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Franzén, Lars
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Publications (10 of 24) Show all publications
Widmark, A., Gunnlaugsson, A., Beckman, L., Thellenberg-Karlsson, C., Hoyer, M., Lagerlund, M., . . . Nilsson, P. (2019). Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. The Lancet, 394(10196), 385-395
Open this publication in new window or tab >>Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial
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2019 (English)In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 394, no 10196, p. 385-395Article in journal (Refereed) Published
Abstract [en]

Background: Hypofractionated radiotherapy for prostate cancer has gained increased attention due to its proposed high radiation-fraction sensitivity. Recent reports from studies comparing moderately hypofractionated and conventionally fractionated radiotherapy support the clinical use of moderate hypofractionation. To date, there are no published randomised studies on ultra-hypofractionated radiotherapy. Here, we report the outcomes of the Scandinavian HYPO-RT-PC phase 3 trial with the aim to show non-inferiority of ultra-hypofractionation compared with conventional fractionation.

Methods: In this open-label, randomised, phase 3 non-inferiority trial done in 12 centres in Sweden and Denmark, we recruited men up to 75 years of age with intermediate-to-high-risk prostate cancer and a WHO performance status between 0 and 2. Patients were randomly assigned to ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) or conventional fractionated radiotherapy (78·0 Gy in 39 fractions, 5 days per week for 8 weeks). No androgen deprivation therapy was allowed. The primary endpoint was time to biochemical or clinical failure, analysed in the per-protocol population. The prespecified non-inferiority margin was 4% at 5 years, corresponding to a critical hazard ratio (HR) limit of 1·338. Physician-recorded toxicity was measured according to the Radiation Therapy Oncology Group (RTOG) morbidity scale and patient-reported outcome measurements with the Prostate Cancer Symptom Scale (PCSS) questionnaire. This trial is registered with the ISRCTN registry, number ISRCTN45905321.

Findings: Between July 1, 2005, and Nov 4, 2015, 1200 patients were randomly assigned to conventional fractionation (n=602) or ultra-hypofractionation (n=598), of whom 1180 (591 conventional fractionation and 589 ultra-hypofractionation) constituted the per-protocol population. 1054 (89%) participants were intermediate risk and 126 (11%) were high risk. Median follow-up time was 5·0 years (IQR 3·1–7·0). The estimated failure-free survival at 5 years was 84% (95% CI 80–87) in both treatment groups, with an adjusted HR of 1·002 (95% CI 0·758–1·325; log-rank p=0·99). There was weak evidence of an increased frequency of acute physician-reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy (158 [28%] of 569 patients vs 132 [23%] of 578 patients; p=0·057). There were no significant differences in grade 2 or worse urinary or bowel late toxicity between the two treatment groups at any point after radiotherapy, except for an increase in urinary toxicity in the ultra-hypofractionation group compared to the conventional fractionation group at 1-year follow-up (32 [6%] of 528 patients vs 13 [2%] of 529 patients; (p=0·0037). We observed no differences between groups in frequencies at 5 years of RTOG grade 2 or worse urinary toxicity (11 [5%] of 243 patients for the ultra-hypofractionation group vs 12 [5%] of 249 for the conventional fractionation group; p=1·00) and bowel toxicity (three [1%] of 244 patients vs nine [4%] of 249 patients; p=0·14). Patient-reported outcomes revealed significantly higher levels of acute urinary and bowel symptoms in the ultra-hypofractionation group compared with the conventional fractionation group but no significant increases in late symptoms were found, except for increased urinary symptoms at 1-year follow-up, consistent with the physician-evaluated toxicity.

Interpretation: Ultra-hypofractionated radiotherapy is non-inferior to conventionally fractionated radiotherapy for intermediate-to-high risk prostate cancer regarding failure-free survival. Early side-effects are more pronounced with ultra-hypofractionation compared with conventional fractionation whereas late toxicity is similar in both treatment groups. The results support the use of ultra-hypofractionation for radiotherapy of prostate cancer.

