Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases.

BACKGROUND: This phase II randomized, placebo-controlled study was conducted to evaluate efficacy and safety of radium-223 in patients with castration-resistant prostate cancer (CRPC) and painful bone metastases. Twelve- and 18-month survival results were reported previously. Here we report 24-month overall survival (OS) and safety data from the period 12 to 24 months after the first injection of study medication. METHODS: Patients with CRPC and bone pain were randomized 1:1 to receive 4 injections of radium-223 (50 kBq/kg [n = 33]) or placebo (n = 31) after external-beam radiotherapy; each injection was given every 4 weeks. Endpoints for this report were 24-month OS, long-term safety, and treatment-related adverse events (AEs) occurring in the 12- to 24-month period. RESULTS: After 24 months, 10 (30%) patients were alive in the radium-223 group compared with 4 patients (13%) in the placebo group. Patients who received at least 1 dose of study medication had a median OS of 65 weeks in the radium-223 group vs. 46 weeks in the placebo group (log-rank P = .056). The hazard ratio (HR) for OS, adjusted for baseline covariates, was 0.476 (95% confidence interval [CI], 0.258-0.877; Cox regression P = .017). The most frequent cause of death for both arms was disease progression. There were no reports of treatment-related AEs or long-term hematologic toxicity during the 12- to 24-month follow-up. CONCLUSION: Radium-223 had a highly favorable safety profile, with no evidence of second malignancies at 24-month follow-up. The significant improvement in OS observed in patients receiving radium-223 vs. placebo suggests that treatment of bone disease with radium-223 has survival benefits.

Outcome in intermediate or high risk prostate cancer patients receiving radiation dose and hormone therapy.

BACKGROUND: To analyse the impact of radiation dose escalation and hormone treatment in prostate cancer patients according to risk groups. MATERIAL AND METHODS: Totally 494 prostate cancer patients received external beam radiation therapy, with or without androgen deprivation, between January 1990 and December 1999. The patients were divided into three risk groups, where the low risk group (stage T(1c), pretreatment prostate-specific antigen (PSA) level < or =10 ng/ml and WHO Grade 1) included 26 patients, the intermediate risk group (either stage T(2), PSA 10.1-20 ng/ml or WHO Grade 2) comprised 149 patients whereas the high-risk group (either stage T(3), PSA >20 ng/ml or WHO Grade 3) included 319 patients. RESULTS: In the intermediate risk group, the 5-years bNED rate was 92%, 69% and 61% after a radiation dose of 70 Gy, 66 Gy or 64 Gy, respectively (p < 0.001). In the high-risk group, the 5-year bNED rate was 79%, 69% and 34% for the same dose levels (p < 0.001). The 5-years CSS rates were not significantly different between the dose levels in the intermediate risk group while for the high-risk group it was 93%, 92% and 80% for the three dose levels (p < 0.001). Risk group and radiation doses were independent predictors of bNED, CSS and overall survival, for bNED also hormone treatment was independent predictors. CONCLUSION: Radiation dose is important for the outcome in intermediate and high risk prostate cancer patients. A dose of 70 Gy should be considered the minimal dose for these patients.

Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study.

BACKGROUND: The alpha-emitter radium-223 ((223)Ra) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone-refractory prostate cancer. We aimed to study mature outcomes from a randomised, multicentre, phase II study of (223)Ra. METHODS: Patients with hormone-refractory prostate cancer and bone pain needing external-beam radiotherapy were assigned to four intravenous injections of (223)Ra (50 kBq/kg, 33 patients) or placebo (31 patients), given every 4 weeks. Primary endpoints were change in bone-alkaline phosphatase (ALP) concentration and time to skeletal-related events (SREs). Secondary endpoints included toxic effects, time to prostate-specific-antigen (PSA) progression, and overall survival. All tests were done at a 5% significance level, based on intention to treat. FINDINGS: Median relative change in bone-ALP during treatment was -65.6% (95% CI -69.5 to -57.7) and 9.3% (3.8-60.9) in the (223)Ra group and placebo groups, respectively (p<0.0001, Wilcoxon ranked-sums test). Hazard ratio for time to first SRE, adjusted for baseline covariates, was 1.75 (0.96-3.19, p=0.065, Cox regression). Haematological toxic effects did not differ significantly between two groups. No patient discontinued (223)Ra because of treatment toxicity. Median time to PSA progression was 26 weeks (16-39) versus 8 weeks (4-12; p=0.048) for (223)Ra versus placebo, respectively. Median overall survival was 65.3 weeks (48.7-infinity) for (223)Ra and 46.4 weeks (32.1-77.4) for placebo (p=0.066, log rank). The hazard ratio for overall survival, adjusted for baseline covariates was 2.12 (1.13-3.98, p=0.020, Cox regression). INTERPRETATION: (223)Ra was well tolerated with minimum myelotoxicity, and had a significant effect on bone-ALP concentrations. Larger clinical trials are warranted to study (223)Ra on the prevention of SREs and on overall survival in patients with hormone-refractory prostate cancer. Bone-targeting properties of (223)Ra could also potentially be used for treating skeletal metastasis from other primary cancers.

