Search Results (12)

Background: Obesity, commonly approximated by body mass index (BMI) ≥ 30 kg/m², is causally associated with at least 13 cancer types (obesity-related cancers) but it is unclear whether weight loss interventions among obese individuals result in risk reduction of cancer. Recently, several trials of short-term use of glucagon-like peptide-1 (GLP-1) receptor agonists, originally designed for use as anti-diabetes medications, have shown substantial weight loss outcomes compared with placebo. Notably, high-dose semaglutide is associated with approximately 15% weight loss in individuals with obesity without diabetes. With these impressive results, hypotheses are emerging that these drugs might have a role in the prevention of obesity-related cancers, mediated through weight loss. Objectives/methods: The aim of this opinion paper is to critically appraise the methodological challenges and pitfalls associated with studying the question ‘does weight loss through use of GLP-1 receptor agonists reduce cancer risk’ through observational studies, and exemplify this through critique of a recent study published in this journal. Results: We modified the ROBINS-E framework for assessing risk of bias, identifying seven methodological criteria specific to this research question, against which data should be interpreted. These include adequate adjustment for key parameters of body fatness; immortal time bias; treatment allocation bias; survival bias; cumulative drug dose effect; sufficient sojourn time between drug intervention and cancer presentation; and treatment effect specific to obesity-related cancers. We found that 6 out of 7 methodological criteria were at high risk of bias. Conclusions: Cancer prevention through GLP-1 receptor agonist use should be explored; however, there are several methodological challenges to overcome in understanding this link before it can inform clinical practice and policy. Full article

Background: The long-term effects of hormone replacement therapy (HRT) on inflammatory bowel disease (IBD) remain unclear, necessitating further investigations of the association between HRT and the development of ulcerative colitis and Crohn’s disease in postmenopausal women. Methods: This retrospective cohort study utilized Taiwan’s National Health Insurance claims (2001–2018) to identify postmenopausal women aged ≥ 50 years with HRT use. A one-year washout period was applied before the index date to ensure new HRT users. To address the immortal time bias, follow-up for HRT users began at HRT initiation. The non-HRT group was selected by 1:1 propensity score matching. Cox proportional hazards models with adjustments for comorbidities and medications were used to estimate hazard ratios. Results: A total of 10,126 postmenopausal women (5063 per group) were included. During a mean follow-up of 11.1 years, the incidence rates of ulcerative colitis were 0.14 and 0.11 per 1000 person-years in the HRT and non-HRT groups, respectively. The adjusted hazard ratios were 1.33 (95% CI, 0.46–3.83; p = 0.600) for ulcerative colitis and 0.72 (95% CI, 0.45–1.16; p = 0.177) for Crohn’s disease. Conclusions: This longitudinal study suggests that HRT use is not significantly associated with the risk of IBD among postmenopausal women. These findings indicate that IBD risk may not need to be a primary concern when considering HRT in this population. Full article

Background: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) represent a high-risk heart failure population with continued unmet therapeutic needs. Sodium–glucose co-transporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with heart failure across the whole spectrum of ejection fraction, and first evidence regarding their safety and effectiveness in patients with ATTR-CM is arising. This study investigates the association between SGLT2i therapy and clinical outcomes in these patients. Methods: This is an analysis of a prospective registry conducted at a referral centre for hypertrophic cardiomyopathies including 116 patients with confirmed ATTR-CM. Fifty-one patients (44%) were treated with SGLT2i while 65 patients (56%) remained SGLT2i-naïve. Results: During a median follow-up of 2.6 (1.7–3.7) years, 38 patients (33%) died, of whom 11 patients (9%) received SGLT2i treatment and 27 patients (23%) were treatment-naïve. SGLT2i therapy was significantly associated with lower mortality (HR 0.457, 95%CI 0.227–0.922, p = 0.029). This association persisted after adjusting for age and sex (HR 0.479, 95%CI 0.235–0.977, p = 0.043) and after additional adjustment for eGFR, NT-proBNP, LVEF, and concomitant therapy with tafamidis (HR 0.328, 95%CI 0.141–0.760, p = 0.009). However, when potential immortal time bias was considered, this association lost statistical significance (HR 1.075, 95%CI 0.524–2.206, p = 0.843). No significant associations between SGLT2i therapy and worsening heart-failure hospitalization or cardiovascular mortality were observed. Conclusions: In crude analysis, SGLT2i therapy associates with better survival in patients with ATTR-CM. However, after adjustment for immortal time, this association becomes statistically insignificant. Hence, to draw final conclusions on the effectiveness of SGLT2i therapy in these patients, a randomized controlled trial is warranted. Full article

