Defining the need for local therapy in locally advanced prostate cancer: an appraisal of the MRC PR07 study.
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Antineoplastic Agents, Hormonal↗
Biomedical subjects
P Warde
Publications and source records attributed to P Warde.
Radiation therapy for high-risk prostate cancer--a review.
The term high-risk prostate cancer has been coined to encompass a group of patients with a poor prognosis (clinical stage T3/T4, or T1/T2 with PSA > 20 ng/ml or GS > 8). It is estimated that 20% of patients in Canada present with high-risk disease, which translates into approximately 4000 new cases each year. The optimal management approach is unclear but the standard of care in North America for this group of patients is radiation therapy (RT) with prolonged adjuvant hormonal therapy. Current clinical trials are evaluating the role of local therapy, the value of RT dose escalation, the potential benefit of regional lymph node irradiation, the appropriate duration of adjuvant hormonal therapy, as well as the possible impact of adjunctive chemotherapy. The high-risk group of patients contains a wide spectrum of disease, ranging from patients with aggressive localized disease to those with widespread occult distant metastases. The current challenge facing clinicians is appropriate treatment selection for individual patients. Information from novel biomarkers and improved imaging, as well as more effective local and adjunctive systemic therapies is necessary to improve outcomes for men with this aggressive disease.
Antineoplastic Agents, Hormonal↗
The relationship of changes in EORTC QLQ-C30 scores to ratings on the Subjective Significance Questionnaire in men with localized prostate cancer.
PURPOSE: To examine the relationship between changes in health-related quality-of-life (HRQOL) on the EORTC Quality of Life Questionnaire (QLQ-C30), and patients' perceptions of HRQOL changes as measured by the Subjective Significance Questionnaire (SSQ). PATIENTS AND METHODS: A total of 101 patients completed the QLQ-C30 on weeks 1, 4 and 7 of radical external-beam radiation therapy (RT) for localized cancer of the prostate. Patients rated their change in physical functioning, emotional functioning, social functioning, and overall/global quality of life (QOL) by completing a seven-category SSQ at weeks 4 and 7. The association between changes in the QLQ-C30 change and the corresponding SSQ ratings were determined by calculation of mean change scores for each SSQ category and by Spearman rank correlation coefficient analysis. RESULTS: Patients' completion of the QLQ-C30 and SSQ exceeded 95%. Statistically significant changes in fatigue, pain, appetite, diarrhea, and global QOL scores were detected during RT. For patients reporting 'a little' change in global QOL on the SSQ, absolute mean QLQ-C30 change scores ranged between 0 to 15 points with 12/16 mean change scores between 2.5 and 8.5 points. In the entire study sample, correlations between SSQ patient ratings and QLQ-C30 change scores were lower than previously reported, ranging between 0.15 and 0.24 for the four different domains, but were higher when QOL scores producing ceiling effects were omitted. CONCLUSION: The SSQ and QLQ-C30 may measure related concepts that could assist in the interpretation of changes in scores and in the calibration of the QLQ-C30. However, the nature of this relationship could not be elucidated in this data set because of a lack of variance in HRQOL scores in the study sample. Further investigation should be carried out in study samples with sufficient variance to allow more robust conclusions.
Adenocarcinoma↗
Cell death in irradiated prostate epithelial cells: role of apoptotic and clonogenic cell kill.