Funding: The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Nursing
Identifiers
urn:nbn:se:umu:diva-162730 (URN)10.1016/S0140-6736(19)31131-6 (DOI)000478698300023 ()31227373 (PubMedID)2-s2.0-85069673767 (Scopus ID)
Available from: 2019-08-27 Created: 2019-08-27 Last updated: 2019-08-30Bibliographically approved
Widmark, A., Gunnlaugsson, A., Beckman, L., Thellenberg-Karlsson, C., Hoyer, M., Lagerlund, M., . . . Nilsson, P. (2018). Ultrahypofractionation for prostate cancer: Outcome from the Scandinavian phase 3 HYPO-RT-PC trial. Paper presented at 37th Meeting of the European-Society-for-Radiotherapy-and-Oncology (ESTRO), APR 20-24, 2018, Barcelona, SPAIN. Radiotherapy and Oncology, 127, S314-S314
Open this publication in new window or tab >>Ultrahypofractionation for prostate cancer: Outcome from the Scandinavian phase 3 HYPO-RT-PC trial
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2018 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 127, p. S314-S314Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-150492 (URN)10.1016/S0167-8140(18)30909-5 (DOI)000437723401204 ()
Conference
37th Meeting of the European-Society-for-Radiotherapy-and-Oncology (ESTRO), APR 20-24, 2018, Barcelona, SPAIN
Available from: 2018-11-01 Created: 2018-11-01 Last updated: 2018-11-01Bibliographically approved
Nyqvist, J., Fransson, P., Laurell, G., Hammerlid, E., Kjellén, E., Franzén, L., . . . Zackrisson, B. (2016). Differences in health related quality of life in the randomised ARTSCAN study; accelerated vs. conventional radiotherapy for head and neck cancer: A five year follow up. Radiotherapy and Oncology, 118(2), 335-341
Open this publication in new window or tab >>Differences in health related quality of life in the randomised ARTSCAN study; accelerated vs. conventional radiotherapy for head and neck cancer: A five year follow up
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2016 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 118, no 2, p. 335-341Article in journal (Refereed) Published
Abstract [en]

Background and purpose: Health related quality of life (HRQoL) was assessed in the randomised, prospective ARTSCAN study comparing conventional radiotherapy (CF) with accelerated radiotherapy (AF) for head and neck cancer.

Material and methods: 750 patients with squamous cell carcinoma (of any grade and stage) in the oral cavity, oro-, or hypopharynx or larynx (except T1-2, NO glottic carcinoma) without distant metastases were randomised to either conventional fractionation (2 Gy/day, 5 days/week in 49 days, total dose 68 Gy) or accelerated fractionation (1.1 + 2.0 Gy/day, 5 days/week in 35 days, total dose 68 Gy). HRQoL was assessed with EORTC QLQ-C30, QLQ-H&N35 and HADS at baseline, at end of radiotherapy (eRT) and at 3 and 6 months and 1, 2 and 5 years after start of treatment.

Results: The AF group reported HRQoL was significantly lower at eRT and at 3 months for most symptoms, scales and functions. Few significant differences were noted between the groups at 6 months and 5 years. Scores related to functional oral intake never reached baseline.

Conclusion: In comparison to CF, AF has a stronger adverse effect on HRQoL in the acute phase.

Keywords
Health related quality of life, Accelerated radiotherapy, Head and neck cancer, Quality of life, Accelerated fractionation
National Category
Cancer and Oncology Nursing
Identifiers
urn:nbn:se:umu:diva-120668 (URN)10.1016/j.radonc.2015.12.024 (DOI)000373420000019 ()26777124 (PubMedID)
Available from: 2016-06-16 Created: 2016-05-18 Last updated: 2019-06-27Bibliographically approved
Widmark, A., Gunnlaugsson, A., Beckman, L., Thellenberg-Karlsson, C., Hoyer, M., Lagerlund, M., . . . Nilsson, P. (2016). Extreme Hypofractionation versus Conventionally Fractionated Radiotherapy for Intermediate Risk Prostate Cancer: Early Toxicity Results from the Scandinavian Randomized Phase III Trial "HYPO-RT-PC". Paper presented at 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO), SEP 25-28, 2016, Boston, MA. International Journal of Radiation Oncology, Biology, Physics, 96(5), 938-939
Open this publication in new window or tab >>Extreme Hypofractionation versus Conventionally Fractionated Radiotherapy for Intermediate Risk Prostate Cancer: Early Toxicity Results from the Scandinavian Randomized Phase III Trial "HYPO-RT-PC"
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2016 (English)In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 96, no 5, p. 938-939Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
Elsevier, 2016
National Category
Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-132161 (URN)10.1016/j.ijrobp.2016.09.049 (DOI)000393292200009 ()
Conference
58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO), SEP 25-28, 2016, Boston, MA
Note

