RESUMO
PURPOSE: Progression-free survival (PFS)-2, defined as the time from randomization to progression on second-line therapy, is potentially a more reliable surrogate than PFS for overall survival (OS), but will require longer follow-up and a larger sample size. We sought to compare the validity and efficiency, defined as proportional increase in follow-up time and sample size, of PFS-2 to PFS. METHODS: We performed an electronic search to identify randomized trials of advanced solid tumors reporting PFS, PFS-2, and OS as prespecified end points. Only studies that had protocols that defined measurement of PFS-2 and follow-up for patients after first disease progression were included. We compared correlations in the relative treatment effect for OS with PFS and PFS-2. We reconstructed individual patient data from survival curves to estimate time to statistical significance (TSS) of the relative treatment effect. We further computed the sample size (person-year [PY] follow-up) required to reach statistical significance. RESULTS: Across the 42 analysis units and 21,255 patients, the correlation of the relative treatment effect between OS and PFS-2, r, was 0.70 (95% CI, 0.41 to 0.80) and r = 0.46 (95% CI, 0.26 to 0.74) for OS and PFS. The median differences in TSS between OS with PFS, OS with PFS-2, and PFS with PFS-2 were 16.59 (95% CI, 4.48 to not reached [NR]), 10.0 (95% CI, 2.2 to NR), and 4.31 (95% CI, 2.92 to 13.13) months, respectively. The median difference in PYs required to reach statistical significance for PFS-2 over PFS was 156 (95% CI, 82 to 500) PYs, equivalent to an estimated median 12.7% increase in PYs. CONCLUSION: PFS-2 offers improved correlation with OS than PFS with a modest increase in follow-up time and sample size. PFS-2 should be considered as a primary end point in future trials of advanced cancers.
Assuntos
Neoplasias , Humanos , Biomarcadores , Neoplasias/mortalidade , Neoplasias/terapia , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: This study investigated whether there was a change in acute appendicitis, appendicectomy admissions or disease severity during the 2020 lockdown period in NSW. METHODS: A retrospective before-and-after study was undertaken of patients admitted to two Sydney hospitals (St. Vincent's and Liverpool Hospitals) who had appendicectomy for presumed acute appendicitis and patients who had confirmed appendicitis but did not undergo surgery. Study periods were the 2020 lockdown period (15 March-15 May 2020), the corresponding period in the previous year, and the 1-month after these periods. Patients were classified as having no, mild or severe appendicitis using operation and histopathological reports. RESULTS: (Thirty-six percent) fewer patients were admitted with acute appendicitis during the lockdown period compared with the previous year with a substantial reduction in normal/mild appendicitis presentations (OR 0.56, 95% CI 0.34-0.93, P = 0.03). There were 46% fewer patients with mild appendicitis during lockdown (56) compared with the previous year (103); numbers of patients with severe appendicitis were very similar (46 vs. 51). There was no increase in number of admissions with severe appendicitis, or in the time from onset of symptoms to admission, in the month following lockdown. CONCLUSION: Compared with the previous year, there were markedly fewer admissions with appendicitis during lockdown, with no evidence of a shift to more cases of severe appendicitis nor delayed presentation in the post-lockdown period. It is plausible that some patients with mild appendicitis may have recovered without hospitalization, supporting the importance of implementing trials on non-surgical management of appendicitis.
