Neutropenia in cancer patients, risk prediction models of neutropenia, and supportive measures

Epidemiology studies the causes and distribution of population health and disease conditions in defined populations. It identifies risk factors for disease which may help to prevent disease and promote health.
Each year, the American Cancer Society describes the epidemiology of cancer in the USA. Breast cancer and CLL are the most common cancers in women and adults, respectively. European data for CLL are limited. For both cancers, chemotherapy is an important treatment option. But side effects such as neutropenia and infections remain the principal dose-limiting toxicities, which may affect the effectiveness of cancer chemotherapy. Several studies evaluated risk factors for chemotherapy-induced neutropenia (CIN; absolute neutrophil count [ANC] <1.5x10^9/L) and febrile neutropenia (FN; ANC <0.5x10^9/L and oral temperature =38° for more than 1 hour): e.g. older age, recent infection, prior chemotherapy, and planned relative dose intensity greater than 85% of standard chemotherapy dosing. The prophylactic use of granulocyte colony-stimulating factors (G-CSFs) has been shown to be protective.
Based on the above mentioned risk factors, a number of risk prediction models have been developed over the years. Very often, the risk prediction models considered patient-related, tumour-related, treatment-related, or genetic factors. The majority of these models are not validated using an independent dataset. Systematic reviews of G-CSFs to prevent neutropenia are available, but do not include new long-acting G-CSFs or observational study designs.
To address the epidemiology of CLL, the incidence and risk factors of CIN and FN, and to develop and externally validate a risk prediction model for the occurrence of FN including a broad range of risk factors, three quantitative studies were conducted and published. The fourth published study summarised the efficacy, effectiveness and safety of G-CSFs for the prevention of CIN and FN.
For the first study, the author conducted a cohort analysis of the UK Clinical Practice Research Datalink (CPRD) to identify the epidemiology of CLL, the incidence of neutropenia, and changes in medical resource utilisation of CLL patients. Due to limited data regarding the incidence of neutropenia, the study focused on the epidemiology of CLL and medical resource utilisation of CLL patients. The incidence of CLL was 6.2 per 100’000 person-years and remained stable between 2006 and 2011. Medical resource utilisation in CLL patients increased over the time period from 2000 to 2012. Primary care data from the UK CPRD seemed to be valid to determine the incidence of CLL. These data may not reflect the total of medical resource use in CLL patients as chemotherapy and treatment of related complications such as infections and neutropenia are mainly performed in secondary or tertiary care.
The second study addressed the identification of risk factors and the development of a risk prediction model for FN in a hospital-based breast cancer cohort. Risk factors for FN were lower platelet count and haemoglobin, higher alanine aminotransferase (ALT), and specific allele variants of two single nucleotide polymorphisms (SNPs) in a gene involved in multidrug resistance. Genetic testing beforehand might be helpful to identify patients at a very high risk of FN. Predictive performance of the model was improved by adding genetic information but overall remained limited.
The third study used an available risk prediction model for FN in Non-Hodgkin lymphoma (NHL) patients and applied its prediction rules to an independent dataset of NHL patients. Age, weight, baseline white blood cell count, and planned chemotherapy dose were confirmed to predict the risk of FN. However, there was a decrease of the predictive performance in the independent validation dataset. This limits its use in clinical practice. But if successful risk prediction models are developed and externally validated, these may help to optimally target prophylaxis with G-CSFs to those patients at high risk of FN.
Finally, a systematic literature review was conducted to identify studies evaluating the efficacy, effectiveness and safety of G-CSFs in the prevention of CIN and FN. Most studies showed better efficacy and effectiveness for the long-acting pegfilgrastim than daily filgrastim. Efficacy and safety profiles of new long-acting G-CSFs such as lipegfilgrastim and balugrastim were comparable to pegfilgrastim. In times of increasing health care costs and scarce resources, the cost-efficient use of supportive measures is necessary.
The studies this work is based on showed that the availability of and access to appropriate data sources are necessary to develop and systematically validate risk prediction models. The findings contribute to the development of an evidence-based, efficient and cost-efficient approach to prevent neutropenia in cancer patients.