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.

Ethnic differences in the characteristics of patients with newly diagnosed lung cancer in the Te Manawa Taki region of New Zealand.

BACKGROUND: Maori have three times the mortality from lung cancer compared with non-Maori. The Te Manawa Taki region has a population of 900 000, of whom 30% are Maori. We have little understanding of the factors associated with developing and diagnosing lung cancer and ethnic differences in these characteristics. AIMS: To explore the differences in the incidence and characteristics of patients with newly diagnosed lung cancer between Maori and non-Maori. METHODS: Patients were identified from the regional register. Incidence rates were calculated based on population data from the 2013 and 2018 censuses. The patient and tumour characteristics of Maori and non-Maori were compared. The analysis used Χ2 tests and logistic models for categorical variables and Student t tests for continuous variables. RESULTS: A total of 4933 patients were included, with 1575 Maori and 3358 non-Maori. The age-standardised incidence of Maori (236 per 100 000) was 3.3 times higher than that of non-Maori. Maori were 1.3 times more likely to have an advanced stage of disease and 1.97 times more likely to have small cell lung cancer. Maori were more likely to have comorbidities, chronic obstructive pulmonary disease, cardiovascular disease and diabetes. They also had higher levels of social deprivation and tended to be younger, female and current smokers. CONCLUSIONS: The findings point to the need to address barriers to early diagnosis and the need for system change including the need to introduce a lung cancer screening focussing on Maori. There is also the need for preventive programmes to address comorbidities that impact lung cancer outcomes as well as a continued emphasis on creating a smoke-free New Zealand.

Effectiveness of nicotine salt vapes, cytisine, and a combination of these products, for smoking cessation in New Zealand: protocol for a three-arm, pragmatic, community-based randomised controlled trial.

BACKGROUND: Combining short-acting nicotine replacement therapy with varenicline increases smoking cessation rates compared with varenicline alone, but not all people tolerate these medications or find them helpful. We aim to investigate the therapeutic potential of an analogous combination, by evaluating the effectiveness, safety, and acceptability of combining nicotine salt e-cigarettes with cytisine, compared to nicotine salt e-cigarettes or cytisine only, on smoking abstinence at six months. METHODS: A pragmatic, community-based, investigator-blinded, randomised superiority trial design will be utilised. Eligible participants will be people who smoke daily (N = 800, 90% power) from throughout New Zealand, who are: aged ≥ 18 years, motivated to quit in the next two weeks, able to provide online consent, willing to use e-cigarettes and/or cytisine, and have daily access to a mobile phone. Recruitment will utilise multi-media advertising. Participants will be randomised (3:3:2 ratio) to 12 weeks of: 1) e-cigarettes (closed pod system, 3% nicotine salt, tobacco flavour) plus cytisine; 2) e-cigarettes alone, or 3) cytisine alone. All groups will receive a six-month, text-message-based behavioural support programme. The primary outcome is self-reported, biochemically verified, continuous abstinence at six months post-quit date. Secondary outcomes, measured at quit date, then one, three, six, and 12 months post-quit date, include self-reported continuous abstinence, 7-day point prevalence abstinence, cigarettes smoked per day, withdrawal and urge to smoke, time to (re)lapse, treatment use and compliance, treatment crossover, dual-use, use of other cessation products, change in e-cigarette products, continuation of product use, acceptability, change in health state, health-related quality of life, change in body mass index, adverse events, and cost per quitter. DISCUSSION: Pragmatic trials are of particular value as they reflect the 'real world' impact of interventions. The trial will provide some of the first evidence on the effectiveness of combining nicotine salt e-cigarettes with cytisine for smoking cessation, in a country with strong tobacco control policy. Findings will be incorporated into relevant systematic reviews, informing practice and policy. TRIAL REGISTRATION: NCT05311085 ClinicalTrials.gov. Registered 5th April, 2022.

Sporadic Metastatic Malignant Peripheral Nerve Sheath Tumour with an NF1 Mutation Responding to Trametinib: A Case Report.

