In a randomized, controlled trial, a ctDNA-guided approach to the postsurgical treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival.
Abstract
Context
Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation ...can be variable.
Objective
This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations.
Methods
We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed.
Results
A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range IQR 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio OR 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy; P < .001), as was female sex (OR 2.02, 95% CI 1.37-2.95; P < .001) and younger age (OR 0.83 per 10 years, 95% CI 0.72-0.95; P = .007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI types. The strongest associations for hypothyroidism were higher baseline thyroid-stimulating hormone (OR 2.33 per mIU/L, 95% CI 1.61-3.33; P < .001) and female sex (OR 3.31, 95% CI 1.67-6.56; P = .01). Overt thyrotoxicosis was associated with longer progression free survival (hazard ratio HR 0.68, 95% CI 0.49-0.94; P = .02) and overall survival (HR 0.57, 95% CI 0.39-0.84; P = .005). There was no association between hypothyroidism and cancer outcomes.
Conclusion
Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.
Time‐to‐event data in medical studies may involve some patients who are cured and will never experience the event of interest. In practice, those cured patients are right censored. However, when data ...contain a cured fraction, standard survival methods such as Cox proportional hazards models can produce biased results and therefore misleading interpretations. In addition, for some outcomes, the exact time of an event is not known; instead an interval of time in which the event occurred is recorded. This article proposes a new computational approach that can deal with both the cured fraction issues and the interval censoring challenge. To do so, we extend the traditional mixture cure Cox model to accommodate data with partly interval censoring for the observed event times. The traditional method for estimation of the model parameters is based on the expectation‐maximization (EM) algorithm, where the log‐likelihood is maximized through an indirect complete data log‐likelihood function. We propose in this article an alternative algorithm that directly optimizes the log‐likelihood function. Extensive Monte Carlo simulations are conducted to demonstrate the performance of the new method over the EM algorithm. The main advantage of the new algorithm is the generation of asymptotic variance matrices for all the estimated parameters. The new method is applied to a thin melanoma dataset to predict melanoma recurrence. Various inferences, including survival and hazard function plots with point‐wise confidence intervals, are presented. An R package is now available at Github and will be uploaded to R CRAN.
Studies in multiple solid tumor types have demonstrated the prognostic significance of ctDNA analysis after curative intent surgery. A combined analysis of data across completed studies could further ...our understanding of circulating tumor DNA (ctDNA) as a prognostic marker and inform future trial design. We combined individual patient data from three independent cohort studies of nonmetastatic colorectal cancer (CRC). Plasma samples were collected 4 to 10 weeks after surgery. Mutations in ctDNA were assayed using a massively parallel sequencing technique called SafeSeqS. We analyzed 485 CRC patients (230 Stage II colon, 96 Stage III colon, and 159 locally advanced rectum). ctDNA was detected after surgery in 59 (12%) patients overall (11.0%, 12.5% and 13.8% for samples taken at 4‐6, 6‐8 and 8‐10 weeks; P = .740). ctDNA detection was associated with poorer 5‐year recurrence‐free (38.6% vs 85.5%; P < .001) and overall survival (64.6% vs 89.4%; P < .001). The predictive accuracy of postsurgery ctDNA for recurrence was higher than that of individual clinicopathologic risk features. Recurrence risk increased exponentially with increasing ctDNA mutant allele frequency (MAF) (hazard ratio, 1.2, 2.5 and 5.8 for MAF of 0.1%, 0.5% and 1%). Postsurgery ctDNA was detected in 3 of 20 (15%) patients with locoregional and 27 of 60 (45%) with distant recurrence (P = .018). This analysis demonstrates a consistent long‐term impact of ctDNA as a prognostic marker across nonmetastatic CRC, where ctDNA outperforms other clinicopathologic risk factors and MAF further stratifies recurrence risk. ctDNA is a better predictor of distant vs locoregional recurrence.
What's new?
Pathology‐based cancer staging, by which a patient is classified as high‐risk or low‐risk, cannot perfectly predict which patients will experience a recurrence. Circulating tumor DNA (ctDNA) analysis can more accurately predict recurrence than clinico‐pathologic features. Here, the authors report a combined analysis of three independent cohort studies of patients with non‐metastatic colorectal cancer (CRC). Patients with detectable ctDNA after surgery had a significantly lower 5‐year survival rate. The ctDNA was sequenced to detect mutations, and recurrence risk increased exponentially with increasing mutant allele fraction of ctDNA.
Compared with the general population, people with a previous melanoma are at increased risk of developing another primary melanoma. Understanding the risk factors associated with multiple primary ...melanomas can inform patient education and tailored surveillance.
To examine the risk factors for subsequent primary melanoma in people with a previous melanoma, by conducting a systematic review and meta-analysis of the available data.
A systematic literature search was conducted in CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Embase and MEDLINE. Studies that reported a risk estimate or raw frequencies and conducted between 1982 and August 2022 were included. Adjusted risk estimates were prioritized over univariable risk estimates. PRISMA reporting guidelines were followed. Random effects meta-analysis was conducted to derive pooled estimates. Quality assessment was conducted by two researchers using the Newcastle-Ottawa scale. GRADE was used to rate the certainty and quality of the evidence.