Assuntos
Apendicite , COVID-19 , Doença Aguda , Apendicectomia , Apendicite/diagnóstico , Apendicite/epidemiologia , Apendicite/cirurgia , COVID-19/epidemiologia , Controle de Doenças Transmissíveis , Hospitalização , Hospitais , Humanos , Estudos RetrospectivosRESUMO
BACKGROUND: Overall survival (OS) is the gold-standard end point for oncology trials. However, the availability of multiple therapeutic options after progression and crossover to receive investigational agents confound and delay OS data maturation. Progression-free survival 2 (PFS-2), defined as the time from randomization to progression on first subsequent therapy, has been proposed as a surrogate for OS. Using a meta-analytic approach, the authors aimed to assess the association between OS and PFS-2 and compare this with progression-free survival 1 (PFS-1) and the objective response rate (ORR). METHODS: An electronic literature search was performed to identify randomized trials of systemic therapies in advanced solid tumors that reported PFS-2 as a prespecified end point. Correlations between OS and PFS-2, OS and PFS-1, and OS and ORR as hazard ratios (HRs) or odds ratios (ORs) were assessed via linear regression weighted by trial size. RESULTS: Thirty-eight trials were included, and they comprised 19,031 patients across 8 tumor types. PFS-2 displayed a moderate correlation with OS (r = 0.67; 95% confidence interval [CI], 0.08-0.69). Conversely, correlations of ORR (r = 0.12; 95% CI, 0.00-0.13) and PFS-1 (r = 0.21; 95% CI, 0.00-0.33) were poor. The findings for PFS-2 were consistent for subgroup analyses by treatment type (immunotherapy vs nonimmunotherapy: r = 0.67 vs 0.67), survival post progression (<12 vs ≥12 months: r = 0.86 vs 0.79), and percentage not receiving subsequent treatment (<50% vs ≥50%: r = 0.70 vs 0.63). CONCLUSIONS: Across diverse tumors and therapies, the treatment effect on PFS-2 correlated moderately with the treatment effect on OS. PFS-2 performed consistently better than PFS-1 and ORR, regardless of postprogression treatment and postprogression survival. PFS-2 should be included as a key trial end point in future randomized trials of solid tumors.
Assuntos
Neoplasias , Biomarcadores , Intervalo Livre de Doença , Humanos , Imunoterapia , Intervalo Livre de Progressão , Modelos de Riscos ProporcionaisRESUMO
PURPOSE: Response Evaluation Criteria in Solid Tumors (RECIST) has limitations but remains the conventional approach for tumor assessments. We explored whether circulating tumor DNA (ctDNA) can be incorporated into RECIST to provide a more robust measure of tumor response in advanced EGFR-mutant NSCLC. PATIENTS AND METHODS: In FASTACT-2, patients with advanced NSCLC received platinum/gemcitabine intercalated with erlotinib or placebo. EGFR mutation (tumor and plasma ctDNA) was detected using cobas v2. Patients selected for this hypothesis-generating analysis had EGFR mutations (on either tumor or plasma) at baseline and evaluable week 8 plasma EGFR. Week 8 ctDNA and radiologic response status were correlated with survival using landmark cox regression analyses. RESULTS: Of the original 451 patients, 86 (19.1%) were eligible for this analysis. 73% (n = 63) had detectable ctDNA at baseline. At week 8, 40% (n = 34) had radiologic partial response (PR), 60% (n = 52) had stable disease (SD); 80% (n = 69) had a ctDNA response (undetectable ctDNA). In patients who had initial PR and undetectable ctDNA, 93% (28/30) had ongoing PR subsequently at week 16. The median duration of response was 14.9 months. In patients with SD and undetectable ctDNA at week 8, 28% had radiological PR at week 16. Amongst those with PR at week 8, survival outcomes for those with undetectable vs detectable ctDNA were not statistically significant (PFS HR 0.49, 95%CI 0.16-1.48, p = 0.21; OS HR 0.39, 95%CI 0.13-1.19, p = 0.10). Amongst those with SD at week 8, there was significantly longer survival for those with undetectable vs detectable ctDNA (PFS HR 0.27, 95% CI 0.13-0.57, p < 0.0001; OS HR 0.40, 95% CI 0.20-0.80, p = 0.009). CONCLUSION: In patients with SD, undetectable ctDNA at week 8 correlated with survival improvement. Both radiologic and ctDNA responses are prognostic of PFS. Incorporation of ctDNA with RECIST may improve tumor response assessment in EGFR-mutant NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , DNA Tumoral Circulante , Neoplasias Pulmonares , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , MutaçãoRESUMO
PURPOSE: Many immune checkpoint inhibitors (ICIs) have been approved on the basis of tumor response end points in nonrandomized trials, including objective response rate (ORR) and duration and depth of response. We aimed to assess the validity of these end points as surrogate end points for overall survival (OS) in patients with advanced solid tumors treated with ICIs at trial and treatment arm levels. METHODS: ICI trials in advanced solid cancers published between January 1, 2000, and March 31, 2020, were included. Correlations between ORR, durable response (DR) of ≥ 6 months, complete response (CR), and OS were assessed for treatment comparisons (trial-level) and for patients receiving ICI (arm-level), using weighted linear regression. RESULTS: Sixty-three trials were eligible, including 58 randomized controlled trials and 20 nonrandomized controlled trials (78 ICI arms and 30,815 patients). The majority were phase III (63%), and OS was the most common primary end point (40%). In relative treatment comparisons, correlations between ORR risk ratio and OS hazard ratio (HR), 6-month DR ratio and OS HR, and CR ratio and OS HR were r = 0.58, r = 0.62, and r = 0.42, respectively. Exploratory studies in melanoma, non-small-cell lung cancer, and other tumors showed similar results, although 6-month DR ratio was strongly correlated with OS HR (r = 0.89). Within ICI arms only, correlations between ORR and 12-month OS, 6-month DR and 12-month OS, and CR and 12-month OS were r = 0.76, r = 0.84, and r = 0.50, respectively, in all eligible trials. CONCLUSION: Relative measures of tumor response (ORR, 6-month DR, and CR) are poor surrogate end points for OS in ICI studies. However, ORR and 6-month DR are prognostic of 12-month OS in ICI studies supporting their use for screening activity of novel agents in early-phase nonrandomized trials.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Inguinal hernias are a common pathology that often requires surgical management. The use of groin ultrasound (GU) to investigate inguinal hernias is a growing area of concern as an inefficient use of healthcare resources. Our aim was to assess changes in the rates of GU and the impact on surgical practice. METHODS: Medicare Item Reports and the Australian Institute of Health and Welfare Database were used to estimate annual GU and inguinal hernia repair (IHR) rates per 100 000 population for the period 2000/2001-2017/2018. Pearson's correlation coefficients and linear regression analyses were performed to assess associations between these variables. RESULTS: Over the 18-year period, GU rates increased 13-fold from 88 to 1174 per 100 000 population. Overall, total IHR rates decreased from 217 to 192 per 100 000. Overall, unilateral IHR rates have decreased (182-146 per 100 000), bilateral IHRs have increased (35-46 per 100 000), laparoscopic IHR has increased (30-86 per 100 000) and open surgery has declined (187-106 per 100 000). The increase in GU rates were strongly associated with the decrease in unilateral (r = -0.936, P = <0.001) and increase in bilateral IHR rates (r = 0.924, P = <0.001). CONCLUSION: The use of GU has increased substantially, potentially representing an unnecessary cost to the healthcare system. Rising GU rates are not associated with an increase in IHR, however, may contribute to the increasing rates of bilateral IHRs. This study supports the opinion that more extensive clinical and health policy initiatives are needed in Australia to address this health issue.
Assuntos
Hérnia Inguinal , Laparoscopia , Idoso , Austrália/epidemiologia , Hérnia Inguinal/diagnóstico por imagem , Hérnia Inguinal/epidemiologia , Hérnia Inguinal/cirurgia , Herniorrafia , Humanos , Programas Nacionais de SaúdeRESUMO
BACKGROUND: There is uncertainty on how multiparametric MRI (mpMRI) and MRI-targeted biopsy (MRI-TB) can be best used to manage low-risk prostate cancer patients on Active Surveillance (AS). We performed a scoping review to evaluate the benefits and harm associated with four different biopsy scenarios in which mpMRI can be implemented in AS. METHODS: Medline, Embase and Cochrane Library databases (1 January 2013-18 September 2020) were searched. Included studies were on men with low-risk prostate cancer enrolled in AS, who had mpMRI ± MRI-TB and standard prostate biopsy (systematic transrectal ultrasound or transperineal saturation biopsy), at confirmatory or follow-up biopsy. Primary outcomes were the number of Gleason score upgrades and biopsies avoided. RESULTS: Eight confirmatory biopsy studies and three follow-up biopsy studies were included. Compared to the benchmark of using standard biopsy (SB) for all men, the addition of MRI-TB increased the detection of Gleason score upgrades at both confirmatory (6/8 studies) and follow-up biopsy (3/3 studies), with increments of 1.7-11.8 upgrades per 100 men. 6/7 studies suggested that the use of a positive mpMRI to triage men for MRI-TB or SB alone would detect fewer Gleason score upgrades than benchmark at confirmatory biopsy, but the combination of MRI-TB and SB would detect more upgrades than the benchmark. For follow-up biopsy, the evidence on mpMRI triage biopsy scenarios was inconclusive due to the small number of included studies. CONCLUSIONS: The addition of MRI-TB to benchmark (SB for all men) maximises the detection of Gleason score upgrades at confirmatory and follow-up biopsy. When the use of mpMRI to triage men for a biopsy is desired, the combination of MRI-TB and SB should be considered for men with positive mpMRI at confirmatory biopsy. The evidence on mpMRI triage scenarios was inconclusive in the follow-up biopsy setting.