Dose-escalated conformal radiotherapy is increasingly being used to radically treat prostate cancer with encouraging results and minimal long-term toxicity, yet little is known regarding the response of normal or malignant prostate cells to ionizing radiation (IR). To clarify the basis for cell killing during prostate cancer radiotherapy, we determined the IR-induced expression of several apoptotic- (bax, bcl-2, survivin and PARP) and G1-cell cycle checkpoint- (p53 and p21(WAF1/Cip1)) related proteins, in both normal (PrEC-epithelial and PrSC-stromal) and malignant (LNCaP, DU-145 and PC-3; all epithelial) prostate cells. For these experiments, we chose doses ranging from 2 to 10 Gy, to be representative of the 1.8-2 Gy daily clinical fractions given during curative radiotherapy and the 8-10 Gy single doses given in palliative radiotherapy. We observed that IR-induced bax and p21(WAF1/Cip1) protein expression were attenuated selectively in normal stromal and epithelial cell cultures, yet maintained their p53-dependency in malignant cell lines. For each cell culture, we also determined total apoptotic and overall radiation cell kill using a short-term nuclear morphologic assay and a long-term clonogenic survival assay, respectively. Clonogenic survival, as measured by the surviving fraction at 2 Gy (SF2), ranged from 0.05 (PrEC) to 0.55 (DU-145), suggesting that malignant prostate cells are more radioresistant than normal prostate cells, for this series. IR-induced apoptotic cell kill was minimal (less than 6% cell after a dose of 10 Gy at times of 24-96 h) and was not dose-dependent. Furthermore, apoptotic kill was not correlated with either molecular apoptotic response or clonogenic cell kill. Using a flow cytometric proliferation assay with the PrSC (stromal) and DU-145 (epithelial) representative cultures, we observed that a senescent-like phenotype (SLP) emerges within a sub-population of cells post-irradiation that is non-clonogenic. Terminal growth arrest was dose-responsive at 96 h following irradiation and associated with long-term expression of both p21(WAF1/Cip1) and p16(INK4a) genes. Future strategies for prostate radiotherapy prediction or novel treatments should additionally focus on terminal growth arrest as an important endpoint in prostate cancer therapy.
Apoptosis↗
Acute toxicity of conventional radiation therapy for high-risk prostate cancer in EORTC trial 22863.
OBJECTIVES: We analysed the acute toxicity observed in the European Organisation for Research and Treatment of Cancer (EORTC) randomised trial 22863 comparing conventional external irradiation with or without an agonist analogue of gonadotropin-releasing hormone in high-risk prostate cancer patients. METHODS: Four hundred five patients that received a dose of at least 30 Gy were considered evaluable for acute toxicity assessment. Toxicity was grouped in a few categories: general, genito-urinary, and lower gastro-intestinal. Univariate and multivariate analyses were performed using the World Health Organisation (WHO) toxicity score and grouping together toxicity scores in different bimodal and trimodal groups. RESULTS: Overall, our data show that age, previous surgery and irradiation dose are important predictive factors for acute toxicity, but not the use of combined hormone therapy. Fifteen percent of patients suffered of moderate to severe acute toxicity (WHO G3-G4). Life threatening toxicity was observed in six cases (1.5%). CONCLUSIONS: The assessment of toxicity combining in different groups the original five scores scale produced conflicting results similar to those commonly reported in literature. Interpretation of the role of pre-treatment factors with uneven distribution in the study requires careful evaluation. These data obtained with conventional curative irradiation of high-risk prostate cancer patients are proposed for comparison with results achieved using modern state-of-the-art irradiation techniques.
Adult↗
The prognostic significance of the tumour infiltrating lymphocyte count in stage I testicular seminoma managed by surveillance.
The degree of lymphocytic infiltration is a significant determinant of outcome for a variety of malignancies, but its role in seminoma is unknown. 150 men with stage I testicular seminoma presenting between 1981 and 1993 were managed by surveillance following orchidectomy. The presence of tumour infiltrating lymphocytes (TILs) in each case was classified as high, intermediate or low. At a median follow-up of 9.4 years, 30 of the 150 men developed recurrent seminoma. On univariate analysis, the risk of relapse was associated with age < or =33 years (P=0.002), tumour diameter >6 cm (P=0.03), lymphatic or vascular invasion (P=0.04), tumour invasion of rete testis (P=0.05), and lower TIL count (P=0.02). On multivariate analysis, statistically significant predictors of risk of relapse were age < or =33 years (hazard ratio (HR) 4.6 (95% confidence intervals (CI): 1.7-12.2)) and tumour diameter >6 cm (HR 2.8 (CI: 1.2-6.5)). Lower TIL count was of borderline statistical significance (HR 1.8 (CI: 0.96-3.44)). The functional role of the lymphocytic infiltrate in testicular seminoma warrants further study.
Adult↗
Management preferences following radical inguinal orchidectomy for Stage I testicular seminoma in Australasia.
