Erlotinib or Gefitinib for Treating Advanced Epidermal Growth Factor Receptor Mutation-Positive Lung Cancer in Aotearoa New Zealand: Protocol for a National Whole-of-Patient-Population Retrospective Cohort Study and Results of a Validation Substudy.

BACKGROUND: Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown. OBJECTIVE: The study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables. METHODS: This study will include all NZ patients with advanced EGFR mutation-positive lung cancer who were first dispensed erlotinib or gefitinib before October 1, 2020, and followed until death or for at least 1 year. Routinely collected health administrative and clinical data will be collated from national electronic cancer registration, hospital discharge, mortality registration, and pharmaceutical dispensing databases by deterministic data linkage using National Health Index numbers. The primary effectiveness and safety outcomes will be time to treatment discontinuation and serious adverse events, respectively. The primary variable will be high-risk concomitant medicines use with erlotinib or gefitinib. For the validation substudy (n=100), data from clinical records were compared to those from national electronic health databases and analyzed by agreement analysis for categorical data and by paired 2-tailed t tests for numerical data. RESULTS: In the validation substudy, national electronic health databases and clinical records agreed in determining patient eligibility and for identifying serious adverse events, high-risk concomitant medicines use, and other categorical data with overall agreement and κ statistic of >90% and >0.8000, respectively; for example, for the determination of patient eligibility, the comparison of proxy and standard eligibility criteria applied to national electronic health databases and clinical records, respectively, showed overall agreement and κ statistic of 96% and 0.8936, respectively. Dates for estimating time to treatment discontinuation and other numerical variables and outcomes showed small differences, mostly with nonsignificant P values and 95% CIs overlapping with zero difference; for example, for the dates of the first dispensing of erlotinib or gefitinib, national electronic health databases and clinical records differed on average by approximately 4 days with a nonsignificant P value of .33 and 95% CIs overlapping with zero difference. As of May 2024, the main study is ongoing. CONCLUSIONS: A protocol is presented for a national whole-of-patient-population retrospective cohort study designed to describe the safety and effectiveness of erlotinib and gefitinib during their first decade of routine use in NZ for treating EGFR mutation-positive lung cancer. The validation substudy demonstrated the feasibility and validity of using national electronic health databases and the methods for determining patient eligibility and identifying the study outcomes and variables proposed in the study protocol. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000998549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368928. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51381.

Oral paclitaxel with encequidar compared to intravenous paclitaxel in patients with advanced cancer: A randomised crossover pharmacokinetic study.

AIMS: Paclitaxel is a widely used anti-neoplastic agent but has low oral bioavailability due to gut extrusion by P-glycoprotein (P-gp). Oral paclitaxel could be more convenient, less resource intensive, and more tolerable than intravenous administration. Encequidar (HM30181A) is a novel, minimally absorbed gut-specific P-gp inhibitor. We tested whether administration of oral paclitaxel with encequidar (oPac+E) achieved comparable AUC to intravenous paclitaxel (IVP) 80 mg/m2 . METHODS: We conducted a multi-centre randomised crossover study with two treatment periods. Patients (pts) with advanced cancer received either oral paclitaxel 615 mg/m2 divided over 3 days and encequidar 15 mg orally 1 hour prior, followed by IVP 80 mg/m2 , or the reverse sequence. PK blood samples were taken up to Day 9 for oPac+E and Day 5 for IVP. RESULTS: Forty-two patients were enrolled; 35 completed both treatment periods. AUC0-∞ was 5033.5 ± 1401.1 ng.h/mL for oPac+E and 5595.9 ± 1264.1 ng.h/mL with IVP. The geometric mean ratio (GMR) for AUC was 89.50% (90% CI 83.89-95.50). Mean absolute bioavailability of oPac+E was 12% (CV% = 23%). PK parameters did not change meaningfully after 4 weeks administration of oPac+E in an extension study. G3 treatment-emergent adverse events occurred in seven (18%) pts with oPac+E and two (5%) with IVP. Seventy-five per cent of patients preferred oPac+E over IVP. CONCLUSIONS: GMR for AUC was within the predefined acceptable range of 80-125% for demonstrating equivalence. oPac+E is tolerable and there is no evidence of P-gp induction with repeat administration. With further study, oPac+E could be an alternative to IVP.

