Summary Background The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes ...years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels. Methods We analysed individual patients' data from 15 071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints. Findings In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ2 =0·83, 95% CI 0·83–0·83 in trials without radiotherapy, and 0·87, 0·87–0·87 in trials with radiotherapy) and excellent at trial level ( R2 =0·92, 95% CI 0·88–0·95 in trials without radiotherapy and 0·99, 0·98–1·00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ2 range 0·77–0·85, dependent on the regimen being assessed) and trial level ( R2 range 0·89–0·97). In studies with data on locoregional control, individual-level correlations were good (ρ2 =0·71, 95% CI 0·71–0·71 for concurrent chemotherapy and ρ2 =0·61, 0·61–0·61 for modified vs standard radiotherapy) and trial-level correlations very good ( R2 =0·85, 95% CI 0·77–0·92 for concurrent chemotherapy and R2 =0·95, 0·91–0·98 for modified vs standard radiotherapy). Interpretation We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted. Funding Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis.
Background
Visual inspection and biopsy is the current standard of care for oral cancer diagnosis, but is subject to misinterpretation and consequently to misdiagnosis. Topically applied PARPi-FL is ...a molecularly specific, fluorescent contrast-based approach that may fulfill the unmet need for a simple, in vivo, non-invasive, cost-effective, point-of-care method for the early diagnosis of oral cancer. Here, we present results from a phase I safety and feasibility study on fluorescent, topically applied PARPi-FL. Twelve patients with a histologically proven oral squamous cell carcinoma (OSCC) gargled a PARPi-FL solution for 60 s (15 mL, 100 nM, 250 nM, 500 nM, or 1000 nM), followed by gargling a clearing solution for 60 s. Fluorescence measurements of the lesion and surrounding oral mucosa were taken before PARPi-FL application, after PARPi-FL application, and after clearing. Blood pressure, oxygen levels, clinical chemistry, and CBC were obtained before and after tracer administration.
Results
PARPi-FL was well-tolerated by all patients without any safety concerns. When analyzing the fluorescence signal, all malignant lesions showed a significant differential in contrast after administration of PARPi-FL, with the highest increase occurring at the highest dose level (1000 nM), where all patients had a tumor-to-margin fluorescence signal ratio of >3. A clearing step was essential to increase signal specificity, as it clears unbound PARPi-FL trapped in normal anatomical structures. PARPi-FL tumor cell specificity was confirmed by ex vivo tabletop confocal microscopy. We have demonstrated that the fluorescence signal arose from the nuclei of tumor cells, endorsing our macroscopic findings.
Conclusions
A PARPi-FL swish & spit solution is a rapid and non-invasive diagnostic tool that preferentially localizes fluorescent contrast to OSCC. This technique holds promise for the early detection of OSCC based on in vivo optical evaluation and targeted biopsy of suspicious lesions in the oral cavity.
Trial registration
Clinicaltrials.gov
—NCT03085147, registered on March 21st, 2017.
The prognostic value of pathologic characteristics of childhood ALK-positive anaplastic large-cell lymphomas (ALCL), such as histologic subtypes, immunophenotype, and presence of the t(2;5) ...translocation or its variants, was assessed.
All 375 patients with systemic ALK-positive ALCL included in an international trial launched by the European Intergroup for Childhood Non-Hodgkin's Lymphoma were reviewed by an international panel of pathologists based on conventional hematoxylin and eosin-stained and immunostained sections and classified according to the 2001 WHO classification.
A small-cell (SC) or lymphohistiocytic (LH) component was observed in 114 (32%) of 361 patients, whereas ALCL of common type was diagnosed in 235 (65%) of 361 patients. Regarding the histologic subtyping of patients within the two categories of ALCL (with v without SC/LH component), the concordance between the national and international reviews was quite good, with a κ index equal to 0.67 (95% CI, 0.57 to 0.75). The presence of an SC/LH component was significantly associated with a high risk of failure (hazard ratio HR, 2.0; 95% CI, 1.3 to 3.0; P = .002) in the multivariate analysis controlling for clinical characteristics, as well as the perivascular pattern (HR, 1.7; 95% CI, 1.1 to 2.7; P = .01), whereas CD3 positivity was significantly associated with a high risk of failure only in univariate analysis.
Our study, which to our knowledge includes the largest series of childhood systemic ALK-positive ALCL so far, demonstrates the adverse prognostic value of SC and/or LH morphologic features. Combining these histologic characteristics with other biologic or clinical factors might have a high potential for future risk stratification and treatment.
The use of settings such as cohorts or clinical trials with interval-censored data and clustered event times are increasingly popular designs. First, the observed outcomes cannot be considered as ...independent and random effects survival models were introduced. Second, the failure time is not known exactly but it is only known to have occurred within a certain interval.
We propose here an extension of shared frailty models to handle simultaneously the interval censoring, the clustering and also left truncation due to delayed entry in the cohort. A simulation study to evaluate the proposed method was conducted. The estimated results are used to obtain dynamic predictions for clustered patients, with interval-censored failure times and with a given history. We apply our method to the Three-City study, a prospective cohort with periodic follow-up in order to study prognostic factors of dementia. In this application scheme, couples are natural clusters and an intra-couple correlation might be present with a possible increased risk for dementia for subjects whose partner already developed incident dementia. No significant intra-couple correlation for the risk of dementia was observed before and after adjustments for covariates. We also present individual predictions of dementia underlining the usefulness of dynamic prognostic tools that can take into account the clustering.
