Cost-effectiveness of palbociclib in early breast cancer patients with a high risk of relapse: Results from the PENELOPE-B trial.

Background: Patients with hormone receptor-positive, HER2-negative breast cancer who have residual invasive disease after neoadjuvant chemotherapy (NACT) are at a high risk of relapse. PENELOPE-B was a double-blind, placebo-controlled, phase III trial that investigated adding palbociclib (PAL) for thirteen 28-day cycles to adjuvant endocrine therapy (ET) in these patients. Clinical results showed no significant improvement in invasive disease-free survival with PAL. Methods: We performed a pre-planned cost-effectiveness analysis of PAL within PENELOPE-B from the perspective of the German statutory health insurance. Health-related quality of life scores, collected in the trial using the EQ-5D-3L instrument, were converted to utilities based on the German valuation algorithm. Resource use was valued using German price weights. Outcomes were discounted at 3% and modeled with mixed-level linear models to adjust for attrition, repeated measurements, and residual baseline imbalances. Subgroup analyses were performed for key prognostic risk factors. Scenario analyses addressed data limitations and evaluated the robustness of the estimated cost-effectiveness of PAL to methodological choices. Results: The effects of PAL on quality-adjusted life years (QALYs) were marginal during the active treatment phase, increasing thereafter to 0.088 (95% confidence interval: -0.001; 0.177) QALYs gained over the 4 years of follow-up. The incremental costs were dominated by PAL averaging EUR 33,000 per patient; costs were higher in the PAL arm but not significantly different after the second year. At an incremental cost-effectiveness ratio of EUR 380,000 per QALY gained, PAL was not cost-effective compared to the standard-of-care ET. Analyses restricted to Germany and other subgroups were consistent with the main results. Findings were robust in the scenarios evaluated. Conclusions: One year of PAL added to ET is not cost-effective in women with residual invasive disease after NACT in Germany.

Toward a Consensus on Centralization in Surgery.

OBJECTIVES: To critically assess centralization policies for highly specialized surgeries in Europe and North America and propose recommendations. BACKGROUND/METHODS: Most countries are increasingly forced to maintain quality medicine at a reasonable cost. An all-inclusive perspective, including health care providers, payers, society as a whole and patients, has ubiquitously failed, arguably for different reasons in environments. This special article follows 3 aims: first, analyze health care policies for centralization in different countries, second, analyze how centralization strategies affect patient outcome and other aspects such as medical education and cost, and third, propose recommendations for centralization, which could apply across continents. RESULTS: Conflicting interests have led many countries to compromise for a health care system based on factors beyond best patient-oriented care. Centralization has been a common strategy, but modalities vary greatly among countries with no consensus on the minimal requirement for the number of procedures per center or per surgeon. Most national policies are either partially or not implemented. Data overwhelmingly indicate that concentration of complex care or procedures in specialized centers have positive impacts on quality of care and cost. Countries requiring lower threshold numbers for centralization, however, may cause inappropriate expansion of indications, as hospitals struggle to fulfill the criteria. Centralization requires adjustments in training and credentialing of general and specialized surgeons, and patient education. CONCLUSION/RECOMMENDATIONS: There is an obvious need in most areas for effective centralization. Unrestrained, purely "market driven" approaches are deleterious to patients and society. Centralization should not be based solely on minimal number of procedures, but rather on the multidisciplinary treatment of complex diseases including well-trained specialists available around the clock. Audited prospective database with monitoring of quality of care and cost are mandatory.

Circulating Free Methylated Tumor DNA Markers for Sensitive Assessment of Tumor Burden and Early Response Monitoring in Patients Receiving Systemic Chemotherapy for Colorectal Cancer Liver Metastasis.

BACKGROUND: Neoadjuvant chemotherapy (neoCTx) followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CLM). Treatment response is generally assessed using radiologic imaging after several cycles of chemotherapy. However, earlier assessment of response would be desirable since nonresponders could be switched early to an alternative chemotherapy regimen. Recent evidence suggests that circulating free methylated tumor DNA is a highly sensitive biomarker and may more accurately reflect tumor burden and treatment response than conventional markers for CRC. PATIENTS AND METHODS: Thirty-four patients with CLM who received neoCTx prior to intended hepatic resection were included in this prospective nonrandomized study. Peripheral blood plasma was collected at baseline and before each cycle of neoCTx and was then analyzed for aberrant methylation of 48 CRC-associated genes. Methylation marker levels were correlated with baseline tumor volume and treatment response and compared with the standard tumor markers CEA and CA 19-9. RESULTS: The methylation markers SEPT9, DCC, BOLL, and SFRP2 were present in all patients at baseline and displayed a stronger correlation with tumor volume than CEA and CA 19-9. Serial measurement of these methylation markers allowed for discrimination between operated and nonoperated patients already after 1 cycle of neoCTx with high sensitivity and specificity. The early dynamic changes of SEPT9 and DCC also seemed to correlate with pathohistological response. CONCLUSION: Our data suggest that serial measurements of CRC-associated methylation markers could be a particularly valuable tool for early response assessment in patients receiving neoCTx for CLM.

