Safety and effectiveness of the radium-223-taxane treatment sequence in patients with metastatic castration-resistant prostate cancer in a global observational study (REASSURE).

BACKGROUND: Radium-223 and taxane chemotherapy each improve survival of patients with metastatic castration-resistant prostate cancer (mCRPC). Whether the radium-223-taxane sequence could extend survival without cumulative toxicity was explored. METHODS: The global, prospective, observational REASSURE study (NCT02141438) assessed real-world safety and effectiveness of radium-223 in patients with mCRPC. Using data from the prespecified second interim analysis (data cutoff, March 20, 2019), hematologic events and overall survival (OS) were evaluated in patients who were chemotherapy-naive at radium-223 initiation and subsequently received taxane chemotherapy starting ≤90 days ("immediate") or >90 days ("delayed") after the last radium-223 dose. RESULTS: Following radium-223 therapy, 182 patients received docetaxel (172 [95%]) and/or cabazitaxel (44 [24%]); 34 patients (19%) received both. Seventy-three patients (40%) received immediate chemotherapy and 109 patients (60%) received delayed chemotherapy. Median time from last radium-223 dose to first taxane cycle was 3.6 months (range, 0.3-28.4). Median duration of first taxane was 3.7 months (range, 0-22.0). Fourteen patients (10 in the immediate and four in the delayed subgroup) had grade 3/4 hematologic events during taxane chemotherapy, including neutropenia in two patients in the delayed subgroup and thrombocytopenia in one patient in each subgroup. Median OS was 24.3 months from radium-223 initiation and 11.8 months from start of taxane therapy. CONCLUSIONS: In real-world clinical practice settings, a heterogeneous population of patients who received sequential radium-223-taxane therapy had a low incidence of hematologic events, with a median survival of 1 year from taxane initiation. Thus, taxane chemotherapy is a feasible option for those who progress after radium-223. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02141438. PLAIN LANGUAGE SUMMARY: Radium-223 and chemotherapy are treatment options for metastatic prostate cancer, which increase survival but may affect production of blood cells as a side effect. We wanted to know what would happen if patients received chemotherapy after radium-223. Among the 182 men treated with radium-223 who went on to receive chemotherapy, only two men had severe side effects affecting white blood cell production (neutropenia) during chemotherapy. On average, the 182 men lived for 2 years after starting radium-223 and 1 year after starting chemotherapy. In conclusion, patients may benefit from chemotherapy after radium-223 treatment without increasing the risk of side effects.

Benefits of early highly effective versus escalation treatment strategies in relapsing multiple sclerosis estimated using a treatment-sequence model.

BACKGROUND: Uncertainty about disproportionate impact on health care budgets limits implementation of early highly effective treatment (EHT) in multiple sclerosis (MS). OBJECTIVE: To estimate cost-effectiveness of escalation versus EHT disease-modifying treatment (DMT) sequences. METHODS: Using a health-economic approach, we analysed health benefits (relapse rate reduction, disability prevention), direct/indirect DMT and societal costs of escalation versus EHT DMT sequences. In scenario analyses, we allowed (1) earlier use of alemtuzumab (ALE) and (2) a single retreatment with cladribine (CLA). RESULTS: In our model, we showed that the ratio between costs and quality-adjusted life years (QALYs) for the most cost-effective EHT and escalation sequence results into a similar net health benefit with higher costs and also higher QALYs associated with an EHT versus escalation strategy. Earlier use of ALE is more cost-effective than in later lines, even when aggravating the impact of its side-effects tenfold. Retreatment with CLA was more cost-effective in both escalation and EHT sequences. CONCLUSIONS: Certain EHT sequences are equally cost-effective to escalation sequences and are likely to result in more health at uncertain additional costs. The favourable cost-benefit ratio of CLA and ALE suggests that a wider application of affordable highly effective therapies could promote the cost-effectiveness both EHT and escalation approaches.

Real-world treatment patterns in patients initiating third-line therapy for relapsed or refractory multiple myeloma in Germany, Italy, the United Kingdom, France, and Spain.