Circuit resistance training and cardiovascular health in breast cancer survivors.

OBJECTIVE: Cardiovascular disease is the leading cause of death in breast cancer survivors. While evidence shows circuit resistance training (CRT) is effective for improving muscle and cardiorespiratory fitness, whether CRT is an efficacious therapy for decreasing cardiovascular risk in cancer survivors is unclear. METHODS: Fifty-one breast cancer survivors were recruited to either 12 weeks CRT (n = 26), or a non-exercising wait-list control (n = 25). Two supervised 60 min CRT sessions per week were undertaken, comprising resistance and functional exercises, and aerobic exercise stations. Primary outcome measure was the gold-standard assessment of arterial stiffness, aortic pulse wave velocity (PWV). Secondary outcomes included: cardiorespiratory fitness (CRF), upper and lower body strength, arterial wave reflections, central blood pressure and rate pressure product. RESULTS: Compared to the control group, the CRT group had a statistically significant medium effect decrease in PWV 0.9 m/s (95% CI: 0.1, 1.7). There were large effect improvements in VO2 max (4.3 ml kg-1  min-1 , 95% CI: 5.8, 2.8), upper and lower body strength (3.7 kg, 95% CI: 1.9, 5.6 and 10.4 kg, 1.6, 19.1) respectively. CONCLUSION: Findings support the existing literature demonstrating that 12 weeks CRT improves muscle and cardiorespiratory fitness and is also an effective strategy for decreasing a proven cardiovascular risk factor in breast cancer survivors.

Cardiorespiratory fitness predicts cardiovascular health in breast cancer survivors, independent of body composition, age and time post-treatment completion.

BACKGROUND: Breast cancer treatment may increase non-cancer related mortality risk due to unintended cardiovascular consequences. The aim of this study was to investigate the strongest correlate of cardiovascular health (CVH) in female breast cancer survivors, cardiorespiratory fitness or fatness. METHODS: Fifty-one women (59 ± 9 years, BMI 26.4 ± 4.8 kg/m2) previously diagnosed and treated for primary breast cancer were assessed using pulse wave analysis to determine central arterial wave reflection (augmentation index, AIx) and central systolic blood pressure (cSBP). A composite Z score calculated which incorporated central double product and AIx, as an indicator of CVH. Dual energy X-ray absorptiometry was used to obtain total body fat percentage (BF%). Cardiorespiratory fitness was determined using the single-stage walk test to predict maximal oxygen uptake ([Formula: see text]). RESULTS: Linear regression analysis revealed that fitness was associated with AIx after adjusting for BF %, age and time post-treatment completion (ß = - 0.271, p = 0.010). A significant association between BF% and AIx after adjusting for fitness and age was found (ß = 0.166, p = 0.0005); however, this association was lost when time post-treatment was included in the model (ß = 0.166, p = 0.167). Both fitness (ß = - 0.347, p = 0.0005) and BF% (ß = 0.333, p = 0.013) were independently associated with CVH in the fully adjusted model. CONCLUSIONS: This study provides evidence for an association between cardiorespiratory fitness and cardiovascular health in female breast cancer survivors. While fatness may be associated with cardiovascular health, it appears to be more strongly associated with age.

An integrative Tai Chi program for patients with breast cancer undergoing cancer therapy: study protocol for a randomized controlled feasibility study.

