FDA and EMA Approvals of New Breast Cancer Drugs-A Comparative Regulatory Analysis.

Breast cancer is the most common cancer in women worldwide and the solid tumor type for which the highest number of drugs have been approved to date. This study examines new drug approvals for breast cancer by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), based on an analysis of regulatory documents from both agencies for the period from 1995 to 2018. Of the 29 breast cancer drugs approved over this time span, 17 received positive decisions from both the FDA and EMA, including all drugs licensed after 2008. Nineteen of the 25 FDA-approved drugs, but none of the EMA approvals, benefited from special regulatory pathways (such as fast track, breakthrough therapy, or priority review). In the U.S.A., four accelerated approvals were granted (of which one, for bevacizumab, was later revoked), while only two drugs received provisional approvals following EMA review. New breast cancer drugs were approved approximately twelve months earlier in the United States than in Europe. These results suggest that a broader use of special regulatory pathways by EMA could help to accelerate access to novel drugs for European breast cancer patients.

Publisher Correction: Breast cancer drug approvals by the US FDA from 1949 to 2018.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Economic burden of symptomatic iron deficiency - a survey among Swiss women.

BACKGROUND: Symptomatic iron deficiency (ID) is a disorder affecting 10-20% of menstruating women. ID is diagnosed by measuring serum ferritin, a protein helping to store iron in the body. A deeper understanding of the association between ID and its societal and economic burden is relevant for patients, physicians, health care decision makers. METHODS: An online household survey was carried out among Swiss women aged 18-50 years suffering from debilitating symptoms due to ID. The data was population-weighted for age and region. The costs of misdiagnosis and the ID-related economic burden (i.e. days of sick leave) from productivity losses on the labor market were determined and extrapolated to the Swiss population. Furthermore, the patient burden was assessed based on quality of life daily measurements. RESULTS: The total sample included 1010 women who received an ID diagnosis with a blood test in the last 2 years (mean age: 33.5 years). Most named symptoms were "being tired or exhausted" (96.4%) and reduced physical energy level (41.0%). In total, 354 (35.0% of the total sample) patients received an initial diagnosis other than ID. Of those, 46.8% were treated prior to the ID diagnosis with a pharmacological medical therapy or psychotherapy. Extrapolating these numbers to the Swiss female population aged 18-50 years, the direct medical costs would be CHF 78 million (assuming an annual ID incidence of ID diagnosis of 9.5%). On average, 28.5% of participants in the work-force had to take sick leave due to ID symptoms within a period of 2 years (mean: 5.2 days, i.e. 2.6 days/year). The estimated annual indirect costs in Switzerland would be CHF 33 million (human capital approach) or CHF 26 million (friction cost method), respectively. Being exhausted and impaired concentration appear to be the most important factors negatively impacting daily living and hence quality of life. CONCLUSION: The societal and economic burden among women due to debilitating symptoms of ID in Switzerland is substantial. Timely, correct diagnosis and treatment of ID may contribute to reducing this burden. Further studies are needed in this area to validate our results.

Budget impact model for oncopharmacogenetics from the perspective of mandatory basic health insurance in Switzerland using the example of breast cancer.

Single-nucleotide polymorphisms (SNPs) can severely impact individual drug response and health outcomes in cancer patients. Genetic tests to screen for marker SNPs are available to adjust the drug dose of oncologicals to the patient's needs. However, it is unclear whether the positive effects outbalance the increased costs or even lead to an overall cost reduction. This very pragmatic analysis used three frequently used oncologicals for the treatment of breast cancer to evaluate whether preemptive pharmacogenetic testing may have a cost-reducing impact on health care spending in the Swiss health care system. Our results indicate that oncopharmacogenetics might help to reduce health care costs (ie, by avoiding adverse drug effects) and to increase efficiency of drugs in oncologic patients.

Cost Effectiveness of Sucroferric Oxyhydroxide Compared with Sevelamer Carbonate in the Treatment of Hyperphosphataemia in Patients Receiving Dialysis, from the Perspective of the National Health Service in Scotland.

