Clinical and prognostic significance of changes in haemoglobin concentration during 1 year of androgen-deprivation therapy for hormone-naïve bone-metastatic prostate cancer.

OBJECTIVE: To estimate the strength of change in haemoglobin (Hb) concentrations during 1 year of androgen-deprivation therapy (ADT) as a predictor of survival in hormone-naïve patients with bone-metastatic (Stage M1b) prostate cancer. PATIENTS AND METHODS: The patients included in this study were taken from the randomised trial (number 5) carried out by the Scandinavian Prostate Cancer Group (SPCG), comparing parenteral oestrogen with total androgen blockade (TAB) in hormone-naïve M1b prostate cancer. We identified 597 men where Hb measurements were made at enrolment, as well as at 3, 6 and 12 months of ADT. The time-dependent impact of Hb concentration changes on overall survival (OS) was analysed using multivariate Cox proportional hazards analysis. The 10-year OS according to increase/decrease in Hb concentration for the three treatment periods was demonstrated using Kaplan-Meier curves. RESULTS: Multivariate analysis of changes in Hb concentration between baseline and 3 months showed better survival in patients with a decrease in Hb concentration (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.11-1.80) compared to those with an increase, whilst there was no difference in survival associated with a change in Hb concentration between 3 and 6 months (HR 0.93, 95% CI 0.76-1.12). Contrary to the first 3 months, poorer survival was seen in patients with a decrease in Hb concentration between 6 and 12 months (HR 0.76, 95% CI 0.62-0.92) compared to those with an increase. CONCLUSIONS: In a large cohort of Scandinavian men with hormone-naïve M1b prostate cancer, an increase in Hb concentration between baseline and 3 months of ADT was associated with significantly poorer survival, whereas an increase between 6 and 12 months was associated with better survival. These findings provide new information about patterns of change in Hb concentrations during 12 months of ADT for M1b prostate cancer, and survival. Clinicians should be aware of the prognostic value of Hb concentration changes during ADT in M1b prostate cancer.

Clinical presentation and predictors of survival related to extent of bone metastasis in 900 prostate cancer patients.

OBJECTIVE: The aim of this study was to investigate the impact of bone metastasis on survival and quality of life (QoL) in men with hormone-naïve prostate cancer. MATERIALS AND METHODS: The study included 900 patients from a randomized trial (No. 5) by the Scandinavian Prostate Cancer Group, comparing parenteral oestrogen with total androgen blockade. Extent of bone metastasis was categorized according to a modified Soloway score: score 1, n = 319; score 2, n = 483; and score 3, n = 98 patients. The primary outcome measurements were mean differences in QoL and overall survival. RESULTS: QoL rating scales showed a decrease with increasing extent of bone metastasis (p < 0.001). The mean global health status decreased from 64.4 to 50.5 for Soloway score 1 and 3, respectively. Following adjustment for performance status, analgesic consumption, grade of malignancy, alkaline phosphatase, prostate-specific antigen, haemoglobin and global health status, Soloway score 2 and 3 had a 47% [hazard ratio (HR) 1.47, 95% confidence interval (CI) 1.21-1.80] and 78% (HR 1.78 95%, CI 1.32-2.42) increased mortality, respectively, compared to Soloway score 1. Independent predictive factors of mortality were assessed. CONCLUSIONS: Patient grouping based on three categories of extent of bone metastasis related to performance status, haemoglobin and global health status at presentation, as independent predictors of mortality, may provide improved accuracy of prognosis.

Predictors of early androgen deprivation treatment failure in prostate cancer with bone metastases.