Meeting Abstract: LBA-5

Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2019-06-27Bibliographically approved
Zackrisson, B., Kjellén, E., Söderström, K., Brun, E., Nyman, J., Friesland, S., . . . Nilsson, P. (2015). Mature results from a Swedish comparison study of conventional versus accelerated radiotherapy in head and neck squamous cell carcinoma - The ARTSCAN trial. Radiotherapy and Oncology, 117(1), 99-105
Open this publication in new window or tab >>Mature results from a Swedish comparison study of conventional versus accelerated radiotherapy in head and neck squamous cell carcinoma - The ARTSCAN trial
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2015 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 117, no 1, p. 99-105Article in journal (Refereed) Published
Abstract [en]

Background and purpose: This report contains the mature five-year data from the Swedish ARTSCAN trial including information on the influence of p16 positivity (p16+) for oropharyngeal cancers. Material and methods: Patients with previously untreated squamous cell carcinoma without distant metastases of the oral cavity, oropharynx, larynx (except T1-2, NO glottic cancers) and hypopharynx were included. Patients were randomised between accelerated fractionation (AF) (1.1 Gy + 2 Gy per day, 5 days/week for 4.5 weeks, total dose 68 Gy) and conventional fractionation (CF) (2 Gy per day, 5 days/week for 7 weeks, total dose 68 Gy). Human papillomavirus (HPV)-associated p16-expression was assessed retrospectively in tumour tissues from patients with oropharyngeal carcinoma. Results: There was no significant difference in loco-regional control (LRC) between AF and CF (log-rank test p = 0.75). LRC at 5 years was 65.5% for AF and 64.9% for CF. Overall survival (OS) was similar in both arms (p = 0.99). The estimated cancer specific survival (CSS) at 5 years was 62.2% (AF) and 63.3% (CF) (p = 0.99). 206 specimens were analysed for p16 with 153 specimens (74%) identified as p16+. P16 status did not discriminate for response to AF vs. CF with regard to LRC, OS or CSS. Patients with p16+ tumours had a statistically significant better overall prognosis compared with p16 tumours. Conclusion: This update confirms the results of the 2-year report. We failed to identify a positive effect resulting from AF with regards to LRC, OS and CSS. The addition of information on the HPV-associated p16 overexpression did not explain this lack of effect.

Keywords
Radiotherapy, Accelerated fractionation, HPV, p16, HNSCC
National Category
Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-112280 (URN)10.1016/j.radonc.2015.09.024 (DOI)000364247700016 ()26427805 (PubMedID)
Available from: 2015-12-07 Created: 2015-12-04 Last updated: 2018-06-07Bibliographically approved
Franzen, L., Sartor, O., Parker, C., Garcia-Vargas, J. & Nilsson, S. (2014). Long-term safety and real world clinical experience of radium-223 dichloride (Ra-223) in patients (pts) with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases (mets) from the phase 3 ALSYMPCA study. European Journal of Nuclear Medicine and Molecular Imaging, 41(suppl 2), S271-S271, Article ID OP506.
Open this publication in new window or tab >>Long-term safety and real world clinical experience of radium-223 dichloride (Ra-223) in patients (pts) with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases (mets) from the phase 3 ALSYMPCA study
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2014 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no suppl 2, p. S271-S271, article id OP506Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-100990 (URN)000348841900357 ()
Available from: 2015-03-16 Created: 2015-03-16 Last updated: 2018-06-07Bibliographically approved
Parker, C., Nilsson, S., Heinrich, D., Helle, S. I., O'Sullivan, J. M., Fossa, S. D., . . . Sartor, O. (2013). Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. New England Journal of Medicine, 369(3), 213-223
Open this publication in new window or tab >>Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer
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2013 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 369, no 3, p. 213-223Article in journal (Refereed) Published
Abstract [en]

Background 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. Methods 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. Results 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. Conclusions 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.)