BACKGROUND: Hyperphosphataemia is common and harmful in patients receiving dialysis. Treatment options include noncalcium-based phosphate binders such as sevelamer carbonate (SC) and sucroferric oxyhydroxide (PA21). OBJECTIVE: The aim of this study was to determine the health economic impact of PA21-based strategies compared with SC-based strategies, from the perspective of the Scottish National Health Service (NHS). METHODS: A Markov model was constructed based on data from a randomised clinical trial comparing PA21 and SC. Model input parameters were derived from published literature, national statistics and unpublished sources. Costs (price year 2012) and effects were discounted at 3.5 %. Analysis with a lifelong time horizon yielded the incremental cost-effectiveness ratio (ICER), expressed as cost or savings per quality-adjusted life-year (QALY) gained or forgone. Deterministic and probabilistic sensitivity analysis was performed to explore uncertainties around assumptions and model input parameters. RESULTS: In the base-case analysis, phosphorus reductions for PA21 and SC were 1.93 and 1.95 mg/dL. Average undiscounted survival was estimated to be 7.61 years per patient in both strategies. PA21 patients accrued less QALYs (2.826) than SC patients (2.835), partially due to differential occurrence of side effects. Total costs were £ 13,119 and £ 14,728 for PA21 and SC, respectively (difference per patient of £ 1609). By using PA21 versus SC, one would save £ 174,999 (or £ 123,463 when including dialysis and transplantation costs) for one QALY forgone. A scenario modelling the nonsignificant reduction in mortality (relative risk 0.714) observed in the trial yielded an ICER for PA21 of £ 22,621 per QALY gained. In probabilistic sensitivity analysis of the base-case, PA21 was dominant in 11 %, and at least cost-effective in 53 %, of iterations, using a threshold of £ 20,000 per QALY gained. CONCLUSIONS: The use of PA21 versus SC in hyperphosphataemic patients being intolerant of calcium-based phosphate binders may be cost saving and yields only very limited disadvantages in terms of quality-adjusted survival. PA21 appears to be cost-effective from the perspective of the Scottish NHS.

Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients.

Anthracycline-induced cardiotoxicity (ACT) is a well-known serious adverse drug reaction leading to substantial morbidity. The purpose of this study was to assess ACT occurrence and clinical and genetic risk factors in early breast cancer patients. In 6 genes of interest (ABCC1, ABCC2, CYBA, NCF4, RAC2, SLC28A3), 10 single nucleotide polymorphisms (SNPs) involved in ACT were selected based on a literature search. Eight hundred and seventy-seven patients treated between 2000 and 2010 with 3-6 cycles of (neo) adjuvant 5-fluorouracil, epirubicin and cyclophosphamide (FEC) were genotyped for these SNPs using Sequenom MassARRAY. Main outcome measures were asymptomatic decrease of left ventricular ejection fraction (LVEF) > 10 % and cardiac failure grade 3-5 (CTCAE 4.0). To evaluate the impact of these 10 SNPs as well as clinical factors (age, relative dose intensity of epirubicin, left-sided radiotherapy, occurrence of febrile neutropenia, and planned and received cycles of epirubicin) on decrease of LVEF and cardiac failure, we performed uni- and multivariable logistic regression analysis. Additionally, exploratory analyses including 11 additional SNPs related to the metabolism of anthracyclines were performed. After a median follow-up of 3.62 years (range 0.40-9.60), a LVEF decline of > 10 % occurred in 153 patients (17.5 %) and cardiac failure in 16 patients (1.8 %). In multivariable analysis, six cycles of FEC compared to three cycles received and heterozygous carriers of the rs246221 T-allele in ABCC1 relative to homozygous carriers of the T-allele were significantly associated with LVEF decline of > 10 % (OR 1.3, 95 % CI 1.1-1.4, p < 0.001 and OR 1.6, 95 % CI 1.1-2.3, p = 0.02). Radiotherapy for left-sided breast cancer was associated with cardiac failure (OR 3.7, 95 % CI 1.2-11.5, p 0.026). The other 9 SNPs and clinical factors tested were not significantly associated. In our exploratory analysis, no other SNPs related to anthracycline metabolism were retained in the multivariate model for prediction of LVEF decline. ACT in breast cancer patients is related to number of received cycles of epirubicin and left-sided radiotherapy. Additional studies should be performed to independently confirm the potential association between rs246221 in ABCC1 and LVEF.

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.

Delivery of health care at the end of life in cancer patients of four swiss cantons: a retrospective database study (SAKK 89/09).