Approximately 15% of men with hormone naïve metastatic prostate cancer primarily fail to respond to androgen deprivation treatment (ADT). The reason why the response to ADT differs in this subgroup of men with prostate cancer remains unclear. The aim of this study was to describe the characteristics of these men and to thereby define predictors of early ADT failure in prostate cancer patients with bone metastases. The study was based on 915 men from the prospective randomized multicenter trial (no. 5) conducted by the Scandinavian Prostate Cancer Group comparing parenteral estrogen with total androgen blockade. Early ADT failure was defined as death from metastatic prostate cancer within 12 months after the start of ADT. Multivariate logistic regression models were applied to identify clinical predictors of early ADT failure. Ninety-four (10.3%) men were primarily nonresponders to ADT. Independent predictors of early ADT failure were poor Eastern Cooperative Oncology Group performance status (PS), analgesic consumption, low hemoglobin, and high Soloway score (extent of disease observed on the scan), in where patients with poor PS and/or high analgesic consumption had a threefold risk of early ADT failure. Not significantly factors related to early ADT failure were age, treatment, cardiovascular comorbidity, T category, grade of malignancy, serum estrogen level, and SHBG at enrolment. We analyzed characteristics of a subgroup of patients who primarily failed to respond to ADT. Four independent clinical predictors of early ADT failure could be defined, and men exhibiting these features should be considered for an alternative treatment.

Clinical characteristics and quality-of-life in patients surviving a decade of prostate cancer with bone metastases.

OBJECTIVE: To describe characteristics and quality-of-life (QoL), and to define factors associated with long-term survival in a subgroup of patients with prostate cancer with M1b disease. PATIENTS AND METHODS: The study was based on 915 patients from a prospective randomised multicentre trial (No. 5) by the Scandinavian Prostate Cancer Group, comparing parenteral oestrogen with total androgen blockade. Long-term survival was defined as patients having an overall survival of ≥10 years, and logistic regression models were constructed to identity clinical predictors of survival. QoL during follow-up was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire - C30 version 1 (EORTC-C30) ratings. RESULTS: In all, 40 (4.4%) of the 915 men survived for >10 years. Factors significantly associated with increased likelihood of surviving for >10 years in the univariate analyses were: absence of cancer-related pain; Eastern Cooperative Oncology Group (ECOG) performance status of <2; negligible analgesic consumption; T-category of 1-2; prostate-specific antigen (PSA) level of <231 µg/L; and a Soloway score of 1. In the multivariate analyses, ECOG performance status of <2, PSA level of <231 µg/L, and Soloway score of 1, were all independent predictors of long-term survival. All subscales of the EORTC-C30 were higher in this group than for patients with short survival, but slowly declined over the decade. CONCLUSION: A subgroup of patients with prostate cancer with M1b disease and certain characteristics showed a positive long-term response to androgen-deprivation therapy with an acceptable QoL over a decade or more. Independent predictors of long-term survival were identified as ECOG performance status of <2, limited extent of bone metastases (Soloway score of 1), and a PSA level of <231 µg/L at the time of enrolment.

Significance of pretreatment cardiovascular morbidity as a risk factor during treatment with parenteral oestrogen or combined androgen deprivation of 915 patients with metastasized prostate cancer: evaluation of cardiovascular events in a randomized trial.

OBJECTIVE: This study aimed to evaluate prognostic risk factors for cardiovascular events during treatment of metastatic prostate cancer patients with high-dose parenteral polyoestradiol phosphate (PEP, Estradurin®) or combined androgen deprivation (CAD) with special emphasis on pretreatment cardiovascular disease. MATERIAL AND METHODS: Nine-hundred and fifteen patients with T0-4, Nx, M1, G1-3, hormone- naïve prostate cancer were randomized to treatment with PEP 240 mg i.m. twice a month for 2 months and thereafter monthly, or to flutamide (Eulexin®) 250 mg per os three times daily in combination with either triptorelin (Decapeptyl®) 3.75 mg i.m. per month or on an optional basis with bilateral orchidectomy. Pretreatment cardiovascular morbidity was recorded and cardiovascular events during treatment were assessed by an experienced cardiologist. A multivariate analysis was done using logistic regression. RESULTS: There was a significant increase in cardiovascular events during treatment with PEP in patients with previous ischaemic heart disease (p = 0.008), ischaemic cerebral disease (p = 0.002), intermittent claudication (p = 0.031) and especially when the whole group of patients with pretreatment cardiovascular diseases was analysed together (p < 0.001). In this group 33% of the patients had a cardiovascular event during PEP treatment. In the multivariate analysis PEP stood out as the most important risk factor for cardiac complications (p = 0.029). Even in the CAD group there was a significant increase in cardiovascular events in the group with all previous cardiovascular diseases taken together (p = 0.036). CONCLUSIONS: Patients with previous cardiovascular disease are at considerable risk of cardiovascular events during treatment with high-dose PEP and even during CAD therapy. Patients without pretreatment cardiovascular morbidity have a moderate cardiovascular risk during PEP treatment and could be considered for this treatment if the advantages of this therapy, e.g. avoidance of osteopenia and hot flushes and the low price, are given priority.