Assuntos
Biópsia Guiada por Imagem/métodos , Imageamento por Ressonância Magnética Multiparamétrica/métodos , Neoplasias da Próstata/patologia , Ultrassonografia de Intervenção/métodos , Conduta Expectante/normas , Humanos , Masculino , Gradação de Tumores , Prognóstico , Neoplasias da Próstata/terapiaRESUMO
OBJECTIVES: To assess the clinical utility of quantitative PCR (qPCR) assays, a routinely used test for detection of epidermal growth factor receptor (EGFR) mutation in circulating tumour DNA (ctDNA) in treatment-naive advanced lung cancer patients. MATERIALS AND METHODS: We performed a meta-analysis of randomized controlled trials (RCTs) with individual patient data. Eligible RCTs compared EGFR-tyrosine kinase inhibitor (EGFR-TKI) and chemotherapy in first line setting for advanced lung cancer, and included tumour EGFR+ (tEGFR+) with paired ctDNA results using real-time (quantitative) PCR. We assessed the proportion of tEGFRâ¯+â¯detected by ctDNA, and compared the effectiveness of EGFR-TKI versus chemotherapy in ctDNAâ¯+â¯and ctDNA- subgroups. RESULTS: Six randomized clinical trials included 1058 tEGFRâ¯+â¯patients with paired baseline EGFR ctDNA testing. Of these, 460 (43 %) tested ctDNA- (ctDNA+ 57 %). Progression-free survival was longer for EGFR-TKI versus chemotherapy for both ctDNA+ (HR 0.28; 95 % CI 0.22-0.36, pâ¯<â¯0.00001) and ctDNA- subgroups (HR 0.37; 95 % CI 0.28-0.49, pâ¯<â¯0.00001; p-interactionâ¯=â¯0.14). Objective response rate (odds ratio 6.21; 95 % CI 4.25-9.07, pâ¯<â¯0.00001 vs 6.44; 95 % CI 4.21-9.87, pâ¯<â¯0.00001) and overall survival (HR 0.82; 95 % CI 0.70-1.04 vs HR 0.77; 95CI% 0.59-1.00) similarly favoured EGFR-TKI in both ctDNAâ¯+â¯and ctDNA- subgroups respectively. CONCLUSION: Our findings indicate that approximately two in five tissue EGFR mutation-positive patients will not be detected using a qPCR assay, but would still potentially benefit from highly effective EGFR-TKI treatment. A negative EGFR ctDNA result via qPCR testing is therefore insufficient to exclude benefit from EGFR-TKI. Attempts should be made to repeat EGFR testing with a tissue biopsy in this patient group. As newer ctDNA assays with better sensitivity become available, the clinical impact for any false negatives will remain an important consideration.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Biomarcadores Tumorais , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Reação em Cadeia da Polimerase , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Objectives This study estimated the frequency of ultrasounds ordered for clinically obvious inguinal hernias in patients referred to surgeons and evaluated the clinical value of ultrasonography for this patient population. Methods The present study was a prospective diagnostic and therapeutic impact study conducted in district, rural and tertiary referral hospitals in Sydney, Hawkesbury and Wagga Wagga, Australia. The study included adult patients (≥18 years of age) who had been referred to one of the participating surgeons for an elective inguinal hernia repair. The study determined the proportion of: (1) patients who underwent an inguinal hernia repair for a clinically obvious hernia and also had an ultrasound; (2) ultrasounds ordered by general practitioners (GPs); and (3) these ultrasounds that altered diagnosis and consequent surgical management from the surgeon's perspective. Results In all, 144 participants were included in this study. Of these patients, 134 had a clinically apparent inguinal hernia on physical examination, and 63 of 133 patients (47%; 95% confidence interval (CI) 39-56%) underwent an ultrasound (information was missing for one patient). Overall 68 ultrasounds were ordered, with 63 ordered by GPs. Following the ultrasound, surgeons reported that one patient (1%; 95% CI 0-8 patients) had an altered diagnosis, and five patients (8%; 95% CI 3-17 patients) had altered management. Conclusion This study found that almost one in two patients referred to a surgeon with a clinically obvious inguinal hernia also underwent a groin ultrasound. These studies represent an unnecessary waste of limited healthcare resources and low-value medical care because they rarely affect the final diagnosis or surgical management. What is known about the