BACKGROUND: The use of cancer related therapy in cancer patients at the end-of-life has increased over time in many countries. Given a lack of published Swiss data, the objective of this study was to describe delivery of health care during the last month before death of cancer patients. METHODS: Claims data were used to assess health care utilization of cancer patients (identified by cancer registry data of four participating cantons), deceased between 2006-2008. Primary endpoints were hospitalization rate and delivery of cancer related therapies during the last 30 days before death. Multivariate logistic regression assessed the explanatory value of patient and geographic characteristics. RESULTS: 3809 identified cancer patients were included. Hospitalization rate (mean 68.5%, 95% CI 67.0-69.9) and percentage of patients receiving anti-cancer drug therapies (ACDT, mean 14.5%, 95% CI 13.4-15.6) and radiotherapy (mean 7.7%, 95% CI 6.7-8.4) decreased with age. Canton of residence and insurance type status most significantly influenced the odds for hospitalization or receiving ACDT. CONCLUSIONS: The intensity of cancer specific care showed substantial variation by age, cancer type, place of residence and insurance type status. This may be partially driven by cultural differences within Switzerland and the cantonal organization of the Swiss health care system.

The use of the EVITA algorithm for clinical assessment of novel agents used in prostate cancer, metastatic melanoma, and systemic lupus erythematosus.

PURPOSE: Existing health technology assessment methods can be time-consuming and complicated to use in practice. EValuation of pharmaceutical Innovations with regard to Therapeutic Advantage (EVITA) is a recently developed drug assessment strategy that provides a detailed and clinically relevant evaluation of new agents compared to standard therapies. We therefore sought to use EVITA to evaluate eight novel agents recently introduced to clinical practice or in late-stage trials for the treatment of prostate cancer, metastatic melanoma, or systemic lupus erythematosus (SLE). METHODS: Eight agents (abiraterone, enzalutamide, sipuleucel-T, Prostvac, radium 223, ipilimumab, vemurafenib, and belimumab) were selected for study using the EVITA algorithm. A comprehensive literature search was performed to find clinical trial data, which were then classified using the EVITA protocol. EVITA was also compared to results from health technology assessments (HTAs) or reimbursement decisions. RESULTS: The EVITA scores for the eight drugs ranged from 5.5 to 9: all the selected agents are therefore classed as 'recommended' and are likely to produce a therapeutic advantage. In particular, vemurafenib is likely to be highly beneficial to patients with metastatic melanoma and radium 223 to patients with metastatic prostate cancer affecting the bone. The EVITA results were generally concordant with HTAs. CONCLUSIONS: All the agents show favourable EVITA scores and are therefore recommended for clinical practice. EVITA is an easy-to-use tool that provides clinical context to the assessment of newly introduced agents and can be easily used by non-specialists.

Multivariable regression analysis of febrile neutropenia occurrence in early breast cancer patients receiving chemotherapy assessing patient-related, chemotherapy-related and genetic risk factors.

BACKGROUND: Febrile neutropenia (FN) is common in breast cancer patients undergoing chemotherapy. Risk factors for FN have been reported, but risk models that include genetic variability have yet to be described. This study aimed to evaluate the predictive value of patient-related, chemotherapy-related, and genetic risk factors. METHODS: Data from consecutive breast cancer patients receiving chemotherapy with 4-6 cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) or three cycles of FEC and docetaxel were retrospectively recorded. Multivariable logistic regression was carried out to assess risk of FN during FEC chemotherapy cycles. RESULTS: Overall, 166 (16.7%) out of 994 patients developed FN. Significant risk factors for FN in any cycle and the first cycle were lower platelet count (OR = 0.78 [0.65; 0.93]) and haemoglobin (OR = 0.81 [0.67; 0.98]) and homozygous carriers of the rs4148350 variant T-allele (OR = 6.7 [1.04; 43.17]) in MRP1. Other significant factors for FN in any cycle were higher alanine aminotransferase (OR = 1.02 [1.01; 1.03]), carriers of the rs246221 variant C-allele (OR = 2.0 [1.03; 3.86]) in MRP1 and the rs351855 variant C-allele (OR = 2.48 [1.13; 5.44]) in FGFR4. Lower height (OR = 0.62 [0.41; 0.92]) increased risk of FN in the first cycle. CONCLUSIONS: Both established clinical risk factors and genetic factors predicted FN in breast cancer patients. Prediction was improved by adding genetic information but overall remained limited. Internal validity was satisfactory. Further independent validation is required to confirm these findings.