OBJECTIVES: To retrospectively analyze real-world treatment patterns in patients with relapsed/refractory multiple myeloma (RRMM) who initiated third-line treatment in Europe. METHODS: German and Italian administrative claims data were sourced from the German AOK PLUS health insurance fund and Italian local health units (2016-2020). Data for the United Kingdom (UK), France, and Spain were sourced from medical chart reviews (MCRs) from 2016 to 2018 (historical) and 2019 to 2021 (new) using electronic case report forms. RESULTS: Across all countries, immunomodulatory imide drug (IMiD)-based regimens were prominent in the third-line setting. From 2016 to 2020, lenalidomide-dexamethasone was most common in Italy (18.0%) and Germany (12.7%). From 2019 to 2021, the most common regimen was ixazomib-lenalidomide-dexamethasone (67.5%) in the UK, pomalidomide-dexamethasone (17.1%) in France, and daratumumab-bortezomib-dexamethasone (15.0%) in Spain. In the historical data (2016-2018), third-line lenalidomide- and pomalidomide-dexamethasone doublet use across the UK (>47%), France (>46%), and Spain (>33%) was high. From historical to new, triplet use increased in Spain (>19% to >60%) as did anti-CD38 agent use in France (15.1% to 51.9%) and Spain (19.7% to 42.1%). CONCLUSIONS: From 2016 to 2021, third-line regimens were mostly IMiD based. The MCR data demonstrated evolving treatment choices from 2016 to 2018 and 2019 to 2021, providing insights into uptake of novel agents and current RRMM European clinical practice.

Assessment of Treatment Sequence in Patients With Stage III Breast Cancer.

INTRODUCTION: Stage III breast cancer is defined as locally advanced breast cancer and is treated with curative intent. Historically, overall survival (OS) did not differ based on treatment sequence (neoadjuvant chemotherapy [NAC] followed by surgery versus surgery followed by chemotherapy). Given recent advancements, we examined if treatment sequence may be associated with improved OS in a contemporary cohort of patients with stage III breast cancer. METHODS: Patients aged 18-80 years with prognostic stage III breast cancer who received chemotherapy and surgery were selected from the Surveillance, Epidemiology, and End Results database. Patients were stratified by treatment sequence (NAC versus surgery first). Unadjusted OS and breast cancer-specific survival (BCSS) were estimated using the Kaplan-Meier method and compared with log-rank tests. Cox proportional hazards models were used to estimate the association of treatment sequence with OS and BCSS after adjustment for selected covariates. RESULTS: The study included 26,573 patients; median follow-up was 62.0 months (95% confidence interval [CI] 61.0-63.0). Patients receiving NAC had a worse OS and BCSS compared to those who underwent surgery first (5-year OS rates 0.66 versus 0.73; 5-year BCSS rates 0.70 versus 0.77; both log-rank P < 0.001). After adjustment for tumor subtype, receipt of NAC (versus surgery first) remained associated with a worse OS (hazard ratio 1.27, 95% CI 1.2-1.34, P < 0.001) and BCSS (hazard ratio 1.35, 95% CI 1.27-1.43, P < 0.001). CONCLUSIONS: Based on data from patients treated largely before 2020, undergoing surgery first may be associated with improved survival, even after adjustment for known covariates including tumor subtype. These findings may inform treatment when caring for patients with operable, locally advanced breast cancer.

Treatment Sequence for Osteoporosis.

BACKGROUND: Osteoporosis is a chronic progressive disease that requires lifelong monitoring and treatment. Sequencing from one treatment to another at different ages and stages of disease is an approach that can maximize benefits and avoid potential risks from long-term treatment with a single agent. OBJECTIVE: This article reviews clinical trial data in postmenopausal women that evaluate the effects of antiresorptive agents followed by other antiresorptives, osteoanabolic agents followed by antiresorptives, and antiresorptives followed by osteoanabolic medications. METHODS: Literature review and discussion. RESULTS: When medications are discontinued, in the absence of sequential therapy, bone turnover rates return to baseline or above baseline, and bone loss occurs. The rate of bone loss differs for different treatments, with a very slow decline after stopping bisphosphonates and a particularly rapid decline after stopping denosumab. Careful attention to osteoporosis medication transitions can mitigate bone density loss and its consequences. For women who remain at high risk, switching from bisphosphonates to the more potent antiresorptive, denosumab, will result in further improvement in bone mineral density (BMD). When indicated, stopping denosumab can be accomplished safely by transition to an adequate bisphosphonate regimen. For high- and very-high-risk patients, treating with osteoanabolic agents first, followed by antiresorptive agents, produces substantially larger BMD gains than the reverse treatment sequence, with the biggest differences seen for BMD of the hip. CONCLUSION: Awareness of the importance of treatment sequences can help improve osteoporosis care across the postmenopausal lifespan.

