First-line chemoimmunotherapy and immunotherapy in patients with non-small cell lung cancer and brain metastases: a registry study.

Introduction: Brain metastases commonly occur in patients with non-small cell lung cancer (NSCLC). Standard first-line treatment for NSCLC, without an EGFR, ALK or ROS1 mutation, is either chemoimmunotherapy or anti-PD-1 monotherapy. Traditionally, patients with symptomatic or untreated brain metastases were excluded from the pivotal clinical trials that established first-line treatment recommendations. The intracranial effectiveness of these treatment protocols has only recently been elucidated in small-scale prospective trials. Methods: Patients with NSCLC and brain metastases, treated with first-line chemoimmunotherapy or anti-PD-1 monotherapy were selected from the Australian Registry and biObank of thoracic cancers (AURORA) clinical database covering seven institutions. The primary outcome was a composite time-to-event (TTE) outcome, including extracranial and intracranial progression, death, or need for local intracranial therapy, which served as a surrogate for disease progression. The secondary outcome included overall survival (OS), intracranial objective response rate (iORR) and objective response rate (ORR). Results: 116 patients were included. 63% received combination chemoimmunotherapy and 37% received anti-PD-1 monotherapy. 69% of patients received upfront local therapy either with surgery, radiotherapy or both. The median TTE was 7.1 months (95% CI 5 - 9) with extracranial progression being the most common progression event. Neither type of systemic therapy or upfront local therapy were predictive of TTE in a multivariate analysis. The median OS was 17 months (95% CI 13-27). Treatment with chemoimmunotherapy was predictive of longer OS in multivariate analysis (HR 0.35; 95% CI 0.14 - 0.86; p=0.01). The iORR was 46.6%. The iORR was higher in patients treated with chemoimmunotherapy compared to immunotherapy (58% versus 31%, p=0.01). The use of chemoimmunotherapy being predictive of iORR in a multivariate analysis (OR 2.88; 95% CI 1.68 - 9.98; p=0.04). Conclusion: The results of this study of real-world data demonstrate the promising intracranial efficacy of chemoimmunotherapy in the first-line setting, potentially surpassing that of immunotherapy alone. No demonstrable difference in survival or TTE was seen between receipt of upfront local therapy. Prospective studies are required to assist clinical decision making regarding optimal sequencing of local and systemic therapies.

Journey to kidney transplantation: patient dynamics, suspensions, transplantation and deaths in the Australian kidney transplant waitlist.

BACKGROUND AND HYPOTHESIS: People on the kidney waitlist are less informed about potential suspensions. Disparities may exist among those who are suspended and who return to the waitlist. We evaluated the patient journey after entering the waitlist, including suspensions and outcomes, and factors associated with these transitions. METHODS: We included all incident patients waitlist for their first transplant from deceased donors in Australia, 2006-19. We described all clinical transitions after entering the waitlist. We predicted the restricted mean survival time (unadjusted and adjusted) until first transplant by number of prior suspensions. We evaluated factors associated with transitions using flexible survival models and clinical endpoints using Cox models. RESULTS: Of 8 466 patients waitlisted and followed over 45 757.4 person-years (median:4.8years), 6 741(80%) were transplanted, 381(5%) died waiting and 1 344(16%) were still waiting. 3 127(37%) people were suspended at least once. Predicted mean time from waitlist to transplant was 3.0 years(95%CI:2.8-3.2) when suspended versus 1.9 years(95%CI:1.8-1.9) when never suspended. Prior suspension increased likeliness of further suspensions 4.2-fold(95%CI:3.8-4.6) and returning to waitlist by 50%(95%CI:36-65%) but decreased likeliness of transplantation by 29%(95%CI:62-82%). Death risk while waiting was 12-fold(95%CI:8.0-18.3) increased when currently suspended. Australian non-Indigenous males were 13% (HR:1.13,95%CI:1.04-1.23) and Asian males 23% (HR:1.23,95%CI:1.06-1.42,) more likely to return to the waitlist compared to females of the same ethnicity. CONCLUSION: The waitlist journey was not straightforward. Suspension was common, impacted chance of transplantation and meant waiting an average one year longer until transplant. We have provided estimates for, and factors associated with, suspension, re-listing and outcomes after waitlisting to support more informed discussions. This evidence is critical to further understand drivers of inequitable access to transplantation.

Epidemiology of cardiovascular death in kidney failure: An Australian and New Zealand cohort study using data linkage.