A survey to evaluate the preferred patterns of management of Stage I seminoma was conducted during March 2001. The questionnaire was distributed by the Royal Australian and New Zealand College of Radiologists to all qualified radiation oncologists, 74 out of 170 responded. All performed a staging CT scan of the abdomen and pelvis. Thoracic imaging consisted of either chest X-ray (29%) or chest CT (38%) while 33% performed both. Fifty-four percent of radiation oncologists discussed surveillance with their patients but estimated that 5% or less would choose this option. The most commonly prescribed dose was 25 Gy in 15 or 20 fractions (79%). Sixty-five percent of respondents treated the para-aortic (PA) nodes alone. Forty-two of 48 clinicians treating the PA field reported a change in practice after publication of the Medical Research Council study in 1999. Of these, 40 and 23% perform CT scans of the pelvis annually and every 6 months. Thirty-one percent did no follow-up CT scan. Compared to a similar survey from North America, we are more likely to use PA fields and less likely to discuss surveillance. As in the USA, and in contrast to Canada, few patients choose surveillance. There is no consensus regarding the frequency of follow-up scans in either North America or Australasia.
Follow-Up Studies↗
Surveillance in stage I testicular seminoma - risk of late relapse.
INTRODUCTION: Surveillance is an alternative to adjuvant radiotherapy for stage I testicular seminoma. We present the long-term results of seminoma surveillance, with emphasis on quantifying the risk of late relapse beyond 5 years. METHODS: From 1981 to 1993, of 431 men with stage I testicular seminoma, 203 were managed by surveillance following radical orchidectomy. The surveillance protocol comprised a combination of clinical examination, CT scans of abdomen and pelvis, chest x-rays and serum markers, at defined intervals. RESULTS: At a median follow-up of 9.2 years, 35 men have relapsed. Five of the relapses occurred more than 5 years after orchidectomy (at 5.1, 6.9, 7.3, 7.3, and 9.0 years). The actuarial risk of relapse at 5 and 10 years was 15% (standard error [SE] 1.1%) and 18% (SE 1.8%) respectively. One hundred sixty one men were free of relapse at 5 years, and have been followed beyond this point for a median of 4.3 years. The actuarial risk of relapse between 5 and 10 years was 4% (SE 0.5%). CONCLUSIONS: These results demonstrate that there is a small but clinically significant risk of relapse more than 5 years after orchidectomy for stage I seminoma. These data support the need for long term surveillance.
Adult↗
The benefits and pitfalls of ipsilateral radiotherapy in carcinoma of the tonsillar region.
PURPOSE: Ipsilateral techniques designed to restrict treatment to the primary tumor and neck on the same side have been used in selected cases of cases of carcinoma of the tonsillar region at our institution for many years. The primary purpose of this study is to evaluate the risk of failure in the opposite neck in cases selected for unilateral radiotherapy over a 21-year period. METHODS AND MATERIALS: Ipsilateral radiotherapy techniques were used in 228 of 642 patients with carcinoma of the tonsillar region from 1970 to 1991. Local control, regional lymph-node control (including contralateral failure), and survival were calculated for different degrees of tumor extent treated with these techniques. RESULTS: Mean follow-up was 7 years. Cases tended to be T1 and T2, with N0 disease. The 3-year actuarial local control rate was 77% and cause-specific survival was 76%. Opposite neck failure was seen in 8 patients (crude rate of 3.5%). In the earlier period of the study, primary coverage was problematic in a proportion of cases and resulted in higher rates of local failure. CONCLUSION: Appropriately selected cases of carcinoma of the tonsil show minimal risk of failure in the opposite neck with ipsilateral techniques. Patients should undergo computed tomography planning to ensure adequate target coverage.
Adult↗
A prospective study of factors predicting clinically occult spinal cord compression in patients with metastatic prostate carcinoma.