A patterns of care analysis of hyperthermia in combination with radio(chemo)therapy or chemotherapy in European clinical centers.

PURPOSE: The combination of hyperthermia (HT) with radio(chemo)therapy or chemotherapy (CT) is an established treatment strategy for specific indications. Its application in routine clinical practice in Europe depends on regulatory and local conditions. We conducted a survey among European clinical centers to determine current practice of HT. METHODS: A questionnaire with 22 questions was sent to 24 European HT centers. The questions were divided into two main categories. The first category assessed how many patients are treated with HT in combination with radio(chemo)therapy or CT for specific indications per year. The second category addressed which hyperthermia parameters are recorded. Analysis was performed using descriptive methods. RESULTS: The response rate was 71% (17/24) and 16 centers were included in this evaluation. Annually, these 16 centers treat approximately 637 patients using HT in combination with radio(chemo)therapy or CT. On average, 34% (range: 3-100%) of patients are treated in clinical study protocols. Temperature readings and the time interval between HT and radio(chemo)therapy or CT are recorded in 13 (81%) and 9 (56%) centers, respectively. The thermal dose quality parameter "cumulative equivalent minutes at 43 °C" (CEM43°C) is only evaluated in five (31%) centers for each HT session. With regard to treatment sequence, 8 (50%) centers administer HT before radio(chemo)therapy and the other 8 in the reverse order. CONCLUSION: There is a significant heterogeneity among European HT centers as to the indications treated and the recording of thermometric parameters. More evidence from clinical studies is necessary to achieve standardization of HT practice.

Sequencing Systemic Therapy in Hepatocellular Carcinoma.

OPINION STATEMENT: Multiple treatment options are now approved for unresectable hepatocellular carcinoma (HCC). An immune checkpoint inhibitor (ICI)-containing regimen should be highly considered as the first-line treatment when there is no contraindication, especially in those with hepatitis virus-related HCC, due to proven superior overall survival (OS) compared to sorafenib. Atezolizumab plus bevacizumab and durvalumab plus tremelimumab remain the treatment of choice among all ICI-containing regimens, unless contraindications to either of the medications exist. Although sorafenib is still the only medication currently approved for select patients with Child-Pugh B (CP) HCC in the first-line setting, atezolizumab plus bevacizumab is being studied in this patient population. Moreover, patients with post-liver transplantation recurrence may benefit from tyrosine kinase inhibitors (TKIs), while more studies are still needed to determine the safety of ICIs in this setting. Interestingly, multiple potential biomarkers, including tumor mutational burden (TMB), microsatellite instability (MSI) status, and PD-L1 expression level, have inconsistently predicted response to ICIs in patients with HCC. Limited evidence is available to guide treatment choice in later-line settings after progressing on ICIs, and decisions should be based on the safety profile of the treatment regimen and patient preference. Multiple trials are ongoing to elucidate the optimal treatment sequence. Of note, we believe that TKIs (e.g., cabozantinib, regorafenib, lenvatinib, and sorafenib) could be more beneficial in later-line settings to broaden inhibition of other pathways apart from vascular endothelial growth factor (VEGF). When conventional treatment options are exhausted, tissue biopsy may be helpful to reveal rare targetable mutations, such as RET gene fusions.

Real-world ramucirumab and immune checkpoint inhibitor sequences in US patients with advanced gastroesophageal cancer.