Sporadically occurring malignant peripheral nerve sheath tumours (MPNSTs) can have a variety of genomic alterations including altered NF1, leading to activation of the RAS-RAF-MEK-ERK signalling pathway. Trametinib is an inhibitor of MEK1 and MEK2. Here we present a case of a patient diagnosed with sporadic MPNST with an identified NF1 gene treated successfully with trametinib.

The impact of COVID-19 on lung cancer detection, diagnosis and treatment for Maori in Aotearoa New Zealand.

AIM: The purpose of this article is to examine disparities in the impact of the COVID-19 pandemic on access to lung cancer diagnosis and access to clinical services between Maori and non-Maori. METHODS: Using national-level data, we examined age-standardised lung cancer registrations, diagnostic procedures (bronchoscopy) and lung surgeries separately by ethnic group for the years 2018-2020, as well as patterns of stage of diagnosis. RESULTS: We found a trend toward a reduction in rates of lung cancer registration in Maori (but not non-Maori/non-Pacific) New Zealanders in 2020 compared to 2018 and 2019, but no apparent shift in the distribution of stage at diagnosis. We found a trend toward a reduction in rates of bronchoscopy for both Maori and non-Maori/non-Pacific patients, with the largest reduction observed for Maori. Rates of lung cancer surgery appeared to have reduced for Maori patients, although this was based on a small number of procedures. CONCLUSIONS: We observed disparities between Maori and non-Maori/non-Pacific patients in lung cancer registration and bronchoscopy as a result of the COVID-19 pandemic.

Letter on an iceberg.

In the public sphere, issues are like icebergs. This somewhat hackneyed metaphor illustrates that, while one facet of an issue is perceived, what is not seen is the hidden substructure of power and culture that form and reinforce it, buoying the issue to prominence above the surface.

Prescribed exercise regimen versus usual care and hypochlorous acid wound solution versus placebo for treating venous leg ulcers: study protocol for a randomised controlled trial (Factorial4VLU).

INTRODUCTION: Compression is the mainstay of treatment for venous leg ulcers (VLUs) and there are few effective adjuvant treatments. There is only observational evidence supporting the use of hypochlorous acid (HOCl) as a topical wound solution on VLU and some limited randomised evidence for the effect of a prescribed regimen of exercise. METHODS AND ANALYSIS: The Factorial4VLU trial is a pragmatic, blinded, factorial randomised controlled trial, with 380 participants receiving either a prescribed exercise regimen compared with usual care and either active HOCl wound solution or placebo wound solution at each dressing change for up to 24 weeks. All participants will receive compression therapy. The primary outcome is the proportion of participants with healed VLU at 12 weeks after randomisation as adjudicated by blinded review of ulcer photographs. Secondary outcomes are proportion healed at 24 weeks, time to healing, estimated change in ulcer area, change in 2-Minute Walk Test, change in health-related quality of life, incidence of infection and incidence of all-cause adverse events. If either of the interventions shows a statistically significant positive difference on healing outcomes, cost-effectiveness will be modelled using a health service perspective. ETHICS AND DISSEMINATION: The Factorial4VLU trial received ethical approval from the Northern B Health and Disability Ethics Committee. We plan to publish the results within 1 year of trial completion and will include the results on the trial registration page. TRIAL REGISTRATION NUMBERS: Australia and New Zealand Clinical Trials Register (http://www.anzctr.org.au) (ACTRN12620000116921); Universal Trial Number (WHO) (U1111-1236-2997).

Evidence of inequitable use of chemotherapy in New Zealand colorectal cancer patients.

