Everolimus, lutetium-177 DOTATATE and sunitinib for advanced, unresectable or metastatic neuroendocrine tumours with disease progression: a systematic review and cost-effectiveness analysis.

BACKGROUND: Neuroendocrine tumours (NETs) are a group of heterogeneous cancers that develop in cells in the diffuse neuroendocrine system. OBJECTIVES: To estimate the clinical effectiveness of three interventions [everolimus (Afinitor®; Novartis International AG, Basel, Switzerland), lutetium-177 DOTATATE (177Lu-DOTATATE) (Lutathera®; Imaging Equipment Ltd, Radstock, UK) and sunitinib (Sutent®; Pfizer Inc., New York, NY, USA)] for treating unresectable or metastatic NETs with disease progression and establish the cost-effectiveness of these interventions. DATA SOURCES: The following databases were searched from inception to May 2016: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Daily, Epub Ahead of Print, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science. REVIEW METHODS: We systematically reviewed the clinical effectiveness and cost-effectiveness literature on everolimus, 177Lu-DOTATATE and sunitinib for treating advanced, unresectable or metastatic progressive NETs. The following NET locations were considered separately: pancreas, gastrointestinal (GI) tract and lung, and GI tract (midgut only). We wrote a survival partition cohort-based economic evaluation in Microsoft Excel® 2013 (Microsoft Corporation, Redmond, WA, USA) from the UK NHS and Personal Social Services perspective. This comprised three health states: (1) progression-free survival (PFS), (2) progressed disease and (3) death. RESULTS: Three randomised controlled trials (RCTs), RADIANT-3 [RAD001 in Advanced Neuroendocrine Tumors, Third Trial; pancreatic NETs (pNETs): everolimus vs. best supportive care (BSC)], A6181111 (pNETs: sunitinib vs. BSC) and RADIANT-4 (RAD001 in Advanced Neuroendocrine Tumors, Fourth Trial; GI and lung NETs: everolimus vs. BSC), met the inclusion criteria for the clinical effectiveness systematic review. The risk of bias was low. Although the NETTER-1 (Neuroendocrine Tumors Therapy) RCT, of 177Lu-DOTATATE plus 30 mg of octreotide (Sandostatin®, Novartis) compared with 60 mg of octreotide, was excluded from the review, we nonetheless present the results of this trial, as it informs our estimate of the cost-effectiveness of 177Lu-DOTATATE. The pNETs trials consistently found that the interventions improved PFS and overall survival (OS) compared with BSC. Our indirect comparison found no significant difference in PFS between everolimus and sunitinib. Estimates of OS gain were confounded because of high rates of treatment switching. After adjustment, our indirect comparison suggested a lower, but non-significant, hazard of death for sunitinib compared with everolimus. In GI and lung NETs, everolimus significantly improved PFS compared with BSC and showed a non-significant trend towards improved OS compared with BSC. Adverse events were more commonly reported following treatment with targeted interventions than after treatment with BSC. In the base case for pNETs, assuming list prices, we estimated incremental cost-effectiveness ratios (ICERs) for everolimus compared with BSC of £45,493 per quality-adjusted life-year (QALY) and for sunitinib compared with BSC of £20,717 per QALY. These ICERs increased substantially without the adjustment for treatment switching. For GI and lung NETs, we estimated an ICER for everolimus compared with BSC of £44,557 per QALY. For GI (midgut) NETs, the ICERs were £199,233 per QALY for everolimus compared with BSC and £62,158 per QALY for a scenario analysis comparing 177Lu-DOTATATE with BSC. We judge that no treatment meets the National Institute for Health and Care Excellence's (NICE) end-of-life criteria, although we cannot rule out that sunitinib in the A6181111 trial does. LIMITATIONS: A RCT with included comparators was not identified for 177Lu-DOTATATE. The indirect treatment comparison that our economic analysis was based on was of a simple Bucher type, unadjusted for any differences in the baseline characteristics across the two trials. CONCLUSIONS: Given NICE's current stated range of £20,000-30,000 per QALY for the cost-effectiveness threshold, based on list prices, only sunitinib might be considered good value for money in England and Wales. FUTURE WORK: Further analysis of individual patient data from RADIANT-3 would allow assessment of the robustness of our findings. The data were not made available to us by the company sponsoring the trial. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016041303. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