Determinants of quality of life of patients with heart failure and iron deficiency treated with ferric carboxymaltose: FAIR-HF sub-analysis.

BACKGROUND: Heart failure (HF) is a burden to patients and health care systems. The objectives of HF treatment are to improve health related quality of life (HRQoL) and reduce mortality and morbidity. We aimed to evaluate determinants of health-related quality of life (HRQoL) in patients with iron deficiency and HF treated with intravenous (i.v.) iron substitution or placebo. METHODS: A randomised, double-blind, placebo-controlled trial (n = 459) in iron-deficient chronic heart failure (CHF) patients with or without anaemia studied clinical and HRQoL benefits of i.v. iron substitution using ferric carboxymaltose (FCM) over a 24-week trial period. Multivariate analysis was carried out with various clinical variables as independent variables and HRQoL measures as dependent variables. RESULTS: Mean change from baseline of European Quality of Life - 5 Dimensions (EQ-5D) (value set-based) utilities (on a 0 to 100 scale) at week 24 was 8.91 (i.v. iron) and 0.68 (placebo; p < 0.01). In a multivariate analysis excluding baseline HRQoL, a higher exercise tolerance and i.v. iron substitution positively influenced HRQoL, whereas impaired renal function and a history of stroke had a negative effect. The level of HRQoL was also influenced by country of residence. When baseline HRQoL was factored in, the multivariate model remained stable. CONCLUSION: In this study, i.v. iron substitution, exercise tolerance, stroke, country of residence and renal function influenced measures of HRQoL in patients with heart failure and iron deficiency.

Population access to new vaccines in European countries.

Time from registration to population access to new vaccines can take considerable time in European countries. Reasons might be found in the regulatory framework, decision-making processes or the assessment of vaccines by evaluating bodies. The aim of this study was to determine whether some decision-making processes can explain between-country differences in the time to population access to new vaccination programs. Information gathered from a survey among European National Vaccine Industry Groups was combined with information from official health authorities, vaccine manufacturers and literature published. Firstly, a retrospective survey was conducted to measure access time to new vaccines against three diseases in 17 European countries. Secondly, qualitative information on the country-specific decision-making frameworks for the introduction of new "vaccination programs" was identified in a cross-sectional survey. Spearman's rank correlation coefficients (ρ) were used for data analysis. The median access time to new vaccines was 6.4 years (95% confidence interval: 5.7-7.1 years) post marketing authorization. National assessments underlying immunization policy decisions (recommendation phase) absorbed most of the access time. Correlation analysis suggested that processes with established timelines and clarity in regard to vaccine evaluation criteria used could ameliorate the effectiveness of the decision-making process. In order to reduce the time to access for new, beneficial vaccines, the underlying vaccination recommendation, implementation and funding process needs to be understood and optimized, where necessary.

Health economic assessment of ferric carboxymaltose in patients with iron deficiency and chronic heart failure based on the FAIR-HF trial: an analysis for the UK.

AIMS: The purpose of this study was to evaluate the cost-effectiveness of iron repletion using intravenous (i.v.) ferric carboxymaltose (FCM) in chronic heart failure (CHF) patients with iron deficiency with or without anaemia. Cost-effectiveness was studied from the perspective of the National Health Service in the UK. METHODS AND RESULTS: A model-based cost-effectiveness analysis was used to compare iron repletion with FCM with no iron treatment. Using data from the FAIR-HF trial and publicly available sources and publications, per patient costs and clinical effectiveness of FCM were estimated compared with placebo. Cost assessment was based on study drug and administration costs, cost of CHF treatment, and hospital length of stay. The incremental cost-effectiveness ratio (ICER) of FCM use was expressed as cost per quality-adjusted life year (QALY) gained, and sensitivity analyses were performed on the base case. The time horizon of the analysis was 24 weeks. Mean QALYs were higher in the FCM arm (difference 0.037 QALYs; bootstrap-based 95% confidence interval 0.017-0.060). The ICER of FCM compared with placebo was €4414 per QALY gained for the FAIR-HF dosing regimen. Sensitivity analyses confirmed the base case result to be robust. CONCLUSION: From the UK payers' perspective, managing iron deficiency in CHF patients using i.v. FCM was cost-effective in this analysis. The base case ICER was clearly below the threshold of €22 200-€33 300/QALY gained (£20 000-£30 000) typically used by the UK National Institute for Health and Clinical Excellence and proved to be robust in sensitivity analysis. Improved symptoms and better quality of life contributed to this result.