AIMS: To explore variations in the use of and timeliness of chemotherapy in patients diagnosed with colorectal cancer in New Zealand. METHODS: This study included patients diagnosed with colorectal cancer in New Zealand between 1 January 2006 and 31 December 2016. The first chemotherapy regime was identified from Pharmaceutical Collection dataset. Logistic regression model was used to estimate the adjusted odds ratio of having chemotherapy by subgroup after adjustment for other factors. RESULTS: 27.8% (6,737/24,217) of colon cancer patients and 43.8% (3,582/8,170) of rectal cancer patients received publicly funded chemotherapy. The uptake and timeliness of chemotherapy has been improving over time. Pacific people were the least likely to receive chemotherapy, followed by Maori and Asian. Younger patients, New Zealand European, patients with metastatic disease and patients in the Southern Cancer Network were more likely to have chemotherapy in less than 10 weeks post-diagnosis. Over half of the advanced colorectal cancer patients who did not receive chemotherapy were aged 80+ years or had a short life expectancy. CONCLUSIONS: Although the uptake and timeliness of chemotherapy for colorectal cancer has been improving, Maori, Pacific, Asian and older patients were less likely to receive chemotherapy and less likely to receive chemotherapy in a timely manner. There is a variation in use of chemotherapy by Region with patients in the Southern Cancer region appearing to be the most likely to receive chemotherapy and to receive it within a timely period.

Screening for anaplastic lymphoma kinase (ALK) gene rearrangements in non-small-cell lung cancer in New Zealand.

BACKGROUND: Lung cancer is a major cause of death in New Zealand. In recent years, targeted therapies have improved outcomes. AIM: To determine the uptake of anaplastic lymphoma kinase (ALK) testing, and the prevalence, demographic profile and outcomes of ALK-positive non-small-cell lung cancer (NSCLC), in New Zealand, where no national ALK-testing guidelines or subsidised ALK tyrosine kinase inhibitor (TKI) therapies are available. METHODS: A population-based observational study reviewed databases to identify patients presenting with non-squamous NSCLC over 6.5 years in northern New Zealand. We report the proportion tested for ALK gene rearrangements and the results. NSCLC samples tested by fluorescence in situ hybridisation were retested by next generation sequencing and ALK immunohistochemistry. A survival analysis compared ALK-positive patients treated or not treated with ALK TKI therapy. RESULTS: From a total of 3130 patients diagnosed with non-squamous NSCLC, 407 (13%) were tested for ALK gene rearrangements, and patient selection was variable and inequitable. Among those tested, 34 (8.4%) had ALK-positive NSCLC. ALK-positive disease was more prevalent in younger versus older patients, non-smokers versus smokers and in Maori, Pacific or Asian ethnic groups than in New Zealand Europeans. Fluorescence in situ hybridisation, ALK immunohistochemistry and next generation sequencing showed broad concordance for detecting ALK-positive disease under local testing conditions. Among patients with ALK-positive metastatic NSCLC, those treated with ALK TKI survived markedly longer than those not treated with ALK TKI (median overall survival 5.12 vs 0.55 years). CONCLUSION: Lung cancer outcomes in New Zealand may be improved by providing national guidelines and funding policy for ALK testing and access to subsidised ALK TKI therapy.

Nicotine patches used in combination with e-cigarettes (with and without nicotine) for smoking cessation: a pragmatic, randomised trial.