Radiation dose escalation combined with hormone therapy improves outcome in localised prostate cancer.

We present the impact of systematic radiation dose escalation from 64 Gy to 66 Gy to 70 Gy on the outcome after radiation therapy (RT) alone or combined with hormonal treatment (HT) in a series of 494 consecutive localised prostate cancer patients treated during 1990-1999. Prognostic factors for prostate-specific antigen (PSA) failure, overall survival (OS) and prostate cancer specific survival (CSS) were investigated using multivariate analysis. T stage, pre-treatment PSA, grade, radiation dose and HT were found to be independent predictors of PSA failure. T stage, grade and HT were also independent predictors of both OS and CSS, while radiation dose was a significant predictor for OS and indicated a trend (p = 0.07) for CSS. A dose of 70 Gy combined with hormonal treatment improves PSA failure free survival and survival in localised prostate cancer compared with doses of 64-66 Gy.

Acute morbidity related to treatment volume during 3D-conformal radiation therapy for prostate cancer.

PURPOSE: To investigate the relation between acute toxicity and irradiated volume in the organs at risk during three-dimensional conformal radiation therapy for prostate cancer. METHODS AND MATERIALS: From January to December 2001, we treated 132 prostate cancer patients to a prescribed target dose of 70 Gy. Twenty-six patients (20%) received irradiation to the prostate only (Group P), 86 patients (65%) had field arrangements encompassing the prostate and seminal vesicles (Group PSV) while 20 (15%) received modified pelvic fields (Group MPF). A four-field conformal box technique was used. Acute toxicity according to the RTOG scoring system was prospectively recorded throughout the course of treatment. RESULTS: Overall, radiation was well tolerated with 11%, 16% and 35% Grade 2 gastro-intestinal (GI) toxicity and 19%, 34% and 35% Grade 2 or higher genito-urinary (GU) toxicity in Groups P, PSV and MPF, respectively. In univariate and multivariate analyses treatment group was a significant predictor for Grade 2 or higher acute morbidity. In multivariate logistic regression, the rectum dose-volume histogram parameters were correlated to the incidence of acute Grade 2 GI toxicity, with the fractional volumes receiving more than 37-40 Gy and above 70 Gy showing the statistically strongest correlation. The fractional bladder volume receiving more than 14-27 Gy showed the statistically strongest correlation with acute GU toxicity. CONCLUSIONS: 3D-CRT radiation therapy to 70 Gy for prostate cancer was well tolerated. Only two of the 132 patients in the cohort experienced acute bladder toxicity Grade 3, none had Grade 3 rectal toxicity. Uni- and multivariate analyses indicated that the volume treated was a significant factor for the incidence of Grade 2 or higher acute morbidity.

Liposomal doxorubicin (Caelyx) in symptomatic androgen-independent prostate cancer (AIPC)--delayed response and flare phenomenon should be considered.

BACKGROUND: Compared with the native drug, liposomal PEG-coated doxorubicin (Caelyx) enhances tumour activity and reduces toxicity. The formulation may therefore be beneficial in anthracycline-sensitive malignancies, where toxicity represents a major problem, as is the case in androgen-insensitive prostate cancer (AIPC). METHODS: In a multi-centre design 28 patients with advanced AIPC received Caelyx 40 mg/m2 as a 1-hour infusion every month. PSA-based biochemical and subjective response was recorded. RESULTS: Three patients had biochemical responses, a subjective response was recorded in a fourth patient. No Grade 4 toxicity was encountered. Three patients developed a spontaneously recovering plantar-palmar erythema. In 3 of the 4 responding patients, the nadir PSA value was noted after 12 and 16 weeks, respectively. A possible flare phenomenon for PSA was evident in 4 patients. CONCLUSION: Caelyx has limited activity in advanced AIPC. Due to its low toxicity profile the drug may be a worthwhile component of combination treatment of this chemotherapy-resistant condition. In general, clinicians should be aware of possible delay in PSA response as well as possible flare phenomenon during investigational systemic treatment of AIPC. Furthermore, standardization of blood sampling and PSA analyses are necessary in future therapeutic trials of AIPC.