OBJECTIVES: Prostate cancer (PC) is the most common cancer in Western countries. Recent advances in the treatment of metastatic castration resistant prostate cancer (mCRPC) have caused significant pressure on health care budgets. We aimed to exemplify this dilemma presenting an example, radium-223 (Xofigo®), and review the literature. METHODS: A 74-year-old man diagnosed with mCRPC was referred to our department in October 2014 for radium-223 therapy. We faced the following dilemma: is radium-223 standard therapy? Is it cost-effective? Medline was searched employing the following search criteria: “radium-223”, “alpharadin”, “Xofigo” and “prostate”. Exclusion and inclusion criteria were applied. Guidelines and cost-effectiveness analyses were focused. We also searched the websites of ASCO, ESMO and ISPOR. The web was searched, using Yahoo and Google search engines, for Health Technology Assessments (HTAs). RESULTS: 181 publications were identified in the Medline database. Only four studies included the word “cost”, three “economics” and none “budget” in heading or abstract. None of the publications were thorough of cost analysis (cost-effectiveness, cost-utility, cost-minimizing or cost-of-illness analysis). Six HTAs and eight national guidelines were identified. The cost per quality adjusted life years was indicated €80.000-94,000. HTAs concluded reimbursement being not recommendable or no ultimate statement could be made. One pointed towards a limited use with caution. CONCLUSION: Guidelines were based on data from randomized clinical trials (RCTs). Health economics was not considered when guidelines were made. Most HTAs concluded this therapy not cost-effective or there was insufficient data for final conclusions. Licensing and reimbursement processes should be run simultaneously.

/pdf/health-economics-and-radium-223-xofigo-in-the-treatment-of-1q1yeeej4e.pdf

Health Economics and Radium-223 (Xofigo®) in the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Case History and a Systematic Review of the Literature

Guidelines for optimal sequencing of radium-223 and chemotherapy for metastatic castration resistant prostate cancer (mCRPC) do not exist. This study evaluated treatment patterns and overall survival (OS) among patients with mCRPC treated with radium-223 in an academic clinical setting. A retrospective study was conducted of bone metastases-predominant mCRPC patients treated with radium-223. Treatment patterns from 2013 to 2018 were evaluated in patients treated with radium-223 pre- vs. post-chemotherapy. OS was examined using Kaplan–Meier medians and 95% confidence intervals. In total, 220 patients were treated with radium-223 (64 pre-chemotherapy, 83 post-chemotherapy, 73 no chemotherapy). Mean radium-223 injections per patient was 5.3 and 4.3 in the pre- vs. post-chemotherapy cohorts, respectively (p < 0.001). The number of chemotherapy cycles was similar for chemotherapy given pre- or post-radium-223. Mean line of mCRPC therapy of radium-223 was 3rd and 5th when given pre- and post-chemotherapy, respectively (p < 0.001). 41.8% patients were treated with radium-223 in combination with another mCRPC therapy, commonly abiraterone acetate (43.5%) or enzalutamide (52.2%). The majority received combination therapy for the duration of radium-223 treatment; 20.7% started another agent after radium-223 initiation; 20.7% initiated radium-223 while on established therapy. Median OS from first mCRPC treatment was 39.4 months (95% CI 33.0, 48.8) for patients with radium-223 pre-chemotherapy vs. 37.4 months (95% CI 32.0, 43.5) post-chemotherapy (and 35.2 months [95% CI 27.9, 43.3] vs. 32.0 months [95% CI 26.9, 36.0] for patients with radium-223 combination vs. monotherapy). This retrospective analysis of patients treated with radium-223 demonstrates that administration of radium-223 pre-chemotherapy increased likelihood of completion of radium-223 treatment. Radium-223 given pre- or post-chemotherapy and with or without combination therapy did not result in significant differences in OS. Additional studies are needed to determine the optimal sequencing strategy of mCRPC in the modern era.

/pdf/treatment-of-metastatic-castration-resistant-prostate-cancer-uzdq5babpf.pdf

Treatment of metastatic castration resistant prostate cancer with radium-223: a retrospective study at a US tertiary oncology center.

Two diagnostic miRNA panels in blood have been identifi ed that could be used to diagnose the early stages of pancreatic cancer, researchers say. Previous studies have focused on raised concentrations of the serum cancer antigen 19-9 (CA19-9), which are reported in about 80% of patients with pancreatic cancer. However, this measure is not specifi c enough to be used as a primary screening test. For the latest study, researchers examined diff erences in miRNA in whole blood samples from 409 patients with pancreatic cancer, 25 patients with chronic pancreatitis, and 312 healthy individuals. Participants were randomly assigned to one of three cohorts for discovery, training, and validation. 38 miRNAs were identifi ed that were signifi cantly dysregulated in patients with pancreatic cancer compared with healthy individuals and patients with chronic pancreatitis. These miRNAs were tested and two diagnostic panels were constructed, with four miRNAs in index I and ten in index II. Overall, the researchers showed that 73 (85%) of the 86 patients with pancreatic cancer in the validation cohort had a correct diagnosis using index I or II with or without serum CA19-9 concentrations. When researchers compared patients with pancreatic cancer with healthy participants using the two indices, the area under the curve was 0·83 (95% CI 0·76–0·90) for index I, 0·82 (0·75–0·89) for