BACKGROUND: Breast cancer patients experience various side effects during cancer therapy, often resulting in reduced quality of life and poor adherence to treatment. A limited range of proven interventions has been developed to target such side effects. While Tai Chi offers benefits for the health and well-being of breast cancer survivors, the effectiveness of Tai Chi across the treatment continuum has not been evaluated. Improved patient education and support has been suggested as a priority for breast cancer care. This pilot study assesses the feasibility of a randomized controlled trial (RCT) to evaluate the effectiveness of "an integrative Tai Chi" (ANITA) program for breast cancer patients undergoing cancer therapy. METHODS/DESIGN: This is a single-centre, two-arm feasibility RCT. Twenty-four patients with breast cancer who have undergone surgical treatment will be recruited from the Dunedin Hospital (New Zealand) over a 12-month period (from August 2017 to July 2018). Subject to informed consent, patients will be randomized to receive standard cancer treatment alone or standard cancer treatment plus the ANITA program, consisting of peer support, health education, and Tai Chi Ruler exercise. The program runs alongside the patient's adjuvant cancer therapy, which may include chemotherapy, radiation therapy, antibody treatment, and/or antihormonal therapy. Analysis in this study will focus on process evaluation of participant recruitment, retention, treatment fidelity, acceptability of the program, and occurrence of adverse events. Clinical outcomes (i.e., fatigue, sleep quality, anxiety and depression and quality of life) will be assessed at baseline, and at 12 weeks and 24 weeks post-randomization. DISCUSSION: Outcomes from this study will inform the feasibility and methodology for a future fully-powered RCT. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry with the identifier ACTRN12617000975392.

Chemotherapy Agents Alter Plasma Lipids in Breast Cancer Patients and Show Differential Effects on Lipid Metabolism Genes in Liver Cells.

Cardiovascular complications have emerged as a major concern for cancer patients. Many chemotherapy agents are cardiotoxic and some appear to also alter lipid profiles, although the mechanism for this is unknown. We studied plasma lipid levels in 12 breast cancer patients throughout their chemotherapy. Patients received either four cycles of doxorubicin and cyclophosphamide followed by weekly paclitaxel or three cycles of epirubicin, cyclophosphamide and 5'-fluorouracil followed by three cycles of docetaxel. Patients demonstrated a significant reduction (0.32 mmol/L) in high density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (apoA1) levels (0.18 g/L) and an elevation in apolipoprotein B (apoB) levels (0.15 g/L) after treatment. Investigation of the individual chemotherapy agents for their effect on genes involved in lipoprotein metabolism in liver cells showed that doxorubicin decreased ATP binding cassette transporter A1 (ABCA1) via a downregulation of the peroxisomal proliferator activated receptor γ (PPARγ) and liver X receptor α (LXRα) transcription factors. In contrast, ABCA1 levels were not affected by cyclophosphamide or paclitaxel. Likewise, apoA1 levels were reduced by doxorubicin and remained unaffected by cyclophosphamide and paclitaxel. Doxorubicin and paclitaxel both increased apoB protein levels and paclitaxel also decreased low density lipoprotein receptor (LDLR) protein levels. These findings correlate with the observed reduction in HDL-C and apoA1 and increase in apoB levels seen in these patients. The unfavourable lipid profiles produced by some chemotherapy agents may be detrimental in the longer term to cancer patients, especially those already at risk of cardiovascular disease (CVD). This knowledge may be useful in tailoring effective follow-up care plans for cancer survivors.

Cardiovascular disease among breast cancer survivors: the call for a clinical vascular health toolbox.

With better detection and treatment, breast cancer is less likely to be the primary cause of death in the majority of breast cancer survivors; mortality due to cardiovascular disease (CVD) is now more common. Given the long latency periods between cancer treatment completion and potential symptomatic CVD, there is a need to detect vascular changes before symptoms appear. This short review provides an overview of non-invasive, widely available, and relatively inexpensive techniques for assessing endothelial function, central and regional arterial stiffness, central blood pressures, and intima-media thickness. These tools exhibit acceptable reliability and validity, and are relatively practical. Clinical assessment recommendations are also provided. There is sufficient evidence to encourage the use of these techniques as a component of routine serial assessments, and to help guide appropriate treatment strategies.

Early-stage testicular cancer: a rare association with dermatomyositis.

Dermatomyositis has a known association with malignancy. We report a case of dermatomyositis occurring in early-stage testicular cancer where the patient was in remission. It stresses the importance of considering testicular cancer as an association with dermatomyositis, as it is a potentially curable malignancy.