Dag Clement Johannessen | University of Oslo (original) (raw)

Papers by Dag Clement Johannessen

A template for the content of a professional evidence based guideline of how to do radiation ther... more A template for the content of a professional evidence based guideline of how to do radiation therapy of various cancer diagnosis in Norway developed under the KVIST programme (Norwegian acronym for «quality assurance in radiotherapy»). KVIST offers to do the implementation of the template for different cancer diagnosis in collaboration with the radiotherapy society in Norway and other health authorities. Prosjektleder: Gunilla Frykholm, KVIST Godkjent: Gunnar Saxebøl, avdelingsdirektør, Avdeling strålevern og sikkerhet Versjon, dato Kommentar/endring Ansvarlig Første gang publisert august 2006 (utkastform) Bygger på StrålevernRapport 2003:12 [4] og ICRU 50/62 [5,6] KVIST 2010 ICRU 83 [7] KVIST 24 sider. Utgitt 2010-03-19. Opplag 100 (10-03). Form, omslag: LoboMedia AS. Trykk: LoboMedia AS, Oslo. Bestilles fra: Statens strålevern, Postboks 55, No-1332 Østerås, Norge. Telefon 67 16 25 00, faks 67 14 74 07. E-post: nrpa@nrpa.no www.nrpa.no ISSN 0804-4910 (print) ISSN 1891-5205 (online)...

Journal of Clinical Oncology

5068 Background: Ra-223, a first-in-class α-emitter, significantly improved median overall surviv... more 5068 Background: Ra-223, a first-in-class α-emitter, significantly improved median overall survival (OS) by 3.6 mo vs placebo (Pbo) in CRPC patients (pts) with bone metastases (mets) receiving best standard of care (BSoC) in the ALSYMPCA study (HR = 0.695; 95% CI, 0.581-0.832; p = 0.00007), and had a highly favorable safety profile in the updated ALSYMPCA analysis (Parker et al. ASCO 2012). This predefined subgroup analysis assessed efficacy and safety of Ra-223 in pts who did or did not receive prior D (pD). Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets; had no known visceral mets; were receiving BSoC; and had received pD, or were unfit for or declined D (npD). Pts were randomized 2:1 to 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching Pbo and stratified by prior D use, baseline alkaline phosphatase level, and current bisphosphonate use. Survival data were compared using a log-rank test. Results: 395/921 (43%) randomized pts had npD (Ra-223, n = 2...

Journal of Clinical Oncology

4551 Background: Ra-223, a 1st-in-class alpha-pharmaceutical, targets bone metastases (mets) with... more 4551 Background: Ra-223, a 1st-in-class alpha-pharmaceutical, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) v placebo (pbo) plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint was OS; secondary endpoints included SREs and ECOG PS. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to 6 injections of Ra‑223 (50 kBq/kg IV) q4 wks or matching pbo and stratified by prior docetaxel use, baseline ALP level, and current bisphosphonate use. Results: 921 pts were randomized from 6/2008-2/2011. In a planned interim analysis (n = 809), Ra-223 significantly improved OS v pbo (median OS 14.0 v 11.2 mo, respectivel...

European Journal of Cancer Supplements

European urology, Jan 10, 2017

In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonge... more In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment. To report updated ALSYMPCA safety, including long-term safety up to 3 yr after the first injection. Safety analyses from phase 3 randomized ALSYMPCA trial included patients receiving ≥1 study-drug injection (600 radium-223 and 301 placebo). Patients (405 radium-223 and 167 placebo) entered long-term safety follow-up starting 12 wk after the last study-drug injection, to 3 yr from the first injection. Forty-eight of 405 (12%) radium-223 and 12/167 (7%) placebo patients completed follow-up, with evaluations every 2 mo for 6 mo, then every 4 mo until 3 yr. All adverse events (AEs) were collected until 12 wk after the last injection; subsequently, only treatment-related AEs wer...