Aim: To describe real-world treatment sequences of ramucirumab relative to immune checkpoint inhibitors (ICIs) in patients with advanced gastroesophageal cancer. Methods: Retrospective, observational study including adult patients treated with ramucirumab (April 2014-June 2020) from a nationwide health-record database. Results: In 1117 eligible patients, ramucirumab + paclitaxel was the most common ramucirumab-containing regimen (72.0%). A total of 217 patients also received an ICI. For ramucirumab then ICI (n = 148) and ICI then ramucirumab (n = 50), ramucirumab + taxane and ICI monotherapy were the most frequent approaches, most commonly observed as second- and third-line (2L and 3L). Median time on ramucirumab in 2L and 3L was similar regardless of sequence with ICI. Conclusion: Most patients with advanced gastroesophageal cancer received ramucirumab before ICI, with ramucirumab + paclitaxel as the most common ramucirumab-based regimen.

What is the Order of New Treatments for Gastroesophageal Cancers in the Real World? What is this summary about? Gastroesophageal cancers (cancers of the stomach or food pipe) which cannot be cured are first treated using traditional chemotherapy. Newer anti-cancer therapies with fewer side effects, such as ramucirumab (RAM) and immune checkpoint inhibitors (ICI), are now available either alone or in combination with chemotherapy. We designed this study to describe the order of use for RAM and ICI. What were the results? The patients in this study were from Flatiron Health database, which includes electronic medical record data of US patients with gastroesophageal cancers. The included patients had been treated with RAM and were grouped based on the treatments received and in the order in which they received RAM and ICI. Of the patients who received both RAM and ICI, RAM then ICI was the most common order, followed by ICI then RAM and then RAM plus ICI at the same time. RAM in combination with paclitaxel (a chemotherapy) was the most common RAM-containing treatment. The duration of RAM therapy was the same whether patients received the treatment before or after ICI. What do results of the study mean? These findings can be used by patients with gastroesophageal cancers and oncologists when making treatment decisions, specifically if RAM might be an option when it is time to change treatments. Real-world studies like this help answer questions that were not addressed in clinical trials.

Romosozumab Efficacy in Postmenopausal Women With No Prior Fracture Who Fulfill Criteria for Very High Fracture Risk.

OBJECTIVE: We evaluated the efficacy of romosozumab in women from FRAME who had no prior fracture but met other criteria for very high fracture risk (VHFR). METHODS: In FRAME, postmenopausal women received romosozumab or placebo for 12 months (year 1) followed by denosumab for 12 months (year 2). In this post hoc analysis, we applied the following criteria from the American Association of Clinical Endocrinology to define VHFR: lumbar spine or total hip T-score <-3.0 and/or Fracture Risk Assessment Tool probability of major osteoporotic fracture >30% or hip fracture >4.5% to women with no fracture history at baseline (no fracture-VHFR [NF-VHFR]). Incidence of new vertebral, clinical, and nonvertebral fractures and mean bone mineral density (BMD) percentage change from baseline were assessed at years 1 and 2. RESULTS: Of the 7180 women in FRAME, 2825 were included in the NF-VHFR subgroup analysis. At year 1, romosozumab versus placebo reduced the incidence of new vertebral fracture (relative risk reduction [RRR]: 76%), clinical fracture (RRR: 60%), and nonvertebral fracture (RRR: 54%) (all P <.05). This fracture reduction was maintained through year 2 in women receiving the romosozumab-to-denosumab sequence versus the placebo-to-denosumab sequence for new vertebral, clinical, and nonvertebral fractures (RRR: 77%, 54%, and 46%, respectively; all P <.05). The mean BMD changes in both treatment groups were similar to those in the overall FRAME population at years 1 and 2. CONCLUSION: Romosozumab significantly reduced vertebral, clinical, and nonvertebral fracture risk and increased the BMD more than placebo in women at VHFR.

Romosozumab and antiresorptive treatment: the importance of treatment sequence.

