or SOC alone throughout the RT administration period. The severity of OM was assessed by NCI-CTC scoring and clinical symptoms by patient questionnaire. RESULTS: A total of 545 patients were randomized to the study. Nine percent of the patients in both the iseganan and placebo groups did not develop ulcerative OM (Grades 2, 3, 4) (p = 0.998) whereas only 2% of the patients receiving SOC alone remained free of oral ulceration (p = 0.049). The maximum severity of mouth pain and difficulty swallowing did not differ in patients treated with iseganan or placebo. However, patients in both intervention groups reported less mouth pain and difficulty swallowing than did patients receiving SOC alone. Nausea was the only adverse event that occurred with >/=5% increased frequency in the iseganan group than in either the placebo or SOC groups (51% vs. 42% vs. 46%). Adverse events leading to study drug discontinuation and death did not differ significantly between groups. CONCLUSION: Iseganan oral solution was safe but did not reduce the risk for developing ulcerative OM relative to placebo. Intensified oral hygiene or the administration of the vehicle used to deliver study drug in this trial appears to have reduced the risk and severity of OM. Our results suggest that antimicrobial intervention may not meaningfully affect the pathogenesis of radiation-induced OM.

Adult↗

The role of hemoglobin concentration in clinically localized prostate cancer treated with radical radiotherapy +/- neoadjuvant androgen deprivation.

PURPOSE: Serum hemoglobin level (Hb) is a significant determinant of treatment outcome after radical radiotherapy (RT) for several cancer types, but its importance in prostate cancer is not well established. METHODS AND MATERIALS: Two treatment-specific cohorts of men with localized prostate cancer (T1-4, Nx/N0, M0) were analyzed. Seven hundred six men who received radical RT at Princess Margaret Hospital between 1987 and 2000 comprise the RT-alone cohort, of whom 536 had a pre-RT Hb. Six hundred fifty-eight men received 3-6 months' neoadjuvant androgen deprivation (NAD) and radical RT at Royal Marsden Hospital between 1989 and 2000 and comprise the NAD + RT cohort, of whom 475 had a pre-NAD Hb and 513 a pre-RT Hb. Time to biochemical failure (TTBF) was the primary end point. Univariate and multivariate analyses using the Cox proportional hazards regression model were used for each data set independently to study the prognostic role of pre-RT Hb, pre-NAD Hb, nadir Hb (lowest Hb during RT), Hb decrement (pre-NAD Hb - pre-RT Hb), Gleason score, presenting PSA, and T stage. RESULTS: On univariate analysis, no significant association was seen between TTBF and any of the Hb variables for either data set. On multivariate analysis, TTBF was associated with presenting PSA (p < 0.001), Gleason score (p < 0.01), and (for the NAD + RT data set) T stage (p < 0.001), but not pre-NAD Hb (p = 0.24) or pre-RT Hb (p > 0.3). CONCLUSION: Hemoglobin level is not an important determinant of RT outcome in localized prostate cancer.

Aged↗

Late toxicity following conventional radiotherapy for prostate cancer: analysis of the EORTC trial 22863.

Late toxicity and other serious adverse events (SAE) were analysed in the European Organisation for Research and Treatment of Cancer (EORTC) trial 22863. The study evaluated the value of adjuvant endocrine treatment for locally advanced prostate cancer treated with radiotherapy. From 1987 to 1995, 415 patients were randomised. There was long-term toxicity information for 377 patients (91%). Median age was 70 years (range 50-80 years). Median follow-up for late toxicity was 42 months (range 3-136 months). Toxicity was graded according to a modified Radiotherapy and Oncology Group (RTOG) scale. Other late SAE, that was not classified as severe treatment toxicity, but were still life-threatening, were also assessed. There were 72 patients with grade 2, 10 patients with grade 3 and 4 patients with grade 4 toxicity. There were 20 patients with other late SAE, who were grouped according to their relationship to treatment; likely related (n = 1), unrelated (n = 7) and not assessable (n = 12). Although four treatment-related deaths (1%) occurred, grade 3 or 4 late complications were less than 5%.

Aged↗