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 20, 2012

LBA4512 Background: Radium-223 chloride (Ra-223), a targeted alpha-emitter, targets bone metastas... more LBA4512 Background: Radium-223 chloride (Ra-223), a targeted alpha-emitter, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 µm). ALSYMPCA, a phase III double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) vs placebo plus BSC in CRPC patients (pts) with bone mets. In a planned interim analysis (n = 809), based on 314 events, Ra-223 significantly improved overall survival (OS) vs placebo (median 14.0 mo vs 11.2 mo, respectively; HR = .695; 95% CI, .552-.875; 2-sided p = .00185). Secondary endpoints were met and Ra-223 safety was favorable. An updated analysis was conducted prior to the crossover to further assess the effect of Ra-223 on the primary endpoint (OS), secondary endpoints including skeletal-related events (SREs), and safety. Eligible pts had confirmed symptomatic CRPC with ≥ 2 bone mets; no known visceral mets; and were post-docetaxel, unfit for docetaxel, or had declined docetaxel. Pts were r...

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 10, 2012

8 Background: Radium-223 chloride (Ra-223) is a first-in-class alpha-pharmaceutical targeting bon... more 8 Background: Radium-223 chloride (Ra-223) is a first-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy alpha-particles of extremely short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared efficacy, in terms of overall survival (OS), and safety of Ra-223 plus best standard of care (BSC) vs placebo plus BSC in patients (pts) with bone mets in CRPC. Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4 wks or matching placebo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. A planned interim analysis (IA) was conducted to assess the effect of Ra-223 on the primary endpoint (OS) using a predefined threshold. Sur...

Clinical chemistry, 1999

In this study, we evaluated the effect of estrogen suppression with three aromatase inhibitors, a... more In this study, we evaluated the effect of estrogen suppression with three aromatase inhibitors, aminoglutethimide (n = 30), formestane (n = 12), and exemestane (n = 10), and the progestin megestrol acetate (n = 21) on plasma total homocysteine (tHcy) in patients suffering from advanced breast cancer. Treatment with 1 g/day aminoglutethimide for 2 and 3-5 months increased plasma tHcy by a mean value of 24.5% [95% confidence interval, 10.5-40.4%] at 2 months and 35.8% (95% confidence interval, 18.2-55.9%) at 3-5 months, corresponding to increases in the mean plasma tHcy of 1.90 and 3.67 micromol/L, respectively. In contrast, none of the other treatment options influenced plasma tHcy concentrations. The finding that aminoglutethimide, but none of the other aromatase inhibitors or megestrol acetate, influenced plasma tHcy suggests that this effect is achieved by mechanisms not related to suppression of plasma estrogens or to the glucocorticoids administered in concert.

British journal of cancer, 1993

Plasma and urinary oestrogens were measured in nine breast cancer patients (eight postmenopausal ... more Plasma and urinary oestrogens were measured in nine breast cancer patients (eight postmenopausal women and one man) before and during treatment with the aromatase inhibitor 4-hydroxyandrostenedione. Urinary oestrogens were measured by using a highly specific GC-MS method. Plasma levels of oestrone, oestradiol and oestrone sulphate were suppressed by 66.6% (+/- 3.6%), 57.7% (+/- 5.1%) and 51.8% (+/- 6.4%) respectively (P < 0.005 for all). Twenty-four hour urinary excretion of total oestrogens, oestradiol, oestriol, 2-hydroxyoestrone, 16 alpha-hydroxyoestrone and the minor metabolites 16 beta- and 15 alpha-hydroxyoestrone were all suppressed by mean values ranging from 60% to 82%, (oestradiol: P < 0.025, otherwise P < 0.005). There were no significant changes in the ratios between the different plasma oestrogens. The finding of sustained plasma and urinary oestrogens at 20-40% compared to their control levels indirectly support a hypothesis of alternative oestrogen sources in...