Background: Check-Mate 274 has demonstrated the disease-free survival (DFS) benefit of adjuvant nivolumab in surgically treated muscle-invasive bladder cancer (MIBC). Since immunotherapy represents an expensive treatment with potential side effects, a better understanding of patient-specific risks of disease progression might be useful for clinicians when weighing the indication for adjuvant nivolumab. Objective: To identify the criteria for risk stratification of disease progression among MIBC patients eligible for adjuvant nivolumab. Materials and methods: A single-institution, prospectively maintained database was queried to identify patients eligible for adjuvant nivolumab according to Check-Mate 274 criteria. To account for immortal bias, patients who died or were lost to follow-up within 3 months of undergoing a radical cystectomy (RC) were excluded. Kaplan–Meier and Cox regression analyses addressed DFS, defined as the time frame from diagnosis to the first documented recurrence or death from any cause, whichever occurred first. Regression tree analysis was implemented to identify criteria for risk stratification. Results: Between 2011 and 2022, 304 patients were identified, with a median follow-up of 50 (IQR 24–72) months. After multivariable adjustment, including NAC as a potential confounder, higher CCI (HR 1.56, 95%CI 1.10–2.21, p = 0.013), T stage (HR 2.06, 95%CI 1.01–4.17, p = 0.046), N stage (HR 1.73, 95%CI 1.26–2.38, p = 0.001) and presence of LVI (HR 1.52, 95%CI 1.07–2.15, p = 0.019) increased the risk of disease recurrence or death. Finally, a two-tier classification was developed. Here, five-year DFS rates were 56.1% vs. 18.1 for low vs. high risk (HR: 2.54, 95%CI 1.79–3.62, p < 0.001). Conclusions: The current risk classification, if externally validated on larger samples, may be useful when weighing the risk and benefit of adjuvant nivolumab treatment and making patients more aware about their disease and about the need for additional treatment after RC. Full article

Immortal time bias (ITB) is common in cohort studies and distorts the association estimates between the treated and untreated. We used data from an Italian study on COVID-19 vaccine effectiveness, with a large cohort, long follow-up, and adjustment for confounding factors, affected by ITB, with the aim to verify the real impact of the vaccination campaign by comparing the risk of all-cause death between the vaccinated population and the unvaccinated population. We aligned all subjects on a single index date and considered the “all-cause deaths” outcome to compare the survival distributions of the unvaccinated group versus various vaccination statuses. The all-cause-death hazard ratios in univariate analysis for vaccinated people with 1, 2, and 3/4 doses versus unvaccinated people were 0.88, 1.23, and 1.21, respectively. The multivariate values were 2.40, 1.98, and 0.99. Possible explanations of this trend of the hazard ratios as vaccinations increase could be a harvesting effect; a calendar-time bias, accounting for seasonality and pandemic waves; a case-counting window bias; a healthy-vaccinee bias; or some combination of these factors. With 2 and even with 3/4 doses, the calculated Restricted Mean Survival Time and Restricted Mean Time Lost have shown a small but significant downside for the vaccinated populations. Full article