BACKGROUND: The objective of this study was to identify clinical parameters that predict occult subarachnoid space or spinal cord (SAS/SC) compression, as determined by magnetic resonance imaging (MRI), in patients with metastatic prostate carcinoma. METHODS: A prospective study was performed in which 68 patients with bone metastases from prostate carcinoma and a normal neurologic examination underwent MRI of the entire spine after documentation of clinical, X-ray, and bone scan parameters potentially predictive of occult SAS/SC compression. RESULTS: Occult SAS/SC compression was diagnosed in 22 patients (32%) using MRI. Nine patients (13%) had compressions at two discontinuous spinal levels. Extensive disease on bone scan, the duration of continuous hormonal therapy prior to study entry, and hemoglobin concentration were found to predict SAS/SC compression by univariate analysis. The extent of disease on bone scan and the duration of continuous hormonal therapy were independent predictors of SAS/SC compression by multivariate analysis (P = 0.02 and P = 0.04, respectively). The risk of occult SAS/SC compression increased from 32% to 44% in patients with a bone scan that showed > 20 metastases as the duration on hormones increased from 0 to 24 months. The risk in patients with fewer metastases increased from 11% to 17% over the same interval. The presence or absence of back pain was not predictive of SAS/SC compression. CONCLUSIONS: Patients who are at high risk for occult SAS/SC compression can be identified using clinical parameters and readily available diagnostic tests. These high-risk patients should undergo MRI screening with the aim of diagnosing and treating spinal cord compression before the development of neurologic deficits that may be irreversible.
Aged↗
Carcinoma-in-situ of the glottic larynx: results of treatment with radiation therapy.
PURPOSE: Carcinoma-in-situ (CIS) of the vocal cords frequently progresses to invasive disease if untreated. Treatment approaches include vocal cord stripping, radiation therapy (RT), and laser excision. The purpose of this analysis was to assess the efficacy and safety of a standard RT regimen in the treatment of this condition. METHODS AND MATERIALS: Between January 1980 and December 1994, 67 patients (52 men, 15 women; median age, 65 years) with glottic CIS were treated with RT. The standard RT regimen was 51 Gy in 20 fractions given over 4 weeks (99% of patients). Prior to receiving RT, 21 patients (31%) had undergone 1 or 2 vocal cord stripping procedures, and 1 had been treated with laser. RESULTS: With a median follow-up of 6.5 years, 1 patient developed invasive glottic cancer, giving a 5-year actuarial local control rate of 98%. This patient recurred 14 months after treatment and was salvaged with laryngectomy. He is currently free of disease 2 years after surgery. There were no serious acute or late treatment complications. Sixteen patients (24%) developed subsequent malignancies, 8 of these being in the upper aerodigestive tract, although none were in the radiation field. CONCLUSIONS: Moderate-dose radiation therapy is an effective treatment for glottic CIS. It is well tolerated, produces no serious acute or long-term side effects, with an excellent cure rate.
Adult↗
The impact of irregularly rising prostate-specific antigen and "impending failure" on the apparent outcome of localized prostate cancer following radiotherapy.
PURPOSE: To examine the impact of irregularly rising prostate-specific antigen (PSA) and "impending" biochemical failure on the apparent rate of biochemical relapse following radiotherapy for localized prostate cancer. METHODS AND MATERIALS: We analyzed the outcome of 572 patients with T1/T2 prostate cancer treated with radiotherapy alone at the Princess Margaret Hospital (median follow-up, 4.21 years). Biochemical outcomes were analyzed using 2 different definitions of failure: (1) the American Society for Therapeutic Radiology and Oncology (ASTRO) definition, and (2) a modified definition that included 2 consecutive rises in PSA, with a minimum rise of 1.5 ng/mL above the nadir, or a nadir value of greater than 4 ng/mL. Patients were defined as having "impending failure" when the last 2 PSA measurements taken demonstrated 2 consecutive rises. RESULTS: Two-hundred and thirty patients (40%) met the ASTRO definition of failure; 258 patients (48%) failed by the modified definition (p = 0.001). Five-year biochemical relapse-free rate (bNED) rate was 55% using the ASTRO definition, and 49% using the modified definition. This difference in 5-year bNED was greatest for patients with high-risk disease (ASTRO definition 30% vs. modified definition 15%). Twenty-four of the 38 additional cases identified as biochemical failures by the modified definition had irregularly rising PSA levels; 14 were "impending failures." These additional 38 patients had a median PSA elevation 5.4 ng/mL above the nadir, and a high risk of subsequent clinical failure (4-year clinical failure-free rate of 63%). The ASTRO definition had a sensitivity of 87% and specificity of 74% for predicting clinical relapse. The modified definition had a sensitivity of 95% and a specificity of 70%. CONCLUSION: A definition of biochemical failure that includes an absolute allowable rise in PSA above the nadir can identify patients with rising PSA who are at substantial risk of clinical relapse, but who are not defined as biochemical failures by the ASTRO definition. This is particularly true for patients with high-risk disease. The use of a uniform definition of biochemical failure is crucial to ensure that differences in apparent outcome are not due to differences in the definition of relapse. Currently, the ASTRO definition should remain the standard. Large cohort studies with long follow-up can be utilized to optimize the definition of biochemical failure following radiotherapy for prostate cancer.