The consideration of frailty models for interval-censoring data and left-truncated data permits useful analysis of very complex clustered data. It could help to improve estimation of the impact of proposed prognostic features in a study with clustering. We proposed here a tractable model and a dynamic prediction tool that can easily be implemented using the R package Frailtypack.
Intravitreal melphalan injections are commonly used in the treatment for intraocular retinoblastoma. This study compares retinal toxicity and ocular survival between two formulations, with and ...without propylene glycol (Alkeran vs. Evomela, respectively). A retrospective cohort study of retinoblastoma patients who received intravitreal injections of Alkeran and Evomela at 30 mug from September 2012 to January 2019 at a single tertiary care center were enrolled. Retinal toxicity was measured using electroretinogram (ERG) and compared using a multivariate analysis of 338 injections in 101 eyes of 96 patients. Ocular survival of 163 eyes in 150 patients was compared across formulations using Cox proportional hazards model. Eyes were censored at the time a patient received a dose other than 30 mug. Overall, ERG decline (mean, 95% CI) for each injection was -5.58 muV (-7.17, -3.99). No significant differences in ERG decrement were found between Alkeran (with alcohol) -5.52uV (-6.99, -4.05). and Evomela (without alcohol) -5.65uV (-8.31 to -2.98) formulations (p = 0.93). Ocular survival at 24 months was 93.6% (95% CI 86.2, 97.1) with alcohol and 91.7% (95% CI 53.9, 98.8) without alcohol. The hazard ratio (HR) for without vs with alcohol was 0.50 (95% CI 0.06 to 4.07); no significant difference in ocular survival was found between formulations (p = 0.52) No differences were found in retinal toxicity and ocular survival between 30 mug intravitreal injections of Alkeran or Evomela for intraocular retinoblastoma. Given the increased stability of Evomela, intravitreal treatment could be expanded to centers without the ability to supply Alkeran due to its shorter safety window; however, Alkeran is less expensive. For those with existing infrastructure, Alkeran is a comparable, cost-effective alternative.
To define the tolerability and outcome of allogeneic hematopoietic stem cell transplant (allo-HSCT) following CAR T-cell therapy, we retrospectively reviewed pediatric/young adult patients with ...relapsed/refractory B-ALL who underwent this treatment. Fifteen patients (median age 13 years; range 1-20 years) with a median potential follow-up of 39 months demonstrated 24-month cumulative incidence of relapse, cumulative incidence of TRM, and OS of 16% (95% CI: 0-37%), 20% (95% CI: 0-40%), and 80% (95% CI: 60-100%), respectively. Severe toxicity following CAR T cells did not impact OS (p = 0.27), while greater time from CAR T cells to allo-HSCT (>80 days) was associated with a decrease in OS. In comparing CD34-selected T-cell depleted (TCD; n = 9) vs unmodified (n = 6) allo-HSCT, the cumulative incidence of relapse, TRM, and OS at 24 months was 22% (95% CI: 0-49%) vs 0% (p = 0.14), 0% vs 50% 95% CI: 10-90% (p = 0.02) and 100% vs 50% 95% CI: 10-90% (p = 0.02). In this small cohort of patients, CAR T cells followed by a CD34-selected TCD allo-HSCT appears to result in less TRM and favorable OS when compared with unmodified allo-HSCT. There was no evidence that disease control was impacted by the type of consolidative allo-HSCT, which demonstrates the feasibility of this approach.
The impact of adding vinblastine to a 4-month chemotherapy regimen, based on the Non-Hodgkin's Lymphoma Berlin-Frankfurt-Münster 90 protocol, in childhood high-risk anaplastic large-cell lymphoma ...(ALCL) was assessed.
Children and adolescents with high-risk ALCL, defined by mediastinal, lung, liver, spleen, or skin involvement, were eligible for the trial. After a prephase and one chemotherapy course, patients were randomly assigned to receive either five further chemotherapy courses without vinblastine or the same regimen with one vinblastine injection (6 mg/m(2)) during each course followed by weekly vinblastine to complete a total of 1 year of treatment. The primary end point was event-free survival (EFS), analyzed on the intent-to-treat population.
Between November 1999 and June 2006, 110 patients were randomly assigned to receive vinblastine, and 107 were randomly assigned not to receive vinblastine. Median follow-up was 4.8 years. Patients in the vinblastine arm had a significantly reduced risk of events during the first year (hazard ratio HR = 0.31; 95% CI, 0.15 to 0.67; P = .002) followed by an increased risk thereafter (HR = 4.98; 95% CI, 1.65 to 15.0; P = .003). Consequently, EFS at 1 year differed significantly (91% in the vinblastine group v 74% in the no-vinblastine group), with no difference at 2 years (73% and 70%, respectively). Overall EFS curves did not differ significantly (HR = 0.91; 95% CI, 0.55 to 1.5; P = .71). Thirty-one percent of weekly doses of vinblastine were reduced as a result of hematologic toxicity, although vinblastine was discontinued for toxicity in only three patients.
Adding vinblastine during induction and as maintenance for a total treatment duration of 1 year significantly delayed the occurrence of relapses but did not reduce the risk of failure.
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