[Lutetium-177-PSMA radioligand therapy : Consensus within the framework of GKV-funded care between the university hospitals in Aachen, Bonn, Düsseldorf, Essen, and Cologne and the MDK Nordrhein]. / Lutetium-177-PSMA-Radioligandentherapie : Konsensus im Rahmen der GKV-finanzierten Versorgung zwischen den Hochschulkliniken in Aachen, Bonn, Düsseldorf, Essen und Köln und dem MDK Nordrhein.

In the last 3 years, Lutetium-177 prostate-specific membrane antigen radioligand therapy (Lu-177-PSMA-RLT) has received increasing attention in nuclear medicine as a new form of treatment for castration-resistant metastatic prostate cancer. This therapy combines the radionuclide Lutetium-177, which has been therapeutically used in nuclear medicine for many years, with a molecular target of the transmembrane prostate-specific membrane antigen expressed by prostate cancer cells. Since there are no prospective randomized studies on Lu-177-PSMA-RLT and the question of reimbursement has repeatedly been the subject of review by the MDK Nordrhein (Medischenische Dienst der Krankenversicherung), there was a desire because of the increasing number of patients being treated to clarify under which circumstances Lu-177-PSMA-RLT can be reimbursed by German statutory health insurance. The goals of this article are to help treating physicians understand how this new therapy option works, to integrate it in the overall therapy concept for castration-resistant metastatic prostate cancer, and, above all, to use Lu-177-PSMA-RLT-based on the current data-at the right place in the therapy sequence of castration-resistant metastatic prostate cancer.

Patient-reported health-related quality of life for men treated with low-dose-rate prostate brachytherapy as monotherapy with 125-iodine, 103-palladium, or 131-cesium: Results of a prospective phase II study.

PURPOSE: To compare quality of life (QoL) after brachytherapy with one of the three approved radioactive isotopes. METHODS AND MATERIALS: Patients with mostly favorable intermediate-risk prostate cancer were treated on this prospective phase II trial with brachytherapy as monotherapy, without hormonal therapy. QoL was recorded at baseline and each follow-up by using the Expanded Prostate Cancer Index Composite instrument. The minimal clinically important difference was defined as half the standard deviation of the baseline score for each domain. Mixed effect models were used to compare the different isotopes, and time-driven activity-based costing was used to compute costs. RESULTS: From 2006 to 2013, 300 patients were treated with iodine-125 (I-125, n = 98, prescribed dose [PD] = 145 Gy), palladium-103 (Pd-103, n = 102, PD = 125 Gy), or cesium-131 (Cs-131, n = 100, PD = 115 Gy). Median age was 64.9 years. Median follow-up time was 5.1 years for the entire cohort, and 7.1, 4.8 and 3.3 years for I-125, Pd-103, and Cs-131 groups, respectively. All three isotope groups showed an initial drop in QoL at first follow-up, which gradually improved over the first 2 years for urinary and bowel domains. QoL profiles were similar between I-125 and Pd-103, whereas Cs-131 showed a statistically significant decrease in QoL regarding bowel and sexual function at 12 months compared with Pd-103. However, these differences did not reach the minimal clinically important difference. Compared with I-125, the use of Pd-103 or Cs-131 resulted in cost increases of 18% and 34% respectively. CONCLUSIONS: The three different isotopes produced a similar QoL profile. Statistically significant differences favored Pd-103/I-125 over Cs-131 for bowel and sexual QoL, but this did not reach clinical significance.