Squamous cell carcinoma of the skin induces considerable sustained cost of care in organ transplant recipients.

BACKGROUND: Squamous cell carcinoma (SCC) is the most frequent cancer in organ transplant recipients (OTR). OBJECTIVE: We retrospectively analyzed the cost of dermatologic care in our OTR specialty clinic. METHODS: We collected billing data for OTR (n = 198) seen at the Dermatology Department of Zurich University Hospital over 4 years (2004-2007). Grouping by histology yielded the groups: SCC (n = 70), with SCC occurring within the observation period; past SCC (n = 40), with SCC before the observation period; in situ SCC (n = 13), when only in situ SCC had been diagnosed; biopsy negative (n = 49) for SCC and in situ SCC; and no biopsy ever (n = 26) within the observation period. RESULTS: Median annual costs for dermatologic care were US$1398 for SCC; US$776 for past SCC; US$308 for in situ SCC; US$211 for biopsy negative; and US$156 for no biopsy ever. Median cost per case of invasive SCC (US$1830) was higher than cost per case of in situ SCC (US$603). Regression analysis showed male sex (P = .006), age at transplantation (P = .001), and time since transplantation (P < .001) as independent cost factors. LIMITATIONS: This was an open, retrospective, single-center study with limited patient numbers. CONCLUSION: Dermatologic care for OTR is costly, and the majority of the costs are associated with SCC. Once SCC occurs, costs increase in a pronounced and sustained fashion. Interventions reducing the progression from in situ SCC to SCC could lead to considerable financial savings. We advocate sun protection, early diagnosis, and intervention to minimize the costs associated with SCC.

Health economic modelling of the cost-effectiveness of microalbuminuria screening in Switzerland.

PRINCIPLES: Current evidence indicates that chronic kidney disease (CKD) can be detected by simple laboratory tests. This study aimed to evaluate the cost-effectiveness of microalbuminuria screening and subsequent treatment in different populations. METHODS: Cost-effectiveness of microalbuminuria screening in a cohort of simulated subjects aged ≥50 years was assessed using a validated microsimulation model. Microalbuminuria screening was simulated for 1-, 2-, 5- or 10-year intervals and for 3 groups: diabetes (DM), hypertension but no diabetes (HTN), and no diabetes or hypertension. Positive microalbuminuria screening was followed by treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). The model outcomes evaluate costs from a health care system perspective. RESULTS: Screening of risk groups is cost-effective at a 2-year interval for the DM group with an incremental cost-effectiveness ratio (ICER) of 54,000 CHF/ Quality-Adjusted-Life-Years (QALY) and at a 5-year interval for the HTN group with an ICER of 33,000 CHF/QALY. Screening of the remaining population is cost-effective at a 10-year interval with an ICER of 34,000 CHF/QALY. The ICER improves with longer screening intervals for all groups. A probabilistic sensitivity analysis (PSA) confirmed 2-year, 5-year and 10-year intervals as the most cost-effective for the DM group, the HTN group and the remaining population respectively. CONCLUSIONS: Microalbuminuria screening can be considered cost-effective starting at the age of 50 years at bi-annual intervals for subjects with diabetes, at 5-year intervals for subjects with hypertension and at 10-year intervals for the remaining population. Our results indicate that early detection and treatment of CKD might lead to optimised patient care, and offer guidance for future implementation of CKD screening programmes.

KRAS and BRAF mutation analysis in metastatic colorectal cancer: a cost-effectiveness analysis from a Swiss perspective.