Background: The effects of steroid-sparing immunosuppressive agents (SSIAs), used for the treatment of immune-related adverse events (irAEs), on immune checkpoint inhibitor (ICI) antitumor activity is not well known. We compared tumor outcomes of patients who received corticosteroid monotherapy (CS) versus a corticosteroid plus SSIA (CS-SSIA) for irAE treatment, using statistical methods to address immortal time bias. Methods: We conducted a retrospective case-control study on patients ≥ 18 years with melanoma or non-small-cell lung cancer (NSCLC) treated with ≥1 ICI at a quaternary care center between 1 January 2016 and 11 January 2021. Patients were divided into two cohorts: CS or CS-SSIA. We used propensity score nearest-neighbor matching to match on tumor type, stage, and prior lines of therapy. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included the time from the start of the irAE treatment to the irAE resolution. Hazard ratios (HRs) for PFS and OS were calculated using the Cox proportional hazard regression method with both (1) the time to the steroid and SSIA as time-varying covariates and (2) a binary exposure classification not accounting for the time to the treatment. Results: A total of 167 patients were included after matching (132 in the CS cohort and 35 in the CS-SSIA cohort). Sixty-six percent of all the patients had melanoma. The most common irAEs requiring treatment were gastroenterocolitis and hepatitis. In an adjusted analysis not accounting for immortal time bias, there were no significant differences in PFS (HR 0.75, 95% CI [0.46–1.23]) or OS (HR 0.82, 95% CI [0.46–1.47]). In analyses using a time-varying treatment indicator, there was a trend toward improved PFS in patients treated with SSIAs (HR 0.54, CI 0.26–1.10). There was no difference in OS (HR 1.11, CI 0.55–2.23). Patients with melanoma who specifically received infliximab had improved PFS compared to patients with CS only, after adjusting for immortal time bias (HR 0.32, CI 0.24–0.43). Conclusions: The use of SSIAs with CS did not have worse outcomes than CS monotherapy. In melanoma, our findings showed improved PFS for the use of infliximab versus steroid monotherapy for irAEs. Large, prospective, randomized controlled trials are needed to confirm these findings and guide the optimal treatment of irAEs. Full article

Methodological biases are common in observational studies evaluating treatment effectiveness. The objective of this study is to emulate a target trial in a competing risks setting using hospital-based observational data. We extend established methodology accounting for immortal time bias and time-fixed confounding biases to a setting where no survival information beyond hospital discharge is available: a condition common to coronavirus disease 2019 (COVID-19) research data. This exemplary study includes a cohort of 618 hospitalized patients with COVID-19. We describe methodological opportunities and challenges that cannot be overcome applying traditional statistical methods. We demonstrate the practical implementation of this trial emulation approach via clone–censor–weight techniques. We undertake a competing risk analysis, reporting the cause-specific cumulative hazards and cumulative incidence probabilities. Our analysis demonstrates that a target trial emulation framework can be extended to account for competing risks in COVID-19 hospital studies. In our analysis, we avoid immortal time bias, time-fixed confounding bias, and competing risks bias simultaneously. Choosing the length of the grace period is justified from a clinical perspective and has an important advantage in ensuring reliable results. This extended trial emulation with the competing risk analysis enables an unbiased estimation of treatment effects, along with the ability to interpret the effectiveness of treatment on all clinically important outcomes. Full article

Local consolidative radiotherapy in the treatment of metastatic malignancies has shown promising results in several types of tumors. The objective of this study was to assess consolidative radiotherapy to the bladder and to residual metastases in metastatic urothelial bladder cancer with no progression following first-line systemic therapy. Materials/methods: Patients who received first-line therapy for the treatment of metastatic urothelial bladder cancer (mUBC) and who were progression-free following treatment with no more than five residual metastases were retrospectively identified through the database of four Comprehensive Cancer Centers, between January 2005 and December 2018. Among them, patients who received subsequent definitive radiotherapy (of EQD2Gy > 45Gy) to the bladder and residual metastases were included in the consolidative group (irradiated (IR) group), and the other patients were included in the observation group (NIR group). Progression-free survival (PFS) and overall survival (OS) were determined from the start of the first-line chemotherapy using the Kaplan–Meier method. To prevent immortal time bias, a Cox model with time-dependent covariates and 6-month landmark analyses were performed to examine OS and PFS. Results: A total of 91 patients with at least stable disease following first-line therapy and with no more than five residual metastases were analyzed: 51 in the IR group and 40 in the NIR group. Metachronous metastatic disease was more frequent in the NIR group (19% vs. 5%, p = 0.02); the median number of metastases in the IR group vs. in the NIR group was 2 (1–9) vs. 3 (1–5) (p = 0.04) at metastatic presentation, and 1 (0–5) vs. 2 (0–5) (p = 0.18) after completion of chemotherapy (residual lesions), respectively. Two grade 3 toxicities (3.9%) and no grade 4 toxicity were reported in the IR group related to radiotherapy. With a median follow up of 85.9 months (95% IC (36.7; 101.6)), median OS and PFS were 21.7 months (95% IC (17.1; 29.7)) and 11.1 months (95% IC (9.9; 14.1)) for the whole cohort, respectively. In multivariable analysis, consolidative radiotherapy conferred a benefit in both PFS (HR = 0.49, p = 0.007) and OS (HR = 0.47, p = 0.015) in the whole population; in the landmark analysis at 6 months, radiotherapy was associated with improved OS (HR = 0.48, p = 0.026), with a trend for PFS (HR = 0.57, p = 0.082). Conclusion: Consolidative radiotherapy for mUBC patients who have not progressed after first-line therapy and with limited residual disease seems to confer both OS and PFS benefits. The role of consolidative radiotherapy in the context of avelumab maintenance should be addressed prospectively. Full article