Budget Impact of Enzalutamide for Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Prostate cancer is expected to account for approximately one quarter of all new diagnoses of cancer in American men in 2015. The cost of prostate cancer care is expected to reach $15.1 billion by the year 2020, up from $11.9 billion in 2010. Given the high burden of prostate cancer, health care payers are interested in quantifying the potential budget impact of new therapies. OBJECTIVE: To estimate the budget impact of enzalutamide for the treatment of chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) from a U.S. payer perspective. METHODS: A model was developed to assess the budget impact of enzalutamide for treatment of chemotherapy-naïve mCRPC patients in a hypothetical 1-million-member U.S. health plan over a 1-year time horizon. Comparators included abiraterone acetate, sipuleucel-T, radium Ra 223 dichloride, and docetaxel. Epidemiologic data, including National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) incidence rates, were used to estimate the number of chemotherapy-naïve mCRPC patients. Dosing, administration, duration of therapy, and adverse event rates were based on package inserts and pivotal studies. Drug costs were obtained from RED BOOK and Centers for Medicare & Medicaid Services (CMS) average sales price pricing files, costs of administration and monitoring from the CMS physician fee schedule, and adverse events from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project and published literature. Market shares were estimated for each comparator before and after adoption of enzalutamide. The incremental aggregate budget impact, per patient per year (PPPY), per patient per month (PPPM), and per member per month (PMPM), was calculated. One-way sensitivity analyses were performed. RESULTS: In a population of 115 chemotherapy-naïve mCRPC patients, adopting enzalutamide had an annual incremental budget impact of $510,641 ($4,426 PPPY, $369 PPPM, and $0.04 PMPM). Results were most sensitive to enzalutamide drug cost, size of the chemotherapy-naïve mCRPC patient population, and enzalutamide adoption rate. CONCLUSIONS: Results indicate a modest 1-year budget impact of adopting enzalutamide for chemotherapy-naïve mCRPC patients, partly because of the cost offset of a moderate incidence of adverse events and lack of additional required monitoring.

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.

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.

[The non-hormonal treatment of metastatic prostate cancer]. / Le traitement non hormonal de la maladie métastatique du cancer de la prostate.

AIM: To describe drugs used in the non-hormonal treatment of metastatic prostate cancer. MATERIAL: Bibliographical search was performed from the database Medline (National Library of Medicine, PubMed) and websites of the HAS and the ANSM. The search was focused on the characteristics, the mode of action, the efficiency and the side effects of the various drugs concerned. RESULTS: The metabolic radiotherapy although under-used for this indication, kept a place at the beginning of the disease. Radium-223 chloride seems to have to occupy an important place in the coming years. The chemotherapy, the only recourse until very recently in the castration-resistant prostate cancer, must redefine its place partially. The denosumab provide an interesting alternative to bisphosphonates. CONCLUSION: The non-hormonal treatment of the metastatic disease of the prostate cancer is changing rapidly with the emergence of new molecules. Urologist must know perfectly these new drugs.

Lessons from the Tc-99m shortage: implications of substituting Tl-201 for Tc-99m single-photon emission computed tomography.

BACKGROUND: In 2009, the Chalk River nuclear reactor closed for repairs that led to a critical shortage of technetium-99m (Tc-99m). Several centers used thallium-201 (Tl-201) as an alternative radiotracer for myocardial perfusion imaging. Because Tl-201 is considered by many as a suboptimal radiotracer, we sought to understand the impact of using Tl-201 (during the Tc-99m shortage) on downstream resource utilization. METHODS AND RESULTS: We performed a retrospective study at the Ottawa Heart Institute of 7402 patients (60% men; mean age, 62.6 ± 11.8 years), patients were referred for myocardial perfusion imaging between May 2008 and January 2011 (PRE_Tc-99m [2938 patients]), during (DURING_Tl-201 [2959 patients]), and after (POST_Tc-99m [1505 patients]) the Tc-99m shortage. Patients were followed for 6 months after their index myocardial perfusion imaging to determine subsequent rates of cardiac catheterization or noninvasive imaging. More downstream testing was seen in the Tl-201 cohort (639 [21.4%] patients) than the Tc-99m cohort (537 [12.1%] patients; P<0.001). After adjustment using propensity scores, differences in downstream referral rates were maintained. The downstream investigations resulted in an estimated increase in per-patient costs ($165.22; 95% confidence interval, 153.00-177.42) in the DURING_Tl-201 cohort compared with the Tc-99m cohort ($90.97; 95% confidence interval, 83.42-98.90; P<0.001). As well, the mean effective radiation dose per-patient was higher in DURING_Tl-201 (23.57 mSv; 95% confidence interval, 23.16-23.96) than in Tc-99m (12.92 mSv; 95% confidence interval, 12.55-13.40; P<0.001). CONCLUSIONS: In this single-center study, the use of Tl-201 during the Tc-99m shortage was associated with an increase in downstream testing, cost, and patient radiation exposure, but these findings may not be generalizable to other centers. Although Tl-201 provided a short-term solution to the unexpected Tc-99m shortage, long-term cost-effective solutions should be areas of future study.