Aged↗
Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate.
PURPOSE: To evaluate the outcome of adjuvant and salvage radiotherapy (RT) after radical prostatectomy (RP) for clinically localized prostate cancer using conventional clinical end-points, and the biochemical relapse-free rate (bRFR). METHODS: Between 1987 and 1994, 113 node negative, hormonally naïve men received RT 1 month to 12 years after RP. Adjuvant RT was given for positive resection margins and/or pT3 disease. Salvage RT was given for a persistently elevated prostatic specific antigen (PSA), a rising PSA, or palpable recurrence post RP. Clinical and biochemical endpoints determined outcome. Log-rank testing and the Cox proportional hazards model identified factors predictive for biochemical relapse free rate. RESULTS: Median follow-up after RT was 3.7 years (range 0.2-9 years). Five-year clinical local control was 95% for patients with no palpable evidence of disease and 59% for those with palpable recurrence (P < 0.0001). 5-year bRFR was 81% for adjuvant RT, 19% for salvage of biochemical recurrence, 0% for patients with palpable disease (P < 0.0001). Improved bRFR for adjuvant and salvage RT was predicted by a Gleason score < 7 vs. 7 vs. > 7 (hazard ratio 1.53; 95% CI 0.99-2.35) and an undetectable pre-RT PSA vs. PSA < 2.0 ng/ml vs. PSA > 2.0 ng/ml (hazard ratio 3.81; 95% CI 2.47-5.87). Seminal vesicle involvement was not a statistically significant independent predictor of bRFR. CONCLUSIONS: The most favourable bRFR was observed for adjuvant therapy. Salvage was most successful with a pre-RT PSA < 2.0 ng/ml, or Gleason score < 7. Few patients with a pre-RT PSA > 2.0 ng/ml were salvaged, and none with palpable recurrence. These patients require investigation of alternative salvage strategies.
Adenocarcinoma↗
Salvage radiotherapy for PSA failure after radical prostatectomy.
BACKGROUND AND PURPOSE: Prostate-specific antigen (PSA) failure after radical prostatectomy is a common clinical scenario, and there is no consensus on how it should be managed. Salvage radiation to the prostatic bed is a potentially curative treatment option, and is the subject of this review. Patient selection, and the efficacy and toxicity of treatment will be discussed, and recommendations made for current practice and future studies. METHODS: An English language MEDLINE search was performed, limited to the years 1989-2000, using the MeSH headings 'prostatic neoplasms' and 'radiotherapy'. The 660 abstracts identified were reviewed, and articles concerning patient selection for, or outcome of, post-operative radiation to the prostatic bed selected. After exclusion of articles concerning adjuvant, rather than salvage, radiation, this left a total of 22 case series, including 1062 patients for the review of treatment efficacy. RESULTS AND CONCLUSIONS: The quality of the evidence makes it difficult to form a judgment regarding the efficacy of salvage radiation following radical prostatectomy, particularly in men with a PSA level in the range 0.01-0.2 ng/ml. Salvage radiation may be more effective given earlier rather than later. These considerations have important consequences for the interpretation of current trials of adjuvant radiation following radical prostatectomy.
Bone Neoplasms↗
Positioning errors and prostate motion during conformal prostate radiotherapy using on-line isocentre set-up verification and implanted prostate markers.