The Journal of steroid biochemistry and molecular biology, 1995

Estrone sulphate (E1S) may be an important estrogen source in breast cancers, particularly in pos... more Estrone sulphate (E1S) may be an important estrogen source in breast cancers, particularly in postmenopausal women. Recent studies have shown that tamoxifen inhibits the uptake and metabolism of E1S to estradiol (E2) in cell cultures. To evaluate a possible influence of tamoxifen on E1S disposition in vivo, we measured plasma levels of E1S together with unconjugated estrogens (E1 and E2), androgens (T, A, DHEA and DHEAS), SHBG, FSH and LH in 32 postmenopausal breast cancer patients before and during tamoxifen treatment. In a subgroup of 10 patients, we measured 24 h urinary excretion of estrogen metabolites to evaluate the influence of tamoxifen treatment on estrogen metabolism and total estrogen production. Tamoxifen increased plasma levels of E1S (mean increase of 18.1%, P < 0.05) and the ratio of E1S/E1 (mean increase of 25.7%, P < 0.01) and E1S/E2 (mean increase of 34.7%, P < 0.0005). No significant change in plasma E1 was seen, but plasma E2 was reduced (mean reduction...

The Lancet Oncology, 2014

Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a... more Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0·70, 95% CI 0·56-0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52-0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3-4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3-4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3-4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. Algeta ASA and Bayer HealthCare Pharmaceuticals.

The Journal of Steroid Biochemistry and Molecular Biology, 1997

Aromatase inhlbition is a weU-defined treatment option for postmenopausal breast cancer. Although... more Aromatase inhlbition is a weU-defined treatment option for postmenopausal breast cancer. Although several aromatase inhibitors such as aminoglutethimide, formestane and fadrozole have been found to inhibit in vivo aromatization by >85%, previous studies reported plasma estrogen levels to be sustained at approximately 20-50% of their control level during treatment with these drugs. The discrepancy could be due to lack of sensitivity or non-specific crossreactions in the radioimmunoassay (RIA) methods. Mean plasma levels of estrone (El) and estradiol (E2) in postmenopausal women are approximately 80 and 20 pmol/l, respectively; on the contrary, mean plasma levels of the estrogen conjugate estrone stflphate (E1S) are approxlmately 4-500 pmol/1. Most RIA methods for plasma E2 and E1 measurements have sensitivity Hmits in the range of 2-3 and 7-10pmolfl, respectively; accordingly, the suppression of plasma estrogens by more than 80-90% will produce hormone values below the sensitivity Hmit of the method in many patients. Recently, we developed a new method to determine plasma EiS. This assay has a sensitivity limit of 2.7 pmol/1. In theory, this method may allow the determination of plasma EiS levels suppressed to less than 2% of control values in the majority of patients. Using this method, we found different aromatase inhibitors such as formestane, aminoglutethimide, formestane and aminoglutethimide administered in concert or anastrozole to suppress plasma EiS levels down to 24, 13, 7 and 4%, respectively. The suppression of plasma EiS evaluated with this method thus approaches the percentage aromatase inhibition measured wlth tracer studies.

The Journal of Steroid Biochemistry and Molecular Biology, 2001

Formestane (Lentaron ® , 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for tr... more Formestane (Lentaron ® , 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for treatment of advanced breast cancer. Clinically, it is administered as a depot form once fortnightly by intramuscular (i.m.) injection. To investigate the pharmacokinetics, bioavailability and metabolism of the drug, seven patients received single 250 mg i.m. doses of commercial formestane on Days 0, 21, 35, 49 and 63 of this trial. On Day 63, three of the patients received an additional single intravenous (i.v.) pulse dose of 1 mg of 14 C-labelled formestane. The plasma kinetics after i.m. dosing confirmed a sustained release of formestane from the site of injection. Within 24-48 h of the first dose, the circulating drug reached a C max of 48.09 20.9 nmol/l (mean9 S.D.; N = 7). At the end of the dosing interval, after 14 days, the plasma concentration was still at 2.3 9 1.8 nmol/l. The kinetic variables did not significantly change during prolonged treatment. Intramuscular doses appear to be fully bioavailable. Following i.v. injection of 14 C-formestane, the unchanged drug disappeared rapidly from plasma, the terminal elimination half-life being 18 92 min (N=3). Plasma clearance, CL was 4.2 91.3 l/(h kg) and the terminal distribution volume V z was 1.8 90.5 l/kg. The drug is mainly eliminated by metabolism, renal excretion of metabolites accounting for 95% of dose. The excretory balance of 14 C-compounds in urine and faeces totals up to 98.9 9 0.8% of the i.v. dose after 168 h. The 14 C-compounds in plasma and urine were separated by HPLC, and three major metabolites were submitted to structural analysis by MS, NMR and UV spectroscopy. One of the metabolites is the direct 4-O-glucuronide of formestane. The other two represent 3-O-sulfates of the exocons 3b,4b-dihydroxy-5a-androstane-17-one and 3a,4b-dihydroxy-5a-androstane-17-one, their ratio being 7:3. These exocons are formed by stereoselective 3-keto reduction, accompanied by reduction of the 4,5-enol function. The exocons do not inhibit human placental aromatase activity in vitro.