BACKGROUND: Combination nicotine replacement therapy shows additive cessation benefits. We aimed to find out the effectiveness of combining nicotine patches with an e-cigarette (with and without nicotine) on six-month smoking abstinence. METHODS: We did a pragmatic, three-arm, parallel-group trial in New Zealand in adult smokers who were e-cigarette naive and motivated to quit smoking. Participants were recruited from the general population using national media advertising. Participants were randomly assigned (1:4:4), with the use of stratified block randomisation, to receive 14 weeks (2 weeks before the agreed quit date) of 21 mg, 24h nicotine patches, patches plus an 18 mg/L nicotine e-cigarette, or patches plus a nicotine-free e-cigarette. We advised participants to use one patch daily, with e-cigarette use as and when necessary or desired. Participants and researchers were masked to e-liquid nicotine content. We offered 6 weeks of telephone-delivered behavioural support. The primary outcome was exhaled carbon monoxide (CO)-verified continuous smoking abstinence 6 months after the agreed quit date. Primary analysis was by intention to treat, with sensitivity analysis by per protocol, treatment adherence, varying CO cutoffs, and complete case analysis. This paper presents the main analyses and is registered with ClinicalTrials.gov, NCT02521662. FINDINGS: Between March 17, 2016 and Nov 30, 2017, 1124 people were assigned to nicotine patches (patches only group, n=125), patches plus a nicotine e-cigarette (patches plus nicotine e-cigarette group, n=500), or patches plus a nicotine-free e-cigarette (patches plus nicotine-free e-cigarette group, n=499). 62 (50%) of 125 participants in the patches only group withdrew or were lost to follow-up by 6 months compared with 161 (32%) of 500 in the patches plus nicotine e-cigarette group and 162 (33%) of 499 in the patches plus nicotine-free e-cigarette group. 35 (7%) participants in the patches plus nicotine e-cigarette group had CO-verified continuous abstinence at 6 months compared with 20 (4%) in the patches plus nicotine-free e-cigarette group (risk difference [RD] 2·99 [95% CI 0·17-5·81]), and three (2%) people in the patches only group (RD 4·60 [1·11-8·09]). 18 serious adverse events occurred in 16 people in the patches plus nicotine e-cigarette group compared with 27 events in 22 people in the patches plus nicotine-free e-cigarette group and four events in three people in the patches only group. In the patches plus nicotine e-cigarette group, two life-threatening serious adverse events were reported (two separate heart attacks in the one participant). In the patches plus nicotine-free e-cigarette group, one death occurred (accidental drug overdose) and one life-threatening serious adverse event (heart attack). No significant between-group differences were noted for serious adverse events, and none were treatment-related. INTERPRETATION: Combining reduced-harm nicotine products, such as nicotine patches with a nicotine e-cigarette, can lead to a modest improvement in smoking cessation over and above that obtained from using patches plus a nicotine-free e-cigarette (or patches alone), with no indication of any serious harm in the short-term. Future e-cigarette trials should focus on their use alone or in combination with usual smoking cessation support, given issues with differential loss to follow-up and withdrawal if a usual care group is used as a comparator. FUNDING: Health Research Council of New Zealand.

Effectiveness and safety of nicotine patches combined with e-cigarettes (with and without nicotine) for smoking cessation: study protocol for a randomised controlled trial.

INTRODUCTION: Evidence indicates e-cigarettes can help people quit smoking; however, more confirmatory trials are needed. To date, no trials have evaluated the effectiveness and safety of combining nicotine patches with e-cigarettes (with and without nicotine) for smoking cessation. METHODS AND ANALYSIS: This study is a pragmatic, three-arm, community-based, single-blind, randomised trial undertaken in New Zealand. Eligible participants are daily/non-daily smokers, aged ≥18 years, naive e-cigarette users and motivated to quit smoking in the next 2 weeks. Participants (n=1809), recruited using multi-media advertising, are randomised to 14 weeks of (1) 21 mg nicotine patches (n=201); (2) 21 mg nicotine patches+18 mg/mL nicotine e-cigarette (n=804); or (3) 21 mg nicotine patches+nicotine free e-cigarette (n=804). Participants receive weekly withdrawal-oriented behavioural support calls for 6 weeks post-randomisation. The primary outcome is self-reported biochemically verified continuous abstinence (CA) at 6 months post quit-date. The primary comparison is nicotine patch + nicotine e-cigarette versus nicotine patch + nicotine free e-cigarette, and the secondary comparison is nicotine patch versus nicotine patch +nicotine e-cigarette (90% power, p=0.05, to detect an absolute difference in 6 month CA rates of 8% and 15% respectively). Secondary outcomes, collected by phone interview at quit date, then 1, 3, 6 and 12 months post-quit date, include self-reported CA, 7 day point prevalence abstinence, cigarettes per day (if smoking, or when smoking for non-daily smokers), time to relapse (if returned to smoking), belief in ability to quit, use of other cessation support, side effects/serious adverse events, treatment compliance, seeking additional support around e-cigarette use, daily use of both e-cigarettes and cigarettes, use of treatment past 14 weeks, views on treatment and recommendation to others, weight and cost-per-quitter. ETHICS AND DISSEMINATION: The Northern A Health and Disability Ethics Committee approved the trial. Findings will be disseminated through publication, conference/meeting presentations, and media. TRIAL REGISTRATION NUMBER: NCT02521662; Pre-results.