PSA kinetics provide improved prediction of survival in metastatic hormone-refractory prostate cancer.

OBJECTIVES: To assess the value of prostate-specific antigen (PSA) kinetics in predicting survival and relate this to the baseline variables in men with metastatic hormone-refractory prostate cancer (HRPC). METHODS: The data from 417 men with HRPC were included in a logistic regression model that included hemoglobin, PSA, alkaline phosphatase, Soloway score, and performance status pain analgesic score at baseline. The posttreatment variables included the PSA level halving time after the start of treatment, PSA level at nadir, interval to nadir, PSA velocity (PSAV), PSA doubling time after reaching a nadir, patient age, and treatment. These variables were added to the baseline model, forming new logistic regression models that were tested for net reclassification improvement. RESULTS: The area under the receiver operating characteristics curve for the baseline model was 0.67. Of all variables related to PSA kinetics, the PSAV was the best predictor. The addition of PSAV to the baseline model increased the area under the receiver operating characteristics curve to 0.81. Only a moderate increase in the area under the receiver operating characteristics curve (0.83) was achieved by combining the baseline model in a multivariate model with PSAV, PSA doubling time, interval to nadir, and patient age at diagnosis of HRPC. CONCLUSIONS: The PSAV alone gave a better prediction of survival value than all other PSA kinetics variables. By combining PSAV with the variables available at baseline, a better ground for treatment decision-making in men with HRPC can be achieved.

Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5.

OBJECTIVE: To compare parenteral estrogen therapy in the form of high-dose polyestradiol phosphate (PEP; Estradurin) with combined androgen deprivation (CAD) in the treatment of prostate cancer patients with skeletal metastases. The aim of the study was to compare anticancer efficacy and adverse events, especially cardiovascular events. MATERIAL AND METHODS: In total, 910 eligible patients with T0-4, NX, M1, G1-3 prostate cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were randomized to treatment with either PEP 240 mg i.m. twice a month for 2 months and thereafter monthly, or flutamide (Eulexin) 250 mg t.i.d. per os in combination with either triptorelin (Decapeptyl) 3.75 mg i.m. per month or on an optional basis bilateral orchidectomy. RESULTS: At this final evaluation of the trial 855 of the 910 patients were dead. There was no difference between the treatment groups in terms of biochemical or clinical progression-free survival or in overall or disease-specific survival. There was no difference in cardiovascular mortality, but a significant increase in non-fatal cardiovascular events in the PEP arm (p<0.05) predominantly caused by an increase in ischemic heart and heart decompensation events. There were 18 grave skeletal events in the CAD group but none in the PEP group (p=0.001). CONCLUSIONS: PEP has an anticancer efficacy equal to CAD and does not increase cardiovascular mortality in metastasized patients, but carries a significant risk of non-fatal cardiovascular events, which should be balanced against the skeletal complications in the CAD group. It is feasible to use Estradurin in the primary or secondary endocrine treatment of metastasized patients without prominent cardiac risk factors and especially those with osteoporosis.

