Abstract Purpose To investigate the dose–response relationship and pain-relieving effect of radium-223, a highly bone-targeted alpha-pharmaceutical. Methods One hundred patients with ...castration-resistant prostate cancer (CRPC) and painful bone metastases were randomized to a single intravenous dose of 5, 25, 50 or 100 kBq/kg radium-223. The primary end-point was pain index (visual analogue scale VAS and analgesic use), also used to classify patients as responders or non-responders. Results A significant dose response for pain index was seen at week 2 ( P = .035). At week 8 there were 40%, 63%, 56% and 71% pain responders (reduced pain and stable analgesic consumption) in the 5, 25, 50 and 100 kBq/kg groups, respectively. On the daily VAS, at week 8, pain decreased by a mean of −30, −31, −27 and −28 mm, respectively ( P = .008, P = .0005, P = .002, and P < .0001) in these responders ( post-hoc analysis). There was also a significant improvement in the brief pain inventory functional index for all dose-groups ( P = .04, .01, .002 and .02, Wilcoxon signed rank test). Furthermore, a decrease in bone alkaline phosphatase in the highest dose-group was demonstrated ( P = .0067). All doses were safe and well tolerated. Conclusion Pain response was seen in up to 71% of the patients with a dose response observed 2 weeks after administration. The highly tolerable side-effect profile of radium-223 previously reported was confirmed.
Liposomal drug delivery enhances the tumour selective localisation and may improve the uptake compared to free drug. However, the drug distribution within the tumour tissue may still be ...heterogeneous. Degradation of the extracellular matrix is assumed to improve the uptake and penetration of drugs. The effect of the ECM-degrading enzyme hyaluronidase on interstitial fluid pressure and microvascular pressure were measured in human osteosarcoma xenografts by the wick-in-needle and micropipette technique, respectively. The tumour uptake and distribution of liposomal doxorubicin were studied on tumour sections by confocal laser scanning microscopy. The drugs were injected i.v. 1 h after the hyaluronidase pretreatment. Intratumoral injection of hyaluronidase reduced interstitial fluid pressure in a nonlinear dose-dependent manner. Maximum interstitial fluid pressure reduction of approximately 50% was found after injection of 1500 U hyaluronidase. Neither intratumoral nor i.v. injection of hyaluronidase induced any changes in the microvascular pressure. Thus, hyaluronidase induced a transcapillary pressure gradient, resulting in a four-fold increase in the tumour uptake and improving the distribution of the liposomal doxorubicin. Hyaluronidase reduces a major barrier for drug delivery by inducing a transcapillary pressure gradient, and administration of hyaluronidase adjuvant with liposomal doxorubicin may thus improve the therapeutic outcome.
Summary 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 of223 Ra. Methods Patients with hormone-refractory prostate cancer and bone pain needing external-beam radiotherapy were assigned to four intravenous injections of223 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 the223 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 discontinued223 Ra because of treatment toxicity. Median time to PSA progression was 26 weeks (16–39) versus 8 weeks (4–12; p=0·048) for223 Ra versus placebo, respectively. Median overall survival was 65·3 weeks (48·7–∞) for223 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). Interpretation223 Ra was well tolerated with minimum myelotoxicity, and had a significant effect on bone-ALP concentrations. Larger clinical trials are warranted to study223 Ra on the prevention of SREs and on overall survival in patients with hormone-refractory prostate cancer. Bone-targeting properties of223 Ra could also potentially be used for treating skeletal metastasis from other primary cancers.
Background
Tumour rupture is a strong predictor of poor outcome in gastrointestinal stromal tumours (GISTs) of the stomach and small intestine. The objective was to determine whether tumour genotype ...was associated with risk of rupture.
Methods
Rupture was classified according to the definition proposed by the Oslo Sarcoma Group. Since January 2000, data were registered retrospectively for all patients at Oslo University Hospital undergoing surgery for localized GIST of the stomach or small intestine. Tumour genotype was analysed by Sanger sequencing.
Results
Two hundred and nine patients with mutation data available were identified. Tumour rupture occurred in 37 patients. Among the 155 patients with KIT exon 11 mutations, an increased risk of rupture was observed with a deletion or insertion–deletion (25 of 86, 29 per cent) compared with substitutions (5 of 50, 10 per cent) or duplications/insertions (2 of 19, 11 per cent) (P = 0·014). Notably, rupture occurred in 17 of 46 tumours (37 per cent) with deletions involving codons 557 and 558 (del557/558) versus 15 of 109 (13·8 per cent) with other exon 11 mutations (P = 0·002). This association was confined to gastric tumours: 12 of 34 (35 per cent) with del557/558 ruptured versus six of 77 (8 per cent) with other exon 11 mutations (P = 0·001). In multivariable logistic regression analysis, del557/558 and tumour size were associated with an increased likelihood of tumour rupture, but mitotic count was not.
Conclusion
Gastric GISTs with KIT exon 11 deletions involving codons 557 and 558 are at increased risk of tumour rupture. This high‐risk feature can be identified in the diagnostic evaluation and should be included in the assessment when neoadjuvant imatinib treatment is considered.
Handle with care
Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition ...to the best standard of care, in men with castration-resistant prostate cancer and bone metastases.
In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223.
At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval CI, 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events.
In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).