Data from 27 studies involving 413 181 participants were pooled and analysed. Risk factors assessed included age and sex, environmental, lifestyle, phenotypic, genetic and histopathological factors, and there was wide variation in how they were categorized and analysed. Independent risk factors identified from pooled analyses included male sex hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.40-1.53, increasing age per 10 years (HR 1.19, 95% CI 1.14-1.24), light skin colour (HR 1.44, 95% CI 1.23-1.70), family history odds ratio (OR) 1.79, 95% CI 1.25-2.56, CDKN2A mutation (OR 5.29, 95% CI 2.70-10.37), a high or moderate naevus count OR 2.63 (95% CI 1.61-4.30) and OR 1.64 (95% CI 1.07-2.51), respectively, one or more atypical naevi (OR 3.01, 95% CI 1.52-5.97), first lesions occurring on the head or neck, lentigo maligna subtype (HR 1.16, 95% CI 1.15-1.17), other subtype (HR 1.14, 95% CI 1.03-1.27) and inadequate sun protection (HR 1.85, 95% CI 0.98-3.50). Based on the GRADE criteria, there was high to very low confidence in the pooled effect estimates.
This meta-analysis identified several consistent, independent risk factors for the development of subsequent primary melanoma. These findings will help stratify the risk of subsequent melanoma, tailor skin-check schedules and inform patient education.
Background
Counterintuitively, more deaths from melanoma occur among patients with thin (T1) primary melanomas (≤ 1 mm) than among those with thick primary melanoma because the great majority present ...with T1 tumors. Therefore, it is important to stratify their risk as accurately as possible to guide their management and follow-up. This study sought to explore the relationship between tumor thickness and prognosis for patients with thin primary melanomas.
Methods
A retrospective, single-institution study investigated 6263 patients with cutaneous melanoma (including 2117 T1 cases) who had a minimum follow-up period of 10 years.
Results
For the entire patient cohort, the 10-year melanoma-specific survival (MSS) rate ranged between 92% for the patients with primary melanomas up to 0.3 mm thick and 32% for those with melanomas thicker than 8 mm. When divided into 25-quantile-thickness groups there was a significant difference in 10-year MSS between the two consecutive groups 0.8 and 0.9 mm; the differences in survival were not significantly different for any other consecutive cut points within the less than or equal to 1 mm thickness range, indicating a biologically-relevant difference in outcome above and below 0.8 mm. For the patients treated initially at the authors’ institution, the 10- and 20-year MSS rates for those with tumors up to 0.8 mm thick were respectively 93.4 and 85.7%, and for tumors 0.9 to 1.0 mm, the rates were respectively 81.1 and 71.4%. Only 29.3% of the T1 patients who died of melanoma were deceased within 5 years.
Conclusions
A naturally occurring thickness cut point of 0.8 mm predicts higher or lower risk for patients with thin primary cutaneous melanomas. Long-term follow-up assessment of patients with T1 melanoma is important because late mortality due to melanoma is more common than early mortality.
The main treatment of primary cutaneous melanoma is surgery. This review aims to assess the width of excision margin that minimises the risk of adverse outcome from surgery, locoregional recurrence, ...distant recurrence, and death.
PRISMA guidelines were followed. MEDLINE, EMBASE, and four other databases were searched by using the term “melanoma”, “margin”, and limiting the search to randomised clinical trials (RCTs).
Seven RCTs involving 4579 patients data were analysed. No statistically significant difference was found in locoregional recurrence RR 1.09 (95%CI 0.98–1.22, p = 0.12), local recurrence RR 1.20 (95%CI 0.66–2.21, p = 0.55), in-transit metastasis RR1.30 (95%CI 0.86–1.97, p = 0.21), regional nodal metastasis RR 1.04 (95%CI 0.91–1.18, p = 0.56), distant metastasis RR 0.95 (95%CI 0.72–1.24, p = 0.68), death RR 1.00 (95%CI 0.93–1.07, p = 0.97), death from melanoma RR 1.11 (95%CI 0.96–1.28, p = 0.16), wound infection RR 1.22 (95%CI 0.68–2.17, p = 0.50), and wound dehiscence RR 0.96 (95%CI 0.54–1.71, p = 0.88) when narrow (1–2 cm) versus wide (3–5 cm) excision margins were compared. In contrast, patients with narrow excision margins had a significant reduction in complex surgical reconstruction RR 0.30 (95%CI 0.19–0.49, p < 00001). When studies were excluded because of high risk of bias the only significant difference was death due to melanoma RR 1.25 (95%CI1.01–1.55, P = 0.04).
No significant difference between narrow and wide excision margins in locoregional or distant recurrence, metastasis, death, or death due to melanoma. Wide margins (2–5 cm) increased the need for surgical reconstruction. Further studies are needed to assess optimal excision margins with regards to Breslow thickness and other prognostic factors and are in progress.
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