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-79605 (URN)10.1056/NEJMoa1213755 (DOI)000321945800007 ()
Available from: 2014-01-31 Created: 2013-08-26 Last updated: 2018-06-08Bibliographically approved
Parker, C., Heinrich, D., Bottomley, D., Hoskin, P., Franzen, L., Solberg, A., . . . Nilsson, S. (2013). Effects of radium-223 dichloride (Ra-223) on health-related quality of life (QOL) outcomes in the phase 3 ALSYMPCA study in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Paper presented at 17th ECCO / 38th ESMO / 32nd ESTRO European Cancer Congress on Reinforcing Multidisciplinarity, SEP 27-OCT 01, 2013, Amsterdam, NETHERLANDS. European Journal of Cancer, 49(Supplement 2), S689-S689, Meeting Abstract: 2878
Open this publication in new window or tab >>Effects of radium-223 dichloride (Ra-223) on health-related quality of life (QOL) outcomes in the phase 3 ALSYMPCA study in patients with castration-resistant prostate cancer (CRPC) and bone metastases
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2013 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, no Supplement 2, p. S689-S689, Meeting Abstract: 2878Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Elsevier, 2013
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-83926 (URN)000326843604240 ()
Conference
17th ECCO / 38th ESMO / 32nd ESTRO European Cancer Congress on Reinforcing Multidisciplinarity, SEP 27-OCT 01, 2013, Amsterdam, NETHERLANDS
Available from: 2013-12-10 Created: 2013-12-10 Last updated: 2018-06-08Bibliographically approved
Nilsson, S., Franzén, L., Parker, C., Tyrrell, C., Blom, R., Tennvall, J., . . . Bruland, Ö. S. (2013). 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. Clinical Genitourinary Cancer, 11(1), 20-26
Open this publication in new window or tab >>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
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2013 (English)In: Clinical Genitourinary Cancer, ISSN 1558-7673, E-ISSN 1938-0682, Vol. 11, no 1, p. 20-26Article in journal (Refereed) Published
Abstract [en]

In this 24-month follow-up of a phase II study in patients with castration-resistant prostate cancer (CRPC) and bone metastases, radium-223 (4 injections of 50 kBq/kg every 4 weeks [n = 33]) improved median overall survival vs. matching placebo (n = 31) (65.3 vs. 46.4 weeks, respectively; log-rank P = .056), with no long-term safety concerns. Data suggest that treatment of bone disease with radium-223 has survival benefits. 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. Clinical Genitourinary Cancer, Vol. 11, No. 1, 20-6 (C) 2013 Elsevier Inc. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Alpha-pharmaceutical, Castration-resistant prostate cancer, Overall survival, Targeted alpha-emitter
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-67578 (URN)10.1016/j.clgc.2012.07.002 (DOI)000315276200004 ()
Available from: 2013-06-04 Created: 2013-03-25 Last updated: 2018-06-08Bibliographically approved
Nilsson, S., Strang, P., Aksnes, A. K., Franzen, L., Olivier, P., Pecking, A., . . . Bruland, O. S. (2012). A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. European Journal of Cancer, 48(5), 678-686
Open this publication in new window or tab >>A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer
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2012 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, no 5, p. 678-686Article, review/survey (Refereed) Published
Abstract [en]

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. (C) 2012 Elsevier Ltd. All rights reserved.

Place, publisher, year, edition, pages
Oxford: Elsevier, 2012
Keywords
Pain, Bone metastases, Prostate cancer, Castration-resistant, Alpha-pharmaceutical, Radium, Alpharadin, BPI, Functional index
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-54130 (URN)10.1016/j.ejca.2011.12.023 (DOI)000301849900007 ()
Available from: 2012-04-23 Created: 2012-04-17 Last updated: 2018-06-08Bibliographically approved
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