The Journal of Steroid Biochemistry and Molecular Biology, 1992

Plasma insulin-like growth factor-I (IGF-I) was measured in breast cancer patients before and dur... more Plasma insulin-like growth factor-I (IGF-I) was measured in breast cancer patients before and during treatment with tamoxifen, goserelin or aminoglutethimide. 24 out of 27 postmenopausal women treated with tamoxifen 20 or 30 mg daily experienced a decrease in plasma IGF-I levels (mean levels before treatment 14.8 nM, during treatment 10.2nM, P < 0.001). In 8 out of 12 premenopausal breast cancer patients there was a reduction in plasma IGF-I during treatment with goserelin (mean levels before treatment 23.3 nM, during treatment 19.4 nM, P = 0.052). Contrary, 15 out of 17 postmenopausal women treated with the aromatase inhibitor aminoglutethimide had an increase in plasma IGF-I level (mean level before treatment 17.0 nM, during treatment 21.1 nM, P < 0.01). These preliminary results indicate that different forms of endocrine treatment of breast cancer may influence plasma IGF-I levels in different directions.

Scandinavian Journal of Urology and Nephrology, 2002

ABSTRACT

The Lancet Oncology, 2014

Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant... more Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82). Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. Algeta and Bayer HealthCare Pharmaceuticals.

The Journal of Urology, 2012

Journal of Radiotherapy in Practice, 2014

Background and purposeIn radiotherapy (RT), there are high requirements for quality assurance (QA... more Background and purposeIn radiotherapy (RT), there are high requirements for quality assurance (QA) in all the steps of the process. Development of QA systems are demanding in terms of financial and human resources. A national QA programme (KVIST) has been established in Norway to facilitate implementation of QA activity on hospital level.MethodThe KVIST organisation comprises the KVIST team, the reference group (RG) and the working groups (WGs). The KVIST team is multidisciplinary and are employed in permanent positions. The RG acts as an advisory body for the KVIST team in defining and ranking the priority of projects. Relevant national QA projects are identified in collaboration with the RG, and WGs are established to carry out the various projects.ResultSeveral national consensus documents have been prepared by the various WGs. Systems for incident handling and activity reporting have been established and clinical audits have been implemented in Norwegian RT. Guidelines for RT of...

Journal of Clinical Oncology, 2004

Purpose To investigate whether the effect of hypofractionated thoracic radiotherapy (TRT) is comp... more Purpose To investigate whether the effect of hypofractionated thoracic radiotherapy (TRT) is comparable to more standard fractionated radiotherapy (RT) in advanced non–small-cell lung cancer (NSCLC). Patients and Methods A total of 421 patients with locally advanced stage III or stage IV NSCLC tumors were included. Inclusion criteria were inoperable, disease too advanced for curative radiotherapy, and chest symptoms or central tumor threatening the airways. Patients were randomly assigned to three arms: A, 17 Gy per two fractions (n = 146); B, 42 Gy per 15 fractions (n = 145); and C, 50 Gy per 25 fractions (n = 130). Four hundred seven patients were eligible for the study; 395 patients (97%) participated in the health-related quality-of-life (HRQOL) study. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and EORTC QLQ-lung cancer–specific module (LC13) were used to investigate airway symptom relief and changes in HRQOL. A...