To evaluate whether treatment sequence affects romosozumab response, this analysis reviewed studies where romosozumab was administered before or following an antiresorptive (alendronate or denosumab). Initial treatment with romosozumab followed by an antiresorptive resulted in larger increases in bone mineral density of both hip and spine compared with the reverse sequence. INTRODUCTION: Teriparatide followed by an antiresorptive increases bone mineral density (BMD) more than using an antiresorptive first. To evaluate whether treatment sequence affects romosozumab response, we reviewed randomized clinical trials where romosozumab was administered before (ARCH, FRAME) or following (STRUCTURE, Phase 2 extension) an antiresorptive (alendronate or denosumab, respectively). METHODS: We evaluated BMD percentage change for total hip (TH) and lumbar spine (LS) and response rates (BMD gains ≥ 3% and ≥ 6%) at years 1 and 2 (except STRUCTURE with only 1-year data available). RESULTS: With 1-year romosozumab initial therapy in ARCH and FRAME, TH BMD increased 6.2% and 6.0%, and LS BMD increased 13.7% and 13.1%, respectively. When romosozumab was administered for 1 year after alendronate (STRUCTURE) or denosumab (Phase 2 extension), TH BMD increased 2.9% and 0.9%, respectively, and LS BMD increased 9.8% and 5.3%, respectively. Over 2 years, TH and LS BMD increased 7.1% and 15.2% with romosozumab/alendronate, 8.5% and 16.6% with romosozumab/denosumab, and 3.8% and 11.5% with denosumab/romosozumab, respectively. A greater proportion of patients achieved BMD gains ≥ 6% when romosozumab was used first, particularly for TH, versus the reverse sequence (69% after romosozumab/denosumab; 15% after denosumab/romosozumab). CONCLUSION: In this study, larger mean BMD increases and greater BMD responder rates were achieved when romosozumab was used before, versus after, an antiresorptive agent. Since BMD on treatment is a strong surrogate for bone strength and fracture risk, this analysis supports the thesis that initial treatment with romosozumab followed by an antiresorptive will result in greater efficacy versus the reverse sequence.

Effectiveness and Cost-Effectiveness of 360 Disease-Modifying Treatment Escalation Sequences in Multiple Sclerosis.

OBJECTIVES: The rapid expansion in treatment options for relapsing-remitting multiple sclerosis (RRMS) of the past decade requires clinical decision making on the sequential prescription of these treatments. Here, we compare 360 treatment escalation sequences for patients with RRMS in terms of health outcomes and societal costs in The Netherlands. METHODS: We use a microsimulation model with a societal perspective, developed in collaboration with MS neurologists, to estimate the effectiveness and cost-effectiveness of 360 treatment sequences starting with first-line therapies in RRMS. This model integrated data on disease progression, disease-modifying treatment efficacy, clinical decision rules, age-dependent relapse rates, quality of life, healthcare, and societal costs. RESULTS: Costs and health outcomes were overlapping among different treatment escalation sequences. In our model for RRMS treatment, optimal lifetime health outcomes (20.24 ± 1.43 quality-adjusted life-years [QALYs], 6.11 ± 0.30 relapses) were achieved with the sequence peginterferon-dimethyl fumarate-ocrelizumab-natalizumab-alemtuzumab. The most cost-effective sequence (peginterferon-glatiramer acetate-ocrelizumab-cladribine-alemtuzumab) yielded numerically worse health outcomes per patient (19.59 ± 1.43 QALYs, 6.64 ± 0.43 relapses), but resulted in €98 127 ± €19 134 less costs than the most effective treatment sequence. CONCLUSIONS: Effectiveness estimates of treatments have overlapping confidence intervals but the treatment sequence that yields most QALYs is not the most cost-effective option, also when taking uncertainty into account. It is important that neurologists are aware of cost constraints and its relationship with prescription behavior, but treatment decisions should be individually tailored.

Real-world treatment patterns and overall survival in BRAF-mutant melanoma patients treated with immunotherapy or targeted therapy.