Summary
Background
Solar ultraviolet (UV) radiation during the summer and vitamin D supplementation are two major sources of vitamin D for humans at northern latitudes. However, little is known about ...the relative efficiency of these two vitamin D sources.
Objectives
The main goal was to compare the efficiency of high‐dose oral vitamin D3 supplementation (2000 IU per day for 30 days) with a simulated summer UV exposure 10 sunbed sessions to a total dose of 23·8 standard erythema doses (SED) to improve vitamin D status.
Methods
Healthy volunteers were randomized into two groups: group 1 received vitamin D supplementation followed by 10 whole‐body sunbed exposures; group 2 started with 10 sunbed exposures followed by vitamin D supplementation.
Results
The oral supplementation with vitamin D3 resulted in a mean (SEM) serum 25‐hydroxyvitamin D 25(OH)D increase of 25·3 (5·4) nmol L−1. A similar increase, 19·8 (5·4) nmol L−1, was observed after simulated summer UV exposure. At the end of the study, serum 25(OH)D concentrations were similar in both groups.
Conclusions
Twice‐weekly whole‐body sunbed exposure to a dose of 4·8 SED is equal to 2000 IU daily of oral vitamin D supplementation for 30 days and enough to achieve and maintain serum 25(OH)D concentrations > 75 nmol L−1 in ~55% of cases. Based on our calculations, this dose corresponds to a cumulative weekly whole‐body exposure of 3·4 SED (~ 40 min around midday during the summer at the latitude of Oslo).
What's already known about this topic?
Solar ultraviolet (UV) radiation and vitamin D supplementation are two major sources of vitamin D for humans.
During winter months (October–March) vitamin D formation in the skin is insufficient due to the low UVB fluences at latitudes above 40ºN.
Little is known about the relative efficiency of these two vitamin D sources, with respect to efficiency in increasing serum 25‐hydroxyvitamin D 25(OH)D.
What does this study add?
Twice‐weekly whole‐body UV exposure to a dose of 4·8 standard erythema doses (SED) for 5 weeks to a total dose of 23·8 SED is equal to 2000 IU daily of oral vitamin D supplementation for 30 days and enough to achieve and maintain serum 25(OH)D concentrations > 75 nmol L−1 in ˜55% of cases.
See also the Commentary by Wolf
The current management of osteosarcoma (OS) is critically reviewed and a modified treatment strategy is put forward for discussion. The overall treatment results in high-grade OS are less impressive ...than widely assumed. Whereas in ‘classical OS’ survival has indeed increased during the past decades from approximately 20% to at least 60%, in other subgroups, comprising more than 40% of the entire OS population, the prognosis has been only modestly improved. Today still more than half of an unselected OS population eventually succumbs to the disease despite the current multimodal primary treatments as well as second-line chemotherapy and surgical metastasectomy(ies). Analysis of the reported results indicates that a survival plateau of approximately 60% can be achieved by several different drug combinations. The inclusion of additional drugs and treatment with complex combinations to all patients has not yielded a convincing survival benefit. These expensive regimens overtreat a large number of patients, namely those who could have been cured by the previous less drastic regimens, and it increases the acute and delayed side-effect. Toxic deaths occur and life-threatening side-effects are not infrequent, necessitating interruption of the treatment or reduction in the dose intensity. A possible marginal early survival benefit may well be offset by late side-effects. For the above reasons, we propose an alternative, risk-adapted, treatment strategy, to retain the present results at a lower price in terms of acute toxicity and late morbidity. It is suggested that all patients with classical OS should be treated pre-operatively with optimal doses of only the two most active agents, methotrexate and doxorubicin. This presumably is sufficient in the majority of these patients. The most toxic treatment involving additional anticancer agents should be reserved for high-risk and relapsing patients, i.e. for situations where drastic measures are necessary and warranted. An important consideration is that relapsing patients are likely to benefit in particular from drugs to which they have not been previously exposed.
Summary Background 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. Methods 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. Findings 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). Interpretation Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. Funding Algeta and Bayer HealthCare Pharmaceuticals.
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 were collected. Additional long-term safety was assessed by development of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and secondary malignancies. Data analysis used descriptive statistics.
During treatment to 12 wk following the last injection, 564/600 (94%) radium-223 and 292/301 (97%) placebo patients had treatment-emergent AEs (TEAEs). Myelosuppression incidence was low. Grade 3/4 hematologic TEAEs in radium-223 and placebo groups were anemia (13% vs 13%), neutropenia (2% vs 1%), and thrombocytopenia (7% vs 2%). Ninety-eight of 600 (16%) radium-223 and 68/301 (23%) placebo patients experienced grade 5 TEAEs. Long-term follow-up showed no AML, MDS, or new primary bone cancer; secondary non–treatment-related malignancies occurred in four radium-223 and three placebo patients. One radium-223 patient had aplastic anemia 16 mo after the last injection. No other cases were observed. Limitations include short (3-yr) follow-up.
Final long-term safety ALSYMPCA analysis shows that radium-223 remained well tolerated, with low myelosuppression incidence and no new safety concerns.
Updated Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial findings show that radium-223 remained well tolerated during treatment and up to 3 yr after each patient's first injection.
Three-year safety follow-up of Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial patients with castration-resistant prostate cancer and symptomatic bone metastases revealed a continued low incidence of myelosuppression, minimal nonhematologic adverse events, and secondary malignancies (none related to treatment) in four radium-223 patients and three placebo patients.
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