Quality of life in patients with skeletal metastases of prostate cancer and status prior to start of endocrine therapy: results from the Scandinavian Prostate Cancer Group Study 5.

OBJECTIVES: Prostate cancer (PC) is a highly lethal neoplastic disease affecting the physical, mental and social well-being of patients, i.e. their quality of life (QOL). Patients suffering from metastatic PC are faced with serious decisions regarding treatment strategies. Therefore, QOL information has become a crucial element of decision making in this group of patients. The first objective of this study was to describe QOL in a group of patients diagnosed with metastatic PC and skeletal metastases. At the time of evaluation the patients had not received any treatment but were evaluated before entering a study of androgen-modulating therapy (the Scandinavian Prostate Cancer Group study 5). The second objective was to identify demographic and disease-related factors affecting QOL. MATERIAL AND METHODS: A total of 917 patients with metastatic PC were evaluated using a well-described and validated questionnaire [European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-C30 (EORTC QLQ-C30)]. The characteristics of the PC were noted, and simultaneously patients were evaluated with respect to use of analgesics, pain and performance status using a scoring system. Biochemical tests were performed when patients entered the study. A multivariate regression analysis was performed to analyse the correlations between QOL scores, patient demographics and disease-related data. RESULTS: The patients reported QOL scores significantly lower than those in the background population. Pain and fatigue were pronounced, whereas dyspnoea, insomnia, loss of appetite, constipation and diarrhoea were less prominent. Patients with high tumour grades, high PSPA scores (the sum of the pain score, the performance status and the use of analgesics) and those using analgesics had significantly lower QOL scores than the other patients. CONCLUSIONS: Patients with metastatic PC have reduced QOL. Our findings are in line with those of other studies of QOL among patients with this disease as evaluated by means of the EORTC QLQ-C30 questionnaire. Baseline data from studies like this provide important information when treatment modalities for PC are evaluated.

Clinical research done by the Scandinavian Prostate Cancer Group during the first 20 years.

In 1981 the Scandinavian Association of Urology initiated the Scandinavian Prostate Cancer Group (SPCG) as one of eight collaborative groups representing different fields of urology. The task of the SPCG was to promote research, education and information concerning prostate cancer. In particular it became a forum for conducting clinical multicenter studies within the Nordic countries. This paper summarizes some aspects of the history of the SPCG and reviews the clinical trials initiated by the group on the occasion of its 20th anniversary.

Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer -- Scandinavian Prostatic Cancer Group (SPCG) Study No. 5.

OBJECTIVE: In the mid-1980s, interest in parenteral estrogen therapy for prostate cancer was renewed when it was found that it influenced liver metabolism only marginally and had very few cardiovascular side-effects. In this study high-dose polyestradiol phosphate (PEP; Estradurin) was compared to combined androgen deprivation (CAD) for the treatment of patients with metastatic prostate cancer. The aim of the study was to compare anticancer efficacy and adverse events, especially cardiovascular side-effects. MATERIAL AND METHODS: A total of 917 patients with T0-4, NX, M1, G1-3 prostate cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were randomized to treatment with either PEP 240 mg i.m. twice a month for 2 months and thereafter once a month or flutamide (Eulexin) 250 mg t.i.d. per os in combination with either triptorelin (Decapeptyl) 3.75 mg per month i.m. or, on an optional basis, bilateral orchidectomy. A total of 556 patients had died at the time of this analysis. RESULTS: There was no difference between the treatment arms in terms of time to biochemical or clinical progression and overall or disease-specific survival. There was no increase in cardiovascular mortality in the PEP arm. The PEP group had a higher prevalence of cardiovascular disease prior to the study and a significantly higher incidence of non-fatal ischemic heart events and heart decompensation during the study. CONCLUSIONS: PEP has an equal anticancer efficacy to CAD and does not increase cardiovascular mortality. Final evaluation of cardiovascular morbidity is awaiting further analysis and follow-up. PEP is considerably cheaper than CAD.