A template for the content of a professional evidence based guideline of how to do radiation ther... more A template for the content of a professional evidence based guideline of how to do radiation therapy of various cancer diagnosis in Norway developed under the KVIST programme (Norwegian acronym for «quality assurance in radiotherapy»). KVIST offers to do the implementation of the template for different cancer diagnosis in collaboration with the radiotherapy society in Norway and other health authorities. Prosjektleder: Gunilla Frykholm, KVIST Godkjent: Gunnar Saxebøl, avdelingsdirektør, Avdeling strålevern og sikkerhet Versjon, dato Kommentar/endring Ansvarlig Første gang publisert august 2006 (utkastform) Bygger på StrålevernRapport 2003:12 [4] og ICRU 50/62 [5,6] KVIST 2010 ICRU 83 [7] KVIST 24 sider. Utgitt 2010-03-19. Opplag 100 (10-03). Form, omslag: LoboMedia AS. Trykk: LoboMedia AS, Oslo. Bestilles fra: Statens strålevern, Postboks 55, No-1332 Østerås, Norge. Telefon 67 16 25 00, faks 67 14 74 07. E-post: nrpa@nrpa.no www.nrpa.no ISSN 0804-4910 (print) ISSN 1891-5205 (online)...

Journal of Clinical Oncology

5068 Background: Ra-223, a first-in-class α-emitter, significantly improved median overall surviv... more 5068 Background: Ra-223, a first-in-class α-emitter, significantly improved median overall survival (OS) by 3.6 mo vs placebo (Pbo) in CRPC patients (pts) with bone metastases (mets) receiving best standard of care (BSoC) in the ALSYMPCA study (HR = 0.695; 95% CI, 0.581-0.832; p = 0.00007), and had a highly favorable safety profile in the updated ALSYMPCA analysis (Parker et al. ASCO 2012). This predefined subgroup analysis assessed efficacy and safety of Ra-223 in pts who did or did not receive prior D (pD). Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets; had no known visceral mets; were receiving BSoC; and had received pD, or were unfit for or declined D (npD). Pts were randomized 2:1 to 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching Pbo and stratified by prior D use, baseline alkaline phosphatase level, and current bisphosphonate use. Survival data were compared using a log-rank test. Results: 395/921 (43%) randomized pts had npD (Ra-223, n = 2...

Journal of Clinical Oncology

4551 Background: Ra-223, a 1st-in-class alpha-pharmaceutical, targets bone metastases (mets) with... more 4551 Background: Ra-223, a 1st-in-class alpha-pharmaceutical, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) v placebo (pbo) plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint was OS; secondary endpoints included SREs and ECOG PS. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to 6 injections of Ra‑223 (50 kBq/kg IV) q4 wks or matching pbo and stratified by prior docetaxel use, baseline ALP level, and current bisphosphonate use. Results: 921 pts were randomized from 6/2008-2/2011. In a planned interim analysis (n = 809), Ra-223 significantly improved OS v pbo (median OS 14.0 v 11.2 mo, respectivel...

European Journal of Cancer Supplements

European urology, Jan 10, 2017

In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonge... more In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment. To report updated ALSYMPCA safety, including long-term safety up to 3 yr after the first injection. Safety analyses from phase 3 randomized ALSYMPCA trial included patients receiving ≥1 study-drug injection (600 radium-223 and 301 placebo). Patients (405 radium-223 and 167 placebo) entered long-term safety follow-up starting 12 wk after the last study-drug injection, to 3 yr from the first injection. Forty-eight of 405 (12%) radium-223 and 12/167 (7%) placebo patients completed follow-up, with evaluations every 2 mo for 6 mo, then every 4 mo until 3 yr. All adverse events (AEs) were collected until 12 wk after the last injection; subsequently, only treatment-related AEs wer...