Human Exposure to Radioactivity From Tobacco Smoke: Systematic Review.

INTRODUCTION: Tobacco has been known to contain radioactive polonium and lead for 50 years but the literature is divided as to the public health significance. I review the data on tobacco radioactivity and its internalization by smokers. METHODS: Data sources: Reports of lead-210 and polonium-210 content of tobacco leaf, cigarettes, cigarette smoke, and human respiratory tissues, published between 1964 and September 2017. Study selection: Any identified study that reported values for lead-210 and polonium-210 content. Data extraction: Data quality was addressed by comparative review of analytic methods. RESULTS: The data about radiation content of tobacco and smoke are robust. Early reports suggesting microsievert lifetime doses of inhaled radioactivity to smokers were not borne out. The results remain sensitive to pharmacological assumptions around absorption and redistribution of inhaled radionuclides, and radiobiological assumptions about interaction with human tissues. CONCLUSIONS: Literature on tobacco radioactivity has not fully contended with pharmacological and radiobiological uncertainty, and is therefore divided as to health significance. This does much to explain regulatory inaction over the last half century. Before radiation safety law can offer a vehicle for tobacco control, more must be learnt about the pharmacology and radiobiology of inhaled radionuclides in tobacco smoke. IMPLICATIONS: This work makes it apparent that the study of tobacco smoke radioactivity has been scientifically stagnant for the last 40 years. The field cannot advance until we improve understanding of the pharmacology and radiobiology of inhaled radionuclides in tobacco smoke. Despite this, a subset of contemporary authors is still suggesting individual health risks about 1000 times higher than can be supported by internationally accepted models.

The effectiveness and safety of combining varenicline with nicotine e-cigarettes for smoking cessation in people with mental illnesses and addictions: study protocol for a randomised-controlled trial.

BACKGROUND: Smoking rates are higher in New Zealand (NZ) adults with mental illnesses and alcohol and other drug (AOD) addictions, compared to the overall population. Quit attempts using "gold standard" smoking cessation treatments often fail in people with these conditions, so more flexible treatment regimens that adapt to a person's responsiveness to treatment are worth investigating. The STATUS trial aims to evaluate the effectiveness and safety of combining varenicline with nicotine e-cigarettes for smoking cessation among varenicline non-responders in treatment for mental health illnesses and/or AOD addictions. METHODS: This is a pragmatic two-arm, open-label, randomised trial. Participants will be daily smokers using mental health and/or addiction services in Auckland, aged ≥18 years, motivated to quit smoking, and eligible to access varenicline through the NZ special authority process. After 2 weeks of using varenicline plus behavioural support, participants who have not reduced their daily smoking by ≥50% will be randomised (1:1) to either 10 weeks of continued varenicline use or 10 weeks of varenicline plus an 18 mg/mL nicotine e-cigarette. All participants will receive weekly withdrawal-orientated behavioural support calls for 6 weeks post-randomisation. The primary outcome is self-reported biochemically-verified (exhaled carbon monoxide) continuous abstinence at 24 weeks post-randomisation. Secondary outcomes, measured at six, 12 and 24 weeks post-randomisation include: self-reported continuous abstinence, 7-day point prevalence abstinence, smoking reduction, time to relapse, cross-over, use of other smoking cessation support, serious adverse events, treatment adherence, compliance, acceptability, dual use, continuation of treatment use, mental illness symptoms and AOD use, health-related quality of life, and cost-analysis. A sample size of 338 will confer 80% power (p = 0.05) to detect a 15% absolute difference between the varenicline alone and varenicline plus e-cigarette groups. DISCUSSION: People with mental illness and/or AOD addictions are just as motivated as others to quit smoking, but are less likely to succeed. Adapting smoking cessation medication after a lack of responsiveness in the first 2 weeks of initial treatment in this priority population by adding a nicotine e-cigarette may be one way to increase long-term quit rates. TRIAL REGISTRATION: Australian NZ Clinical Trial Registry: ACTRN12616001355460 (29 September 2016).