Explained variation in shared frailty models.

Explained variation measures the relative gain in predictive accuracy when prediction based on prognostic factors replaces unconditional prediction. The factors may be measured on different scales or may be of different types (dichotomous, qualitative, or continuous). Thus, explained variation permits to establish a ranking of the importance of factors, even if predictive accuracy is too low to be helpful in clinical practice. In this contribution, the explained variation measure by Schemper and Henderson (2000) is extended to accommodate random factors, such as center effects in multicenter studies. This permits a direct comparison of the importance of centers and of other prognostic factors. We develop this extension for a shared frailty Cox model and provide an SAS macro and an R function to facilitate its application. Interesting empirical properties of the variation explained by a random factor are explored by a Monte Carlo study. Advantages of the approach are exemplified by an Austrian multicenter study of colon cancer.

Therapeutic Bone-Modifying Agents in the Nonmetastatic Breast Cancer Setting: The Controversy and a Value Assessment.

Clinical trials and meta-analyses investigating bisphosphonates as an adjuvant breast cancer therapy have shown a consistent trend, with postmenopausal women and women receiving ovarian suppression with gonadotropin-releasing hormone therapy gaining improved breast cancer outcomes with the use of adjuvant bisphosphonate therapy. The interpretation of these data is controversial, because the primary endpoints of the majority of adjuvant bisphosphonate studies have been negative. Pros and cons as well as the value of adjuvant bisphosphonate therapy are discussed here.

Cost-effectiveness analysis of prognostic gene expression signature-based stratification of early breast cancer patients.

BACKGROUND: The individual risk of recurrence in hormone receptor-positive primary breast cancer patients determines whether adjuvant endocrine therapy should be combined with chemotherapy. Clinicopathological parameters and molecular tests such as EndoPredict(®) (EPclin) can support decision making in patients with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative cancer. OBJECTIVE: Using a life-long Markov state transition model, we determined the health economic impact and incremental cost effectiveness of EPclin-based risk stratification in combination with clinical guidelines [German-S3, National Comprehensive Cancer Center Network (NCCN), and St. Gallen] to decide on chemotherapy use. METHODS: Information on overall and metastasis-free survival came from Austrian Breast & Colorectal Cancer Study Group clinical trials 6/8 (n = 1,619) and published literature. Effectiveness was assessed as quality-adjusted life-years (QALYs). Costs (2010) were assessed from a German third-party payer perspective. RESULTS: Lifetime costs per patient ranged from 28,268 (St.Gallen and EPclin) to 33,756 (NCCN). Due to an imperfect prognostic value and differences in chemotherapy use, strategies achieved between 13.165 QALYs (NCCN) and 13.173 QALYs (EPclin alone) per patient. Using German-S3 as reference, three strategies showed dominant results (St. Gallen and EPclin, German-S3 and EPclin, EPclin alone). Compared to German-S3, the addition of EPclin saved 3,388 and gained 0.002 QALYs per patient. Combining guidelines with EPclin remained preferable in sensitivity analysis. CONCLUSION: Our study suggests that molecular markers can be sensibly combined with clinical guidelines to determine the risk profile of adjuvant breast cancer patients. Compared with the current German best practice (German-S3), combinations of EPclin with the St. Gallen, German-S3 or NCCN guideline and EPclin alone were dominant from the perspective of the German healthcare system.

The impact of educational materials on compliance and persistence rates with adjuvant aromatase inhibitor treatment: first-year results from the compliance of aromatase inhibitors assessment in daily practice through educational approach (CARIATIDE) study.

The CARIATIDE study was designed to assess the impact of educational materials (EMs) on compliance and persistence rates with aromatase inhibitor (AI) treatment in postmenopausal women with hormone-receptor-positive early breast cancer. Patients were randomized to standard AI treatment (Group A; N = 1379) or standard AI treatment plus EMs containing information on a range of breast-cancer-related topics (Group B; N = 1379). Standardized questionnaires assessed investigator-perceived levels of care and evaluated patient compliance and behavior. At 1 year, there was no significant difference in compliance between Group A and Group B (81% vs. 82%, p = 0.4524). However, higher compliance in patients receiving EMs was observed in Sweden/Finland (p = 0.0246). Compliance with initial AI and persistence rate were not significantly altered by EM. Other factors associated with improved compliance, irrespective of EMs, e.g. administration of chemotherapy were identified.