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 20, 2012

LBA4512 Background: Radium-223 chloride (Ra-223), a targeted alpha-emitter, targets bone metastas... more LBA4512 Background: Radium-223 chloride (Ra-223), a targeted alpha-emitter, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 µm). ALSYMPCA, a phase III double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) vs placebo plus BSC in CRPC patients (pts) with bone mets. In a planned interim analysis (n = 809), based on 314 events, Ra-223 significantly improved overall survival (OS) vs placebo (median 14.0 mo vs 11.2 mo, respectively; HR = .695; 95% CI, .552-.875; 2-sided p = .00185). Secondary endpoints were met and Ra-223 safety was favorable. An updated analysis was conducted prior to the crossover to further assess the effect of Ra-223 on the primary endpoint (OS), secondary endpoints including skeletal-related events (SREs), and safety. Eligible pts had confirmed symptomatic CRPC with ≥ 2 bone mets; no known visceral mets; and were post-docetaxel, unfit for docetaxel, or had declined docetaxel. Pts were r...

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 10, 2012

8 Background: Radium-223 chloride (Ra-223) is a first-in-class alpha-pharmaceutical targeting bon... more 8 Background: Radium-223 chloride (Ra-223) is a first-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy alpha-particles of extremely short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared efficacy, in terms of overall survival (OS), and safety of Ra-223 plus best standard of care (BSC) vs placebo plus BSC in patients (pts) with bone mets in CRPC. Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4 wks or matching placebo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. A planned interim analysis (IA) was conducted to assess the effect of Ra-223 on the primary endpoint (OS) using a predefined threshold. Sur...

Clinical chemistry, 1999

In this study, we evaluated the effect of estrogen suppression with three aromatase inhibitors, a... more In this study, we evaluated the effect of estrogen suppression with three aromatase inhibitors, aminoglutethimide (n = 30), formestane (n = 12), and exemestane (n = 10), and the progestin megestrol acetate (n = 21) on plasma total homocysteine (tHcy) in patients suffering from advanced breast cancer. Treatment with 1 g/day aminoglutethimide for 2 and 3-5 months increased plasma tHcy by a mean value of 24.5% [95% confidence interval, 10.5-40.4%] at 2 months and 35.8% (95% confidence interval, 18.2-55.9%) at 3-5 months, corresponding to increases in the mean plasma tHcy of 1.90 and 3.67 micromol/L, respectively. In contrast, none of the other treatment options influenced plasma tHcy concentrations. The finding that aminoglutethimide, but none of the other aromatase inhibitors or megestrol acetate, influenced plasma tHcy suggests that this effect is achieved by mechanisms not related to suppression of plasma estrogens or to the glucocorticoids administered in concert.

British journal of cancer, 1993

Plasma and urinary oestrogens were measured in nine breast cancer patients (eight postmenopausal ... more Plasma and urinary oestrogens were measured in nine breast cancer patients (eight postmenopausal women and one man) before and during treatment with the aromatase inhibitor 4-hydroxyandrostenedione. Urinary oestrogens were measured by using a highly specific GC-MS method. Plasma levels of oestrone, oestradiol and oestrone sulphate were suppressed by 66.6% (+/- 3.6%), 57.7% (+/- 5.1%) and 51.8% (+/- 6.4%) respectively (P < 0.005 for all). Twenty-four hour urinary excretion of total oestrogens, oestradiol, oestriol, 2-hydroxyoestrone, 16 alpha-hydroxyoestrone and the minor metabolites 16 beta- and 15 alpha-hydroxyoestrone were all suppressed by mean values ranging from 60% to 82%, (oestradiol: P < 0.025, otherwise P < 0.005). There were no significant changes in the ratios between the different plasma oestrogens. The finding of sustained plasma and urinary oestrogens at 20-40% compared to their control levels indirectly support a hypothesis of alternative oestrogen sources in...