AIM: Cardiovascular mortality risk evolves over the lifespan of kidney failure (KF), as patients develop comorbid disease and transition between treatment modalities. Absolute cardiovascular death rates would help inform clinical practice and health-care provision, but are not well understood across a continuum of dialysis and transplant states. We aimed to characterize cardiovascular death across the natural history of KF using a lifespan approach. METHODS: We performed a population-based cohort study of incident patients commencing kidney replacement therapy in Australia and New Zealand. Cardiovascular deaths were identified using data linkage to national death registers. We estimated the probability of death and kidney transplant using multi-state models, and calculated rates of graft failure and cardiovascular death across demographic factors and comorbidities. RESULTS: Among 60 823 incident patients followed over 381 874 person-years, 25% (8492) of deaths were from cardiovascular disease. At 15 years from treatment initiation, patients had a 15.2% probability of cardiovascular death without being transplanted, but only 2.3% probability of cardiovascular death post-transplant. Females had a 3% lower probability of cardiovascular death at 15 years (15.3% vs. 18.6%) but 4% higher probability of non-cardiovascular death (54.5% vs. 50.8%). Within the first year of dialysis, cardiovascular mortality peaked in the second month and showed little improvement across treatment era. CONCLUSION: Despite improvements over time, cardiovascular death remains common in KF, particularly among the dialysis population and in the first few months of treatment. Multi-state models can provide absolute measures of cardiovascular mortality across both dialysis and transplant states.

Cause of death for people with end-stage kidney disease withdrawing from treatment in Australia and New Zealand.

BACKGROUND: Withdrawal from renal replacement therapy is common in patients with end-stage kidney disease (ESKD), but end-of-life service planning is challenging without population-specific data. We aimed to describe mortality after treatment withdrawal in Australian and New Zealand ESKD patients and evaluate death-certified causes of death. METHODS: We performed a retrospective cohort study on incident patients with ESKD in Australia, 1980-2013, and New Zealand, 1988-2012, from the Australian and New Zealand Dialysis and Transplant registry. We estimated mortality rates (by age, sex, calendar year and country) and summarized withdrawal-related deaths within 12 months of treatment modality change. Certified causes of death were ascertained from data linkage with the Australian National Death Index and New Zealand Mortality Collection database. RESULTS: Of 60 823 patients with ESKD, there were 8111 treatment withdrawal deaths and 26 207 other deaths over 381 874 person-years. Withdrawal-related mortality rates were higher in females and older age groups. Rates increased between 1995 and 2013, from 1142 (95% confidence interval 1064-1226) to 2706/100 000 person-years (95% confidence interval 2498-2932), with the greatest increase in 1995-2006. A third of withdrawal deaths occurred within 12 months of treatment modality change. The national death registers reported kidney failure as the underlying cause of death in 20% of withdrawal cases, with other causes including diabetes (21%) and hypertensive disease (7%). Kidney disease was not mentioned for 18% of withdrawal patients. CONCLUSIONS: Treatment withdrawal represents 24% of ESKD deaths and has more than doubled in rate since 1988. Population data may supplement, but not replace, clinical data for end-of-life kidney-related service planning.

Diagnostic delay in pulmonary arterial hypertension: Insights from the Australian and New Zealand pulmonary hypertension registry.

BACKGROUND AND OBJECTIVE: Early diagnosis of PAH is clinically challenging. Patterns of diagnostic delay in Australian and New Zealand PAH populations have not been explored in large-scale studies. We aimed to evaluate the magnitude, risk factors and survival impact of diagnostic delay in Australian and New Zealand PAH patients. METHODS: A cohort study of PAH patients from the PHSANZ Registry diagnosed from 2004 to 2017 was performed. Diagnostic interval was the time from symptom onset to diagnostic right heart catheterization as recorded in the registry. Factors associated with diagnostic delay were analysed in a multivariate logistic regression model. Survival rates were compared across patients based on the time to diagnosis using Kaplan-Meier method and Cox regression. RESULTS: A total of 2044 patients were included in analysis. At diagnosis, median age was 58 years (IQR: 43-69), female-to-male ratio was 2.8:1 and majority of patients were in NYHA FC III-IV (82%). Median diagnostic interval was 1.2 years (IQR: 0.6-2.7). Age, CHD-PAH, obstructive sleep apnoea and peripheral vascular disease were independently associated with diagnostic interval of ≥1 year. No improvement in diagnostic interval was seen during the study period. Longer diagnostic interval was associated with decreased 5-year survival. CONCLUSION: PAH patients experience significant diagnostic interval, which has not improved despite increased community awareness. Age, cardiovascular and respiratory comorbidities are significantly associated with longer time to diagnosis. Mortality rates appear higher in patients who experience longer diagnostic interval.