https://www.thelancet.com/pdfs/journals/lanonc/PIIS147020451470052X.pdf

Idelalisib: targeting PI3Kδ in B-cell malignancies

The often modest therapeutic value, the uncertain level of innovation, and the high costs of new drugs suggest a pressing need for early evaluation of emerging pharmaceuticals. The Italian Horizon Scanning Project (IHSP) critically reports on emerging drugs in order to timely assess their potential impact on the National Health System. IHSP identifies, filters and prioritizes emerging drugs for which a European Marketing Authorization (MA) is expected within 12–36 months. The final New Product Information Report, issued 12 months before the MA, critically reports on efficacy and safety of selected drugs, on their possible level of innovation, place in therapy and social and economic impact. Since 2008, 39 new drugs were prioritized (corresponding to 44 indications) due to (i) their potential high epidemiological and economic impact; (ii) the limited availability or the complete lack of treatments; (iii) the uncertainty of the possible place in therapy of the emerging drug; (iv) the possible better efficacy and/or safety profile or possible better compliance of the new medicine versus the available therapies. Among the 39 drugs, 14 active principles were indicated in cancer patients, eight for cardiovascular diseases, and four for multiple sclerosis. Horizon Scanning is a useful tool to support policy-makers in allocating resources more efficiently.

/pdf/italian-horizon-scanning-project-44wgrh3caj.pdf

Italian Horizon Scanning Project

1403 POSTER DISCUSSION Molecular Testing for BRAF V600 Mutations in Clinical Trials of the BRAF Inhibitor Vemurafenib (RG7204/PLX4032) in Metastatic Melanoma – a Comparison With Sánger Sequencing

In patients with advanced castration-resistant prostate cancer (CRPC), symptomatic bone metastases are frequently present. Xofigo® is a radiopharmaceutical that contains the active substance radium-223 dichloride, which targets bone tissue and bone metastases. The EMA licensed the agent for the treatment of adults with CRPC, symptomatic bone metastases and no known visceral metastases in November 2013, the FDA licensed Xofigo® for the same indication already in May 2013. 
In a phase III trial, radium-223 was compared to placebo in 921 patients who either had progressed on docetaxel or were docetaxel-naive (i.e. they were either not eligible or chose not to receive it). The primary endpoint was overall survival (OS). Secondary endpoints included time to first symptomatic skeletal event, time to increase in total ALP/PSA levels or quality of life. For patients treated with radium-223, OS was extended by 3.6 months compared with the control group. Secondary endpoints improved in the intervention group compared with placebo, as well as quality of life. In terms of safety, the most frequent adverse events were bone pain, nausea, anaemia and diarrhoea in both groups. 
With the licensing of radium-223, treatment options for patients with mCRPC are increased. The questions of how to best sequence or combine radium-223 with other already licensed agents such as docetaxel, cabazitaxel, abiraterone acetate, enzalutamide or mitoxantrone has not yet been a answered satisfactorily. Moreover, clarification is needed on optimised dosing for radium-223. Therefore, further clinical trials are needed.

Radium-223 dichloride (Xofigo®) for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease

In Europe, ipilimumab is currently licensed only for pre-treated patients. However, one phase III trial compared ipilimumab + dacarbazine to placebo + dacarbazine in previously untreated patients. In this trial, overall survival was significantly longer in the ipilimumab group, but the gain was with 2.1 months rather modest. Moreover, although the duration of response was considerably longer in the combination arm than in the control arm, responses occurred in both groups only in a minority of patients and were not statistically significant between the two groups. In terms of adverse events (AEs), the incidence of grade 3 or grade 4 AEs, foremost driven by immune-related AEs, was also higher in the combination arm than in the dacarbazine + placebo group. Subsequently, considerably more patients stopped treatment due to drug-related AEs in the ipilimumab + dacarbazine group. 
Open questions associated with first-line ipilimumab therapy concern, for example, which dosing regimen should be used, a factor considerably influencing costs. Identifying both further selection criteria and other agents ipilimumab can be combined with, may yield better results.