The Journal of steroid biochemistry and molecular biology, 1995

Estrone sulphate (E1S) may be an important estrogen source in breast cancers, particularly in pos... more Estrone sulphate (E1S) may be an important estrogen source in breast cancers, particularly in postmenopausal women. Recent studies have shown that tamoxifen inhibits the uptake and metabolism of E1S to estradiol (E2) in cell cultures. To evaluate a possible influence of tamoxifen on E1S disposition in vivo, we measured plasma levels of E1S together with unconjugated estrogens (E1 and E2), androgens (T, A, DHEA and DHEAS), SHBG, FSH and LH in 32 postmenopausal breast cancer patients before and during tamoxifen treatment. In a subgroup of 10 patients, we measured 24 h urinary excretion of estrogen metabolites to evaluate the influence of tamoxifen treatment on estrogen metabolism and total estrogen production. Tamoxifen increased plasma levels of E1S (mean increase of 18.1%, P < 0.05) and the ratio of E1S/E1 (mean increase of 25.7%, P < 0.01) and E1S/E2 (mean increase of 34.7%, P < 0.0005). No significant change in plasma E1 was seen, but plasma E2 was reduced (mean reduction...

The Lancet Oncology, 2014

Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a... more Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0·70, 95% CI 0·56-0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52-0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3-4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3-4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3-4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. Algeta ASA and Bayer HealthCare Pharmaceuticals.

The Journal of Steroid Biochemistry and Molecular Biology, 1997

Aromatase inhlbition is a weU-defined treatment option for postmenopausal breast cancer. Although... more Aromatase inhlbition is a weU-defined treatment option for postmenopausal breast cancer. Although several aromatase inhibitors such as aminoglutethimide, formestane and fadrozole have been found to inhibit in vivo aromatization by >85%, previous studies reported plasma estrogen levels to be sustained at approximately 20-50% of their control level during treatment with these drugs. The discrepancy could be due to lack of sensitivity or non-specific crossreactions in the radioimmunoassay (RIA) methods. Mean plasma levels of estrone (El) and estradiol (E2) in postmenopausal women are approximately 80 and 20 pmol/l, respectively; on the contrary, mean plasma levels of the estrogen conjugate estrone stflphate (E1S) are approxlmately 4-500 pmol/1. Most RIA methods for plasma E2 and E1 measurements have sensitivity Hmits in the range of 2-3 and 7-10pmolfl, respectively; accordingly, the suppression of plasma estrogens by more than 80-90% will produce hormone values below the sensitivity Hmit of the method in many patients. Recently, we developed a new method to determine plasma EiS. This assay has a sensitivity limit of 2.7 pmol/1. In theory, this method may allow the determination of plasma EiS levels suppressed to less than 2% of control values in the majority of patients. Using this method, we found different aromatase inhibitors such as formestane, aminoglutethimide, formestane and aminoglutethimide administered in concert or anastrozole to suppress plasma EiS levels down to 24, 13, 7 and 4%, respectively. The suppression of plasma EiS evaluated with this method thus approaches the percentage aromatase inhibition measured wlth tracer studies.

The Journal of Steroid Biochemistry and Molecular Biology, 2001

Formestane (Lentaron ® , 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for tr... more Formestane (Lentaron ® , 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for treatment of advanced breast cancer. Clinically, it is administered as a depot form once fortnightly by intramuscular (i.m.) injection. To investigate the pharmacokinetics, bioavailability and metabolism of the drug, seven patients received single 250 mg i.m. doses of commercial formestane on Days 0, 21, 35, 49 and 63 of this trial. On Day 63, three of the patients received an additional single intravenous (i.v.) pulse dose of 1 mg of 14 C-labelled formestane. The plasma kinetics after i.m. dosing confirmed a sustained release of formestane from the site of injection. Within 24-48 h of the first dose, the circulating drug reached a C max of 48.09 20.9 nmol/l (mean9 S.D.; N = 7). At the end of the dosing interval, after 14 days, the plasma concentration was still at 2.3 9 1.8 nmol/l. The kinetic variables did not significantly change during prolonged treatment. Intramuscular doses appear to be fully bioavailable. Following i.v. injection of 14 C-formestane, the unchanged drug disappeared rapidly from plasma, the terminal elimination half-life being 18 92 min (N=3). Plasma clearance, CL was 4.2 91.3 l/(h kg) and the terminal distribution volume V z was 1.8 90.5 l/kg. The drug is mainly eliminated by metabolism, renal excretion of metabolites accounting for 95% of dose. The excretory balance of 14 C-compounds in urine and faeces totals up to 98.9 9 0.8% of the i.v. dose after 168 h. The 14 C-compounds in plasma and urine were separated by HPLC, and three major metabolites were submitted to structural analysis by MS, NMR and UV spectroscopy. One of the metabolites is the direct 4-O-glucuronide of formestane. The other two represent 3-O-sulfates of the exocons 3b,4b-dihydroxy-5a-androstane-17-one and 3a,4b-dihydroxy-5a-androstane-17-one, their ratio being 7:3. These exocons are formed by stereoselective 3-keto reduction, accompanied by reduction of the 4,5-enol function. The exocons do not inhibit human placental aromatase activity in vitro.