Standardization of morbidity assessment in breast cancer surgery using the Clavien Dindo Classification.

INTRODUCTION: There are no published data on standardized scoring systems for morbidity after breast cancer surgery. Aim of the study was to establish the Clavien Dindo Classification (CDC) as assessment tool and to identify risk factors for morbidity after breast surgery investigating new techniques including oncoplastic surgery and neoadjuvant chemotherapy. PATIENTS AND METHODS: Between 2008 and 2010, data were retrospectively evaluated from 485 women with breast cancer who underwent surgery at a university hospital. The CDC was used to assess the severity of postoperative complications. Multivariable analyses were adjusted by body-mass index, smoking, diabetes mellitus and tumour size. RESULTS: Overall complications (CDC 1-4) were reported in 28.7%. Second surgery related to major complications (CDC 3-4) was mandatory in 4.7%. Axillary dissection was an independent predictor for CDC 1-4 in all patients (P = 0.008, OR of 1.81, 95%CI 1.17-2.82). We found no independent predictor for CDC 3-4. Oncoplastic surgery increased the rate of wound infections (P = 0.010, OR: 2.94, 95%CI 1.30-6.67) and necroses (P < 0.001, OR: 8.38, 95%CI 3.28-21.4). Axillary dissection elevated wound infection (P = 0.040, OR: 2.07, 95%CI 1.03-4.14) and seroma rates (P < 0.001, OR: 2.46, 95%CI 1.51-4.01). Neoadjuvant chemotherapy had no impact on morbidity. CONCLUSION: The CDC is a valid assessment tool for future clinical trials and may be useful for hospital quality control. While axillary dissection and oncoplastic surgery raised morbidity, no single factor predicted for morbidity related second surgery.

Cost-effectiveness of zoledronic acid plus endocrine therapy in premenopausal women with hormone-responsive early breast cancer.

PURPOSE: The aim of this study was to estimate the cost-effectiveness of adding zoledronic acid 4 mg intravenously every 6 months to endocrine therapy in premenopausal women with hormone receptor-positive early breast cancer from a US health care system perspective. MATERIALS AND METHODS: A Markov model was developed to predict disease progression, mortality, and costs of breast cancer care for premenopausal women with hormone receptor-positive early breast cancer receiving up to 3 years of (1) endocrine therapy (goserelin plus tamoxifen or anastrozole); or (2) endocrine therapy plus zoledronic acid. Model parameters were obtained from ABCSG-12 (Austrian Breast and Colorectal Cancer Study Group Trial-12) and the literature. The incremental cost per quality-adjusted life year (QALY) gained with zoledronic acid was calculated under 2 scenarios: (1) benefits of zoledronic acid persist to maximum (7 years) follow-up in ABCSG-12 ("trial benefits") or (2) benefits persist until death ("lifetime benefits"). RESULTS: Adding zoledronic acid to endocrine therapy was projected to yield a gain of 0.41 life years (LYs) and 0.43 QALYs assuming trial benefits and 1.34 LYs and 1.41 QALYs assuming lifetime benefits. Assuming trial benefits, the incremental cost per QALY gained with zoledronic acid was $9300. Assuming lifetime benefits, zoledronic acid was estimated to increase QALYs and reduce costs. Cost per QALY gained was

Results of the Zometa cost-utility model for the german healthcare system based on the results of the ABCSG-12 study.

BACKGROUND: The ABCSG-12 trial investigated the efficacy of gonadotropin-releasing hormone (GnRH)analogs in combination with tamoxifen or anastrozole + or - zoledronic acid (4 mg, q6m for 3 years) in 1,803 premenopausal women with hormone receptor-positive (HR+) breast cancer. After 48 months of follow-up, there was a 36% improvement in the disease-free survival (DFS) (recurrence-free survival 35%) using zoledronic acid. Based on these data, the costutility of zoledronic acid was calculated for the German healthcare system. MATERIALS AND METHODS: Costs of surveillance, adverse effects, recurrence, contralateral breast cancer, metastasis, and end-of-life care were determined based on the Einheitlicher Bewertungsmabetastab (EBM 2009) and the diagnosis-related groups (DRG) system. Utilities were surveyed with a questionnaire (n = 95). Estimation of the cost-utility was made by calculating the incremental costeffectiveness ratio (ICER) per quality-adjusted life year (QALY), using a Markov model. RESULTS: Including zoledronic acid as adjuvant therapy for 3 years resulted in total costs of euro 2,262. The use of zoledronic acid is dominant when clinical efficacy and quality of life are taken into consideration (- euro 45.83/QALY) (95% confidence interval (CI) - euro 1,838 to E 2,375; 0.02-0.41 QALY). The sensitivity analyses present with a probability of 90% that the cost per QALY gained are