A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence. Full article

Palliative care has the potential to improve the quality of life of patients with incurable diseases or cancer, such as hepatocellular carcinoma (HCC). A common misconception of palliative care with respect to the patient’s survival remains a significant barrier to the discipline. This study aimed to provide causal evidence for the effect of palliative care consultation on the survival time after diagnosis among HCC patients. An emulation of a target trial was conducted on a retrospective cohort of HCC patients from January 2017 to August 2019. The primary endpoint was the restricted mean survival time (RMST) at 12 months after HCC diagnosis. We used the clone–censor–weight approach to account for potential immortal time bias. In this study, 86 patients with palliative care consultation and 71 patients without palliative care consultation were included. The adjusted RMST difference was −29.7 (95% confidence interval (CI): −81.7, 22.3; p-value = 0.263) days in favor of no palliative care consultation. However, palliative care consultation was associated with an increase in the prescription of symptom control medications, as well as a reduction in life-sustaining interventions and healthcare costs. Our findings suggest that palliative care consultation was associated with neither additional survival benefit nor harm in HCC patients. The misconception that it significantly accelerates the dying process should be disregarded. Full article

Using observational data to assess the treatment effects on outcomes of kidney transplantation relative to dialysis for patients on renal replacement therapy is challenging due to the non-random selection into treatment. This study applied the propensity score weighting approach in order to address the treatment selection bias of kidney transplantation on survival time compared with dialysis for patients on the waitlist. We included 2676 adult waitlisted patients who started renal replacement therapy in Sweden between 1 January 1995, and 31 December 2012. Weibull and logistic regression models were used for the outcome and treatment models, respectively. The potential outcome mean and the average treatment effect were estimated using an inverse-probability-weighted regression adjustment approach. The estimated survival times from start of renal replacement therapy were 23.1 years (95% confidence interval (CI): 21.2−25.0) and 9.3 years (95% CI: 7.8−10.8) for kidney transplantation and dialysis, respectively. The survival advantage of kidney transplantation compared with dialysis was estimated to 13.8 years (95% CI: 11.4−16.2). There was no significant difference in the survival advantage of transplantation between men and women. Controlling for possible immortality bias reduced the survival advantage to 9.1–9.9 years. Our results suggest that kidney transplantation substantially increases survival time compared with dialysis in Sweden and that this consequence of treatment is equally distributed over sex. Full article

This study aimed to illustrate and account for immortal time bias in pregnancy observational investigations, using the relationship between late use of antibiotics and risk of preterm birth as an example. We conducted a population-based cohort study including 549,082 deliveries between 2007 and 2017 in Lombardy, Italy. We evaluated the risk of preterm births, low birth weight, small for gestational age, and low Apgar score associated with antibiotic dispensing during the third trimester of pregnancy. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of the outcomes, considering the use of antibiotics as time-fixed (with biased classification of exposure person-time) and time-varying (with proper classification of exposure person-time) exposure. There were 23,638 (4.3%) premature deliveries. There was no association between time-fixed exposure to antibiotics and preterm delivery (adjusted HR 0.96; 95% CI 0.92 to 1.01) but an increased risk of preterm birth when time-varying exposure to antibiotics was considered (1.27; 1.21 to 1.34). The same trend was found for low birth weight and low Apgar score. Immortal time bias is a common and sneaky trap in observational studies involving exposure in late pregnancy. This bias could be easily avoided with suitable design and analysis. Full article