The Journal of Steroid Biochemistry and Molecular Biology, 1992

Plasma insulin-like growth factor-I (IGF-I) was measured in breast cancer patients before and dur... more Plasma insulin-like growth factor-I (IGF-I) was measured in breast cancer patients before and during treatment with tamoxifen, goserelin or aminoglutethimide. 24 out of 27 postmenopausal women treated with tamoxifen 20 or 30 mg daily experienced a decrease in plasma IGF-I levels (mean levels before treatment 14.8 nM, during treatment 10.2nM, P < 0.001). In 8 out of 12 premenopausal breast cancer patients there was a reduction in plasma IGF-I during treatment with goserelin (mean levels before treatment 23.3 nM, during treatment 19.4 nM, P = 0.052). Contrary, 15 out of 17 postmenopausal women treated with the aromatase inhibitor aminoglutethimide had an increase in plasma IGF-I level (mean level before treatment 17.0 nM, during treatment 21.1 nM, P < 0.01). These preliminary results indicate that different forms of endocrine treatment of breast cancer may influence plasma IGF-I levels in different directions.

Scandinavian Journal of Urology and Nephrology, 2002

ABSTRACT

The Lancet Oncology, 2014

Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant... more Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82). Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. Algeta and Bayer HealthCare Pharmaceuticals.

The Journal of Urology, 2012

Journal of Radiotherapy in Practice, 2014

Background and purposeIn radiotherapy (RT), there are high requirements for quality assurance (QA... more Background and purposeIn radiotherapy (RT), there are high requirements for quality assurance (QA) in all the steps of the process. Development of QA systems are demanding in terms of financial and human resources. A national QA programme (KVIST) has been established in Norway to facilitate implementation of QA activity on hospital level.MethodThe KVIST organisation comprises the KVIST team, the reference group (RG) and the working groups (WGs). The KVIST team is multidisciplinary and are employed in permanent positions. The RG acts as an advisory body for the KVIST team in defining and ranking the priority of projects. Relevant national QA projects are identified in collaboration with the RG, and WGs are established to carry out the various projects.ResultSeveral national consensus documents have been prepared by the various WGs. Systems for incident handling and activity reporting have been established and clinical audits have been implemented in Norwegian RT. Guidelines for RT of...

Journal of Clinical Oncology, 2004

Purpose To investigate whether the effect of hypofractionated thoracic radiotherapy (TRT) is comp... more Purpose To investigate whether the effect of hypofractionated thoracic radiotherapy (TRT) is comparable to more standard fractionated radiotherapy (RT) in advanced non–small-cell lung cancer (NSCLC). Patients and Methods A total of 421 patients with locally advanced stage III or stage IV NSCLC tumors were included. Inclusion criteria were inoperable, disease too advanced for curative radiotherapy, and chest symptoms or central tumor threatening the airways. Patients were randomly assigned to three arms: A, 17 Gy per two fractions (n = 146); B, 42 Gy per 15 fractions (n = 145); and C, 50 Gy per 25 fractions (n = 130). Four hundred seven patients were eligible for the study; 395 patients (97%) participated in the health-related quality-of-life (HRQOL) study. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and EORTC QLQ-lung cancer–specific module (LC13) were used to investigate airway symptom relief and changes in HRQOL. A...