Aim: To assess overall survival (OS) in patients with advanced BRAF-mutant melanoma by first-line (1L) targeted therapy (TT) or checkpoint inhibitor (CPI) use, second-line (2L) TT or CPI use, and treatment sequence. Patients & methods: Advanced BRAF-mutant melanoma patients treated with 1L CPI or TT were selected from a real-world, electronic health record-derived database. Results: CPI was associated with improved survival after adjustment for potential confounders (hazard ratio, 0.75 [95% CI, 0.66-0.87]). Median OS was similar between 2L therapies and among likely treatment sequences. Conclusion: This real-world study demonstrated a survival benefit with 1L CPI versus TT. Analyses of 2L and treatment sequences were unable to detect or rule out clinically relevant differences in OS.

Immune checkpoint inhibitors and targeted therapies are the preferred treatment options for patients with advanced BRAF-mutant melanoma, with more patients starting first-line treatment with checkpoint inhibitors in the real world. Our study suggests that starting treatment with checkpoint inhibitors instead of targeted therapies may improve survival; however, we were unable to determine the optimal sequence of treatments that patients should be given. The findings of this study highlight the need for further investigation into the optimal treatment sequence with checkpoint inhibitors and targeted therapies in advanced BRAF-mutant melanoma.

Keeping up the 'race pace' in a patient with nonuterine leiomyosarcoma.

The most common site of involvement of leiomyosarcoma is the retroperitoneum, accounting for approximately 50% of all cases. The case study presented herein describes the journey of a man with a grade 2 retroperitoneal leiomyosarcoma at the time of diagnosis. The patient received first-line doxorubicin (six cycles) and evofosfamide (11 cycles) during participation in the phase III, randomized, double-blind SARC021 trial and achieved stable disease. Upon progression, he received 24 cycles of second-line trabectedin with stable disease, then third-line pazopanib for 14 months with stable disease. Finally, he received fourth-line gemcitabine monotherapy for 5 months until disease progression, which was followed by death. Notably, trabectedin provided long-term disease control and maintained the patient's functional performance throughout treatment.

Multi-level process mining methodology for exploring disease-specific care processes.

BACKGROUND: Public healthcare is a complex domain with many actors and highly variable protocols, which makes traditional process mining tools less effective and calls for specialized methods. AIM: The objective of the work was to develop a generally applicable process mining methodology to explore care processes related to diseases. METHODS: The proposed methodology called Process Mining Methodology for Exploring Disease-specific Care Processes (MEDCP) is based on a systematic, step-wise refinement of the raw event logs by using such a multi-level expert taxonomy of events that encapsulates the professional concepts of the analysis. A treatment process is defined according to domain-specific rules to identify the starting (index) and closing events. Concepts from various levels of the taxonomy support the final process definition for an analysis that can deliver meaningful conclusions for domain experts. RESULTS: The applicability of the methodology was demonstrated on two case studies in the cardiological and oncological care domains, in the public health care system in Hungary over a period of ten years. Thanks to the multi-level taxonomy, these studies successfully identified the most important high-level event sequence patterns and some key anomalies in the national care system, such as the significantly different behavior of low-volume vs. high volume care providers in the oncology study or the geographically connected, homogeneous clusters of providers with similar care spectra in the cardiology study. DISCUSSION: As the case studies showed, the proposed methodology can improve the efficiency of standard process mining methods, and deliver high level conclusions that are easy to interpret by domain experts. System-level insight into health care processes can serve as a basis for the optimisation and long-term planning of the whole care system.

Lorlatinib as a treatment for ALK-positive lung cancer.

Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, has been approved as a treatment for ALK-positive lung cancer. This review provides information regarding the pharmacology and clinical features of lorlatinib, including its efficacy and associated adverse events. Pivotal clinical trials are discussed along with the current status of lorlatinib as a treatment for ALK-positive lung cancer and future therapeutic challenges.

Lorlatinib has been approved as a new standard treatment for lung cancer with gene alteration known as ALK fusion. This review provides information regarding the characteristics of lorlatinib, including its efficacy and the unexpected medical problems that occur during treatment. Today, treatment of ALK-positive lung cancer is more complicated because of the active development of drugs like lorlatinib. This review demonstrates the logic of including lorlatinib as part of the treatment plan and sheds light on the future of treatment for ALK-positive lung cancer.

Hospital variation and outcomes of simultaneous resection of primary colorectal tumour and liver metastases: a population-based study.