PURPOSE: To evaluate treatment errors from set-up and inter-fraction prostatic motion with port films and implanted prostate fiducial markers during conformal radiotherapy for localized prostate cancer. METHODS: Errors from isocentre positioning and inter-fraction prostate motion were investigated in 13 men treated with escalated dose conformal radiotherapy for localized prostate cancer. To limit the effect of inter-fraction prostate motion, patients were planned and treated with an empty rectum and a comfortably full bladder, and were instructed regarding dietary management, fluid intake and laxative use. Field placement was determined and corrected with daily on-line portal imaging. A lateral portal film was taken three times weekly over the course of therapy. From these films, random and systematic placement errors were measured by matching corresponding bony landmarks to the simulator film. Superior-inferior and anterior-posterior prostate motion was measured from the displacement of three gold pins implanted into the prostate before planning. A planning target volume (PTV) was derived to account for the measured prostate motion and field placement errors. RESULTS: From 272 port films the random and systematic isocentre positioning error was 2.2 mm (range 0.2-7.3 mm) and 1.4 mm (range 0.2-3.3 mm), respectively. Prostate motion was largest at the base compared to the apex. Base: anterior, standard deviation (SD) 2.9 mm; superior, SD 2.1 mm. Apex: anterior, SD 2.1 mm; superior, SD 2.1 mm. The margin of PTV required to give a 99% probability of the gland remaining within the 95% isodose line during the course of therapy is superior 5.8 mm, and inferior 5.6 mm. In the anterior and posterior direction, this margin is 7.2 mm at the base, 6.5 mm at the mid-gland and 6.0 mm at the apex. CONCLUSIONS: Systematic set-up errors were small using real-time isocentre placement corrections. Patient instruction to help control variation in bladder and rectal distension during therapy may explain the observed small SD for prostate motion in this group of patients. Inter-fraction prostate motion remained the largest source of treatment error, and observed motion was greatest at the gland base. In the absence of real-time pre-treatment imaging of prostate position, sequential portal films of implanted prostatic markers should improve quality assurance by confirming organ position within the treatment field over the course of therapy.
Humans↗
Surveillance for stage I testicular seminoma. a review.
There is good evidence that patients with stage I seminoma can be managed equally well after orchidectomy with surveillance and adjuvant retroperitoneal radiation therapy. There is considerable reluctance amongst many physicians to accept surveillance as a management option in stage I seminoma and this is largely based on the excellent results achieved with adjuvant retroperiteonal radiation for many years. However, patients with stage I seminoma have a long life span and it is possible that the long-term sequelae of radiation treatment could have a negative impact on quality of life and longevity. It is of utmost importance to continue the study of the long-term effects of all current treatment approaches, in particular the risk of induction of second malignancies. However, the psychosocial impact on patients of surveillance and other management strategies must also be assessed. Stage I testicular seminoma is highly curable with currently available management approaches and the current challenge for clinicians is to maintain these excellent results while minimizing toxicity and individualising treatment to the specific social, economic and emotional circumstances of each patient. Surveillance should be one of the management options offered to patients with stage I seminoma.
Journal Article↗
Does age influence the behaviour of localized prostate cancer?
OBJECTIVE: To assess, in a meta-analysis of published studies, whether age influences the behaviour of localized prostate cancer. METHODS: The Medline database was searched from 1966 to 2000 to identify studies analysing the outcome of localized prostate cancer by age, using disease-specific outcome measures, and having controlled for the established prognostic factors of grade, T stage and, where available, serum prostate-specific antigen (PSA) level. RESULTS: In all, 34 studies were identified, which included a total of 27 551 patients. The incomplete and heterogeneous nature of the reports precluded any quantitative overview. The findings of these reports are described and methodological shortcomings discussed. CONCLUSION: The evidence suggests that young age was an adverse prognostic factor in some series of radiation therapy before the advent of PSA assays, when men typically presented clinically with locally advanced disease, but that age has no significant prognostic effect in contemporary series of localized prostate cancer. Possible explanations for this difference are discussed, together with implications for further studies.
Age Factors↗
The inclusion of capillary distribution in the adiabatic tissue homogeneity model of blood flow.
We have developed a non-invasive imaging tracer kinetic model for blood flow which takes into account the distribution of capillaries in tissue. Each individual capillary is assumed to follow the adiabatic tissue homogeneity model. The main strength of our new model is in its ability to quantify the functional distribution of capillaries by the standard deviation in the time taken by blood to pass through the tissue. We have applied our model to the human prostate and have tested two different types of distribution functions. Both distribution functions yielded very similar predictions for the various model parameters, and in particular for the standard deviation in transit time. Our motivation for developing this model is the fact that the capillary distribution in cancerous tissue is drastically different from in normal tissue. We believe that there is great potential for our model to be used as a prognostic tool in cancer treatment. For example, an accurate knowledge of the distribution in transit times might result in an accurate estimate of the degree of tumour hypoxia, which is crucial to the success of radiation therapy.
Capillaries↗