Application of pharmacoepidemiological approaches to generate real-world evidence on the use and impact of metastatic colorectal cancer medicines

Introduction: Metastatic colorectal cancer (mCRC) is characterised by multiple treatment strategies. Randomised clinical trials are not always aligned with clinical practice, and greater use of real-world (RW) studies has been suggested to inform health care decisions by providing results that reflect RW practice. Methods: This thesis utilised multiple methods. First, a systematic review and meta-analyses (SRMA) of RW studies including mCRC patients treated with first-line (1L) systemic anti-cancer therapy (SACT) was conducted to explore the comparative safety and effectiveness, including overall survival (OS), progression free survival (PFS) and objective response of 1L mCRC SACTs. Second, a retrospective observational cohort study using linkage of routinely collected data of mCRC patients treated with 1L SACT in NHS GGC from 01/01/2015 to 31/12/2016 was performed to investigate the factors influencing selection of 1L mCRC SACTs, treatment pathways, and treatment outcomes including median OS (mOS) and time-to-next-treatment (TTNT) of mCRC patients. Results: Between 2015 and 2016, A total of 220 new mCRC SACT users were identified in NHS GGC, with 52.3% (N=115) of the patients treated with a doublet of FOLFOX or FOLFIRI, 22.3% (N=49) with 5FU, 19.5% (N=43) with cetuximab+FOLFIRI, and 5% (N=11) of patients treated initially with aflibercept+FOLFIRI. Treatment choices for 1L mCRC were made based on patients’ age and gender, tumour RAS status, and previous treatment response. The median overall survival (mOS) for these patients was statistically influenced by the initial mCRC SACT and the performance status. The combination of cetuximab+FOLFIRI demonstrated a statistically significant prolonged mOS compared to 5FU (HR 0.4 (95% CI 0.24-0.85) and the longest time to next treatment (TTNT (12.93 months (95%CI 5.85-15.25)). The SRMA also indicated an OS, PFS, and overall response rate benefit for bevacizumab+chemotherapy over chemotherapy alone with a statistically increased risk of non-haematological toxicities and a non-statistically significant increased risk for haematological toxicity. Conclusions: Real-world evidence can help understand the impact of mCRC SACT on evidence-based practice.Introduction: Metastatic colorectal cancer (mCRC) is characterised by multiple treatment strategies. Randomised clinical trials are not always aligned with clinical practice, and greater use of real-world (RW) studies has been suggested to inform health care decisions by providing results that reflect RW practice. Methods: This thesis utilised multiple methods. First, a systematic review and meta-analyses (SRMA) of RW studies including mCRC patients treated with first-line (1L) systemic anti-cancer therapy (SACT) was conducted to explore the comparative safety and effectiveness, including overall survival (OS), progression free survival (PFS) and objective response of 1L mCRC SACTs. Second, a retrospective observational cohort study using linkage of routinely collected data of mCRC patients treated with 1L SACT in NHS GGC from 01/01/2015 to 31/12/2016 was performed to investigate the factors influencing selection of 1L mCRC SACTs, treatment pathways, and treatment outcomes including median OS (mOS) and time-to-next-treatment (TTNT) of mCRC patients. Results: Between 2015 and 2016, A total of 220 new mCRC SACT users were identified in NHS GGC, with 52.3% (N=115) of the patients treated with a doublet of FOLFOX or FOLFIRI, 22.3% (N=49) with 5FU, 19.5% (N=43) with cetuximab+FOLFIRI, and 5% (N=11) of patients treated initially with aflibercept+FOLFIRI. Treatment choices for 1L mCRC were made based on patients’ age and gender, tumour RAS status, and previous treatment response. The median overall survival (mOS) for these patients was statistically influenced by the initial mCRC SACT and the performance status. The combination of cetuximab+FOLFIRI demonstrated a statistically significant prolonged mOS compared to 5FU (HR 0.4 (95% CI 0.24-0.85) and the longest time to next treatment (TTNT (12.93 months (95%CI 5.85-15.25)). The SRMA also indicated an OS, PFS, and overall response rate benefit for bevacizumab+chemotherapy over chemotherapy alone with a statistically increased risk of non-haematological toxicities and a non-statistically significant increased risk for haematological toxicity. Conclusions: Real-world evidence can help understand the impact of mCRC SACT on evidence-based practice

Home Testing of Blood Counts in Patients with Cancer

Background: Neutropenia is a dose-limiting toxicity of chemotherapy administered to patients with cancer. Neutrophil counts are usually measured using venous samples on centralised analysers. The aim of this work was to explore the feasibility and potential of home neutrophil count monitoring during chemotherapy. Methods: The prevalence of febrile neutropenia was defined in an unselected population using routine electronic health records of patients receiving chemotherapy for cancer. Patient and professional attitudes to home blood count monitoring were explored through questionnaires. Performance of the Hemocue WBC DIFF analyser in measuring capillary neutrophil counts was evaluated in the neutropenic range. Daily neutrophil counts were measured for the duration of a cycle of chemotherapy. Results: Baseline pathways were quantified in a Markov model using data from 28,919 patients receiving chemotherapy for cancer. Ten percent of all cancer site and chemotherapy combinations had a prevalence of febrile neutropenia of >10% (highest prevalence was 66.7%). The majority (86.9%) of patients surveyed would use home neutrophil count monitoring. Correlation of capillary Hemocue WBC DIFF measured neutrophil counts in the neutropenic range to venous ADVIA 2120 measured counts was r = 0.867, y = 0.95x + 0.01. The capillary neutrophil threshold <1.1 x10⁹/L performed best in identifying both patients at risk of febrile neutropenia and patients whose neutrophil count had not recovered prior to subsequent chemotherapy. The 21 daily neutrophil count profiles recorded during chemotherapy were heterogeneous. Four out of 10 patients with a neutrophil nadir <0.5 x10⁹/L were admitted with febrile neutropenia. Four out of 21 patients had insufficient neutrophil count recovery by day 21 for subsequent chemotherapy. Conclusion: Home neutrophil count monitoring during chemotherapy is feasible. Electronic health records can be utilised to quantify patient pathways. This work generated much evidence in support of adoption of home neutrophil count monitoring during chemotherapy, and informs future work defining the true potential

IX Malta Medical School Conference

Abstracts of papers presented at the 9th Malta Medical School Conference held at the Hilton Malta Hotel, Portomaso, St. Julians between 3rd and 5th December 2015.peer-reviewe