BACKGROUND: The optimal treatment sequence for patients with synchronous colorectal liver metastases (CRLM) remains uncertain. This study aimed to assess factors associated with the use of simultaneous resections and impact on hospital variation. METHOD: This population-based study included all patients who underwent liver surgery for synchronous colorectal liver metastases between 2014 and 2019 in the Netherlands. Factors associated with simultaneous resection were identified. Short-term surgical outcomes of simultaneous resections and factors associated with 30-day major morbidity were evaluated. RESULTS: Of 2146 patients included, 589 (27%) underwent simultaneous resection in 28 hospitals. Simultaneous resection was associated with age, sex, BMI, number, size and bilobar distribution of CRLM, and administration of preoperative chemotherapy. More minimally invasive and minor resections were performed in the simultaneous group. Hospital variation was present (range 2.4%-83.3%) with several hospitals performing simultaneous procedures more and less frequently than expected. Simultaneous resection resulted in 13% 30-day major morbidity, and 1% mortality. ASA classification ≥3 was independently associated with higher 30-day major morbidity after simultaneous resection (aOR 1.97, CI 1.10-3.42, p = 0.018). CONCLUSION: Distinctive patient and tumour characteristics influence the choice for simultaneous resection. Remarkable hospital variation is present in the Netherlands.

Modeling the Cost-Utility of Treatment Sequences for Multiple Sclerosis.

OBJECTIVES: Most patients with multiple sclerosis (MS) switch between disease-modifying therapies (DMTs) during their lifetime. Our aim was to develop an MS cost-utility model that takes treatment switching into account to provide a more realistic estimate of treatment benefit than previous models that assume lifetime use of 1 DMT. METHODS: A treatment sequence model using a microsimulation framework with a lifetime time horizon and a societal perspective was developed in R. Clinical plausibility and decision rules for switching were defined in consultation with Dutch MS neurologists. The ability of DMTs to prevent relapses and delay disease progression was modeled by applying DMT-specific estimates derived from a network meta-analysis of randomized controlled trials to natural history data. A total of 2 treatment strategies were compared: a first-line DMT sequence (peginterferon-glatiramer-teriflunomide-interferon-beta-dimethyl fumarate) and an escalation DMT sequence (peginterferon-glatiramer-ocrelizumab-natalizumab-alemtuzumab). Scenario analyses explored impact of alternative sources of natural history data, societal versus healthcare perspective, and condition-specific versus generic utilities. Predicted short-term switches (<5 years) were externally validated with Dutch claims data on DMT use. RESULTS: Short-term switches predicted by the model compared well with Dutch claims data. Transition from relapsing-remitting MS to secondary progressive MS was delayed by the escalation sequence (24.7 vs 20.3 years on first-line sequence). Model results were sensitive to utility values and medical resource consumption was a large driver of uncertainty. CONCLUSIONS: This microsimulation model overcomes the limitation of previous models by modeling treatment sequences. Because it better reflects clinical reality, it facilitates incorporating cost-utility information in clinical guidelines.

Anabolic Agents for Postmenopausal Osteoporosis: How Do You Choose?

PURPOSE OF REVIEW: There are now three anabolic agents available for the treatment of postmenopausal women at high risk for fracture. The purpose of this review is to supply a rationale to aid in determining which agent should be used in which clinical settings. RECENT FINDINGS: Studies over the last decade have shown that anabolic agents produce faster and larger effects against fracture than antiresorptive agents. Furthermore, trials evaluating anabolic antiresorptive treatment sequences have shown that anabolic first treatment strategies produce the greatest benefits to bone density, particularly in the hip region. However, there are no head-to-head evaluations of the three anabolic therapies with fracture outcomes or bone density, and these studies are not likely to occur. How to decide which agent to use at which time in a woman's life is unknown. We review the most significant clinical trials of anabolic agents which have assessed fracture, areal or volumetric bone density, microarchitecture, and/or bone strength, as well as information gleaned from histomorphometry studies to provide a rationale for consideration of one agent vs another in various clinical settings. There is no definitive answer to this question; all three agents increase bone strength and reduce fracture risk rapidly. Since the postmenopausal lifespan could be as long as 40-50 years, it is likely that very high-risk women will utilize different anabolic agents at different points in their lives.