Ipilimumab (Yervoy®) for the first-line therapy of advanced/metastatic cutaneous melanoma

Metastatic melanoma has a poor prognosis with a median survival for patients with stage IV melanoma ranging from 6 to 9 months and a 3-year survival rate of only 10-15%. Generally, metastatic melanoma is difficult to treat, because advanced melanomas are refractory to most standard systemic therapies and therapeutic options are limited. Vemurafenib, a kinase which also inhibits the BRAF V600E mutation, is one in a series of BRAF-kinase inhibitors and is indicated for patients with BRAF V600E mutation positive advanced/metastatic unresectable melanoma. It is currently not approved by the EMA, but approval was recommended by the Committee for Medicinal Products for Human Use of EMA as first-in-class treatment for metastatic or unresectable melanoma in December 2011. The approval is expected in February 2012. In the US, the FDA granted market authorization based on the (ongoing) BRIM-3 study in August 2011. The BRIM-3 study, a phase III trial, evaluated vemurafenib in comparison to dacarbazine, in previously untreated patients. Improved results for progression-free survival (i.e. a gain of 3.7 months for patients treated with vemurafenib), were found, but no reliable OS data are available, since cross-over was allowed after an interim-analysis. About one third of patients treated with vemurafenib develop – as a side effect – squamous cell carcinoma of the skin. 
The assessment was carried out in collaboration with the Italian Horizon Scanning project ULSS 20.

https://eprints.hta.lbg.ac.at/940/1/DSD_HSO_Nr.23.pdf

Vemurafenib for patients with BRAF V600E mutation positive advanced/metastatic melanoma

Idelalisib (Zydelig®) is an inhibitor of the B-cell receptor signaling pathway; it is indicated in combination with rituximab in adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy, or as first-line treatment for patients with deletion 17p and/or TP53 mutation who are unsuitable for chemoimmunotherapy. Idelalisib has been approved for this indication by both the EMA in September 2014 and the FDA in July 2014. 
The marketing authorisation was based on the results of a phase III trial assessing idelalisib in combination with rituximab compared to placebo in combination with rituximab in 220 pretreated patients who were considered ineligible for further cytotoxic therapy. 
Analyses showed a significant improvement of progression-free survival (PFS), overall survival (OS) and overall response rate (ORR). The median PFS was 5.5 months in the placebo group but was not yet reached in the idelalisib group. As a result of meeting its efficacy endpoints at the first interim data analysis, the trial was stopped early. 
At least one adverse event occurred in 90% of patients in each group, but most of them were grade 2 or lower. 40% of patients in the idelalisib group and 35% of patients in the placebo group had at least one serious adverse event; most frequently were pneumonia, pyrexia and febrile neutropenia. Due to adverse events, 8% of idelalisib group patients and 10% of placebo group patients discontinued study treatment. 
The combination therapy of idelalisib and rituximab is a feasible treatment option for patients with relapsed CLL who are ineligible for cytotoxic therapy; particularly for those with genetic factors including 17p deletion, TP53 mutation or unmutated IGVH. The median duration of exposure during the trial was about 5 months; therefore, no long-term data is available. Further trials are needed to evaluate efficacy and safety in long-term use of idelalisib. Moreover, the important issue of potential idelalisib resistance needs to be resolved.

Idelalisib (Zydelig®) in addition to rituximab for the treatment of relapsed chronic lymphocytic leukaemia

Trametinib, a MEK kinase inhibitor, is currently neither licensed in the Europe nor in the U.S. Its efficacy was tested in a phase III trial, comprising 322 patients with BRAF V600 mutation-positive melanoma. Patients were randomised in a 2:1 ratio to either trametinib or chemotherapy consisting of either dacarbazine or paclitaxel. Enrolled individuals could have received one prior line of therapy but the majority of patients that is about 70% were treatment-naive. 
Progression-free survival, the primary outcome was prolonged by 3.3 months for patients treated with trametinib in comparison to chemotherapy, yielding a hazard ratio of 0.45 (95%CI 0.33-0.63; p<0.001). Results for subgroups according to mutation-status and prior treatment, age, LDH levels, disease stage and sex mainly favoured the trametinib group. Only for older patients (≥65 years) and patients with V600K mutations statistical significance was not shown, but both groups comprised rather few patients. Median overall survival was not yet reached, but OS rates at 6 months were 81% vs 67%. Based on these results, crossing-over to the trametinib arm was given permission. The most common side-effects were rash, diarrhoea, fatigue and nausea, and more dose-interruptions (I 35% vs C 22%) and dose reductions (I 27% vs C 10%) due to AEs were observed in the trametinib group. 
Treatment of melanoma has undergone substantial changes in the last years. Until recently, only few drugs with rather limited activity have been available, but now several new drugs can be used. Even though the activity of trametinib was shown in the phase III trial, best timing and sequencing of therapeutic options remain uncertain. Development of secondary resistance creates problems and further contributes to uncertainties on first-choice therapy. Moreover, duration of response and delay of resistance is believed to be overcome by combination therapies, for example trametinib and a BRAF inhibitor, potentially impacting considerably on treatment costs. As longs as direct head-to-head comparisons of new agents are missing, enrolment onto clinical trials might offer the best treatment strategy for patients with advanced/metastatic melanoma.

Trametinib for advanced or metastatic BRAF V600 mutation-positive melanoma

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