Barriers to clinical translation with diagnostic drugs.

Radioactive imaging agents, like diagnostic drugs generally, undergo a drug development process that parallels that of therapeutic agents, with similar development times but substantially lower development costs and substantially smaller postapproval markets. Although rapid advances in genetic and expression profiling are furthering the development of expensive pharmacotherapies targeted to small patient populations, the commercial development of imaging agents for small patient populations is blocked by the limited revenues available with current per-dose pricing and the relatively small numbers of imaging procedures that would be performed. A wide-ranging discussion on the best approaches to allow new diagnostic imaging agents to become part of the health-care system, and benefit the patient, is needed.

Alternative production methods to face global molybdenum-99 supply shortage.

The sleeping giant of molybdenum-99 ((99)Mo) production is grinding to a halt and the world is wondering how this happened. Fewer than 10 reactors in the world are capable of producing radio nuclides for medicine; approximately 50% of the world's supply of raw material comes from National Research Universal (NRU) reactor in Canada. Many of these reactors, like the NRU, are old and aging. No one of these reactors, and probably not even all of them in combination, can replace the production of NRU. As the healthcare industry faces an aging population and the demand for diagnostic services using (99m)Tc continues to rise, the need for a consistent, reliable supply of (99)Mo has become increasingly important, so alternative methods to produce (99)Mo or even directly (99m)Tc had to be considered to avoid a supply shortage in the coming years. This need guides to the production of (99)Mo by replacing the Highly Enriched Uranium (HEU) target in a nuclear reactor with Low Enriched Uranium (LEU) and furthermore to the use of accelerators for manufacturing (99)Mo or for directly producing (99m)Tc.

Radioisotope therapy of bone metastases.

Radionuclide therapy has been an integral part of systemic treatment of patients with advanced and disseminated cancer for 50 years. Specific radioisotopes (b- or a-emitters) with selective concentration at sites of bone cancer damage are used in the treatment. Radioisotopes are an important addition to the armamentarium of clinicians who take care of patients with advanced cancer and painful cancer bone metastases (especially osteoblastic and mixed type). They offer a high degree of efficacy with minimal toxicity and simple administration, fulfilling the fundamental criteria for palliative treatment that should combine minimal patient discomfort and toxicity with maximal clinical effect.

Reactors are indispensable for radioisotope production.

Radioisotopes can be produced by reactors and accelerators. For certain isotopes there could be an advantage to a certain production method. However, nowadays many reports suggest, that useful isotopes needed in medicine, industry and research could be produced efficiently and dependence on reactors using enriched U-235 may be eliminated. In my view reactors and accelerators will continue to play their role side by side in the supply of suitable and economical sources of isotopes.

[Precarious matters. The radium economy, episteme of risk and the emergence of tracer technique in national socialism]. / Prekäre Stoffe. Radiumökonomie, Risikoepisteme und die Etablierung der Radioindikatortechnik in der Zeit des Nationalsozialismus.

Following the traces of radioactive material is--as scholars have recently shown--a valuable historical approach in order to evaluate the material 'factor' of science in action. Even though the origins of materials like radium and artificial isotopes are quite different, their circulation is interconnected. A material pathway can be drawn from the radium industry to the scientific rise of artificial isotopes as indicator substances in the 1930s, continuing to the building of networks by German scientists working for the war efforts. Also, this pathway reveals the role of radiation protection in establishing that material culture. Finally, the dynamics of material traces and institutional linkages is shown by the tracer work of biophysicists and radiation biologists working at the Genetic Department of the Kaiser Wilhelm Institute for Brain Research in Berlin and at the Institut de Chimie Nucléaire at Paris, which at that time was occupied by German troops.