PURPOSE: Monoclonal antibodies against the epidermal growth factor receptor (EGFR), such as cetuximab, have led to significant clinical benefits for metastatic colorectal cancer (mCRC) patients but have also increased treatment costs considerably. Recent evidence associates KRAS and BRAF mutations with resistance to EGFR antibodies. We assessed the cost-effectiveness of predictive testing for KRAS and BRAF mutations, prior to cetuximab treatment of chemorefractory mCRC patients. EXPERIMENTAL DESIGN: A life-long Markov simulation model was used to estimate direct medical costs (€) and clinical effectiveness [quality-adjusted life-years (QALY)] of the following strategies: KRAS testing, KRAS testing with subsequent BRAF testing of KRAS wild-types (KRAS/BRAF), cetuximab treatment without testing. Comparison was against no cetuximab treatment (reference strategy). In the testing strategies, cetuximab treatment was initiated if no mutations were detected. Best supportive care was given to all patients. Survival times/utilities were derived from published randomized clinical trials. Costs were assessed from the perspective of the Swiss health system. RESULTS: Average remaining lifetime costs ranged from €3,983 (no cetuximab) to €38,662 (no testing). Cetuximab treatment guided by KRAS/BRAF achieved gains of 0.491 QALYs compared with the reference strategy. The KRAS testing strategy achieved an additional gain of 0.002 QALYs compared with KRAS/BRAF. KRAS/BRAF testing was the most cost-effective approach when compared with the reference strategy (incremental cost-effectiveness ratio: €62,653/QALY). CONCLUSION: New predictive tests for KRAS and BRAF status are currently being introduced in pathology. Despite substantial costs of predictive testing, it is economically favorable to identify patients with KRAS and BRAF wild-type status.

Risk factors for chemotherapy-induced neutropenia occurrence in breast cancer patients: data from the INC-EU Prospective Observational European Neutropenia Study.

BACKGROUND: Chemotherapy-induced neutropenia (CIN) places patients at risk of life-threatening infections. While reduction of chemotherapy dose or delay of the subsequent treatment cycle and, consequently, reduction of relative dose intensity (RDI) may limit myelotoxicity, these actions can also impact adversely on treatment outcome and should be avoided in adjuvant settings. PATIENTS AND METHODS: Based on data from 444 breast cancer patients in the INC-EU Prospective Observational European Neutropenia Study, we have evaluated patient-specific and treatment-specific factors that impact on the incidence of grade 4 CIN (absolute neutrophil count <0.5 × 10(9)/L), either during the first or in any cycle of (neo)adjuvant chemotherapy, across a range of regimens and doses. RESULTS: Using multivariate logistic regression analysis, risk factors for grade 4 CIN were identified as older age, lower weight, higher planned dose intensity of doxorubicin, epirubicin, or docetaxel, higher number of planned cycles, vascular comorbidity, lower baseline white blood cell count, and higher baseline bilirubin. Use of colony-stimulating factor before a neutropenic event occurred, dose delays, and dose reductions were protective against grade 4 CIN. CONCLUSIONS: By identifying risk factors for grade 4 CIN, CSF prophylaxis may be appropriately targeted to prevent low RDI in patients treated with curative intent.

Hodgkin lymphoma treatment with ABVD in the US and the EU: neutropenia occurrence and impaired chemotherapy delivery.

BACKGROUND: In newly diagnosed patients with Hodgkin lymphoma (HL) the effect of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD)-related neutropenia on chemotherapy delivery is poorly documented. The aim of this analysis was to assess the impact of chemotherapy-induced neutropenia (CIN) on ABVD chemotherapy delivery in HL patients. STUDY DESIGN: Data from two similarly designed, prospective, observational studies conducted in the US and the EU were analysed. One hundred and fifteen HL patients who started a new course of ABVD during 2002-2005 were included. The primary objective was to document the effect of neutropenic complications on delivery of ABVD chemotherapy in HL patients. Secondary objectives were to investigate the incidence of CIN and febrile neutropenia (FN) and to compare US and EU practice with ABVD therapy in HL. Pooled data were analysed to explore univariate associations with neutropenic events. RESULTS: Chemotherapy delivery was suboptimal (with a relative dose intensity < or = 85%) in 18-22% of patients. The incidence of grade 4 CIN in cycles 1-4 was lower in US patients (US 24% vs. EU 32%). Patients in both the US and the EU experienced similar rates of FN across cycles 1-4 (US 12% vs. EU 11%). Use of primary colony-stimulating factor (CSF) prophylaxis and of any CSF was more common in the US than the EU (37% vs. 4% and 78% vs. 38%, respectively). The relative risk (RR) of dose delays was 1.54 (95% confidence interval [CI] 1.08-2.23, p = 0.036) for patients with vs. without grade 4 CIN and the RR of grade 4 CIN was 0.35 (95% CI 0.12-1.06, p = 0.046) for patients with vs. without primary CSF prophylaxis. CONCLUSIONS: In this population of HL patients, CIN was frequent and FN occurrence clinically relevant. Chemotherapy delivery was suboptimal. CSF prophylaxis appeared to reduce CIN rates.