Systemic treatment for metastatic castrate resistant prostate cancer: Does seqence matter?

BACKGROUND: Optimal sequencing of systemic therapy in the management for metastatic castration resistant prostate cancer (mCRPC) remains poorly elucidated. The CHAARTED and STAMPEDE studies have proven that early chemotherapy in the hormone-sensitive setting yields a greater net survival advantage than docetaxel for mCRPC. In a retrospective study, we attempt to investigate the two most common treatment sequences for mCRPC and investigate whether earlier chemotherapy for mCRPC is consequential to survival outcomes. METHODS: We identified 112 patients with mCRPC treated at the Mayo Clinic between 2011 and 2017. We identified two cohorts, 80 patients (group A) received full course docetaxel chemotherapy followed by second generation hormone therapy (2nd gen androgen deprivation therapy [ADT]; Abiraterone or Enzalutamide) and 32 patients (group B) treated with 2nd gen ADT followed by docetaxel. The primary endpoint evaluated was 3-year cancer-specific survival. RESULTS: Mean prostate specific antigen at initiation of first treatment was 32.0 in group A and 21.7 in group B (P = .4). Bone metastases were more prevalent in group B (87% vs 58%, P = .01). All other clinicopathologic variables were statistically similar between group A and group B. Three-year cancer-specific survival was 87.4% vs 64.1% for group A and group B, respectively (P = .016). We report a univariate hazard ratio of 3.61 (95% CI, 1.74-9.5, 0 P = .01). Three-year overall survival was 82.4% and 60.8% for group A and group B, P = .01. These results held true when excluding patients with lymph node only metastasi. CONCLUSION: Our data indicates that sequence of systemic therapy may influence outcomes for mCRPC and that docetaxel should be considered before 2nd generation ADT. Our results support the importance of earlier chemotherapy in the castration resistant state.

Interim analysis of the REASSURE (Radium-223 alpha Emitter Agent in non-intervention Safety Study in mCRPC popUlation for long-teRm Evaluation) study: patient characteristics and safety according to prior use of chemotherapy in routine clinical practice.

PURPOSE: REASSURE is a global, prospective, non-interventional study to assess long-term safety of radium-223 in patients with bone metastatic castration-resistant prostate cancer. Here we report an interim analysis of patients according to previous use of chemotherapy. METHODS: Radium-223 was administered in routine clinical practice. Interim safety analysis was planned after enrolment of the first 600 patients. Patient characteristics and safety data by previous administration of chemotherapy (docetaxel and/or cabazitaxel) were investigated. RESULTS: This interim analysis included 583 patients. Median duration of observation was 7 months (range, 0-20). Nineteen patients treated with concomitant chemotherapy were excluded, 564 (97%) were eligible for exploratory analysis according to prior use of chemotherapy; 190 (34%) had previously received and completed chemotherapy, and 374 (66%) had not. In the prior versus no prior chemotherapy group, a higher proportion of patients had an Eastern Cooperative Oncology Group performance status of ≥2 (22% vs 11%) and > 20 metastatic lesions (26% vs 15%), median alkaline phosphatase (162.0 vs 115.0 U/L) and prostate-specific antigen (132.0 vs 40.2 ng/mL) levels were higher, and a lower proportion completed 6 radium-223 injections (45% vs 63%). Drug-related treatment-emergent adverse events (TEAEs) occurred in 63 and 48%, and haematological drug-related TEAEs in 21 and 9% of patients who had or had not previously received chemotherapy. Four drug-related deaths were reported, all in the prior chemotherapy group. CONCLUSIONS: The short-term safety profile of radium-223 in routine clinical practice was comparable to other clinical studies, irrespective of prior chemotherapy use. Haematological TEAEs occurred more frequently in the prior chemotherapy group, presumably due to decreased bone marrow function as a consequence of more advanced disease and prior exposure to cytotoxic therapy. Patients who had not previously received chemotherapy appeared to have a lower burden of disease at baseline, and a lower proportion discontinued radium-223 treatment.