topic? Inguinal hernias are one of the most common presenting complaints to surgeons in Australia. Currently, there are no accepted Australian guidelines for the diagnosis of inguinal hernias. Ultrasound investigation has been shown to aid diagnosis when there is uncertainty after physical examination. There is increasing concern regarding low-value medical care that contributes to a significant waste of healthcare resources within Australia. The use of ultrasounds for the diagnosis of clinically apparent inguinal hernias is a potential area of concern. What does this paper add? This paper is the first to estimate the frequency of ultrasounds being ordered for clinically apparent inguinal hernias. The study shows that approximately one in two patients who present to surgeons with a clinically obvious inguinal hernia have an ultrasound. GPs were the major referral source for these ultrasounds. Finally, these ultrasounds rarely altered final diagnosis or management for patients who presented to surgeons for definitive management. What are the implications for practitioners? This study confirms that ultrasounds for clinically obvious inguinal hernias represent low-value medical care. Based on the results of this study, it is estimated that the cost to Medicare for unnecessary ultrasounds is approximately A$2.5 million per annum. Although it is beyond the scope of the present study to comment on the reasons for the apparent overinvestigation of ultrasounds for inguinal hernias, the findings suggest that clinical guidelines may help address this problem.
Assuntos
Hérnia Inguinal , Cirurgiões , Adulto , Idoso , Austrália/epidemiologia , Hérnia Inguinal/diagnóstico por imagem , Hérnia Inguinal/cirurgia , Humanos , Programas Nacionais de Saúde , Estudos Prospectivos , Encaminhamento e Consulta , UltrassonografiaRESUMO
Importance: Progression-free survival (PFS) rate at 6 months has been proposed as a potential surrogate for overall survival (OS) rate at 12 months for immune checkpoint inhibitor (ICI) trials but requires further assessment for validation. Objective: To validate 6-month PFS and objective response rate (ORR) as estimators of 12-month OS in the ICI arms of randomized clinical trials (RCTs). Data Sources: Electronic databases (Medline, EMBASE, and the Cochrane Central Register of Controlled Trials) were searched for ICI RCTs published between January 2000 and June 2019. Study Selection: Eligible studies were phase 2 and phase 3 ICI RCTs in advanced solid cancers that reported ORR, PFS, and OS. A total of 99 articles (from 60 studies) of 2502 articles were selected by consensus. Data Extraction and Synthesis: Data were screened and extracted independently. Estimation models for 12-month OS and to assess correlation coefficient between end points were developed using linear regression. Data were extracted in July 2019, and analyses were conducted in September 2019. This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: Validation of previously reported 6-month PFS and ORR estimation models for 12-month OS using contemporary RCTs. Calibration of 6-month PFS and ORR model-estimated vs observed 12-month OS in ICI arms were assessed by correlation coefficient (r) and weighted Brier scores. Secondary analyses were performed for subgroups (ie, ICI-only, ICI-combination, line of therapy, programmed cell death 1 ligand 1 selected, and unselected). Results: Data from 60 RCTs with 74 experimental ICI arms were used. The development data set included 25 arms from studies published January 2000 to January 2017. The estimation model for 12-month OS using 6-month PFS was: (1.06 × PFS6) + 0.16 + (0.04 × melanoma) - (0.03 × NSCLC) + (0 × other tumors), in which PFS6 indicates 6-month PFS and NSCLC indicates non-small cell lung cancer. The estimation model for 12-month OS using ORR was (0.15 × ORR) + 0.52 + (0 × melanoma) - (0.02 × NSCLC) - (0.01 × other tumors). A total of 49 arms from studies published after January 2017 to June 2019 formed the validation data set. When the models were applied on the validation data set, calibration between the 6-month PFS model estimated vs observed 12-month OS was good (r = 0.89; Brier score, 0.008), but poor for the ORR model (r = 0.47; Brier score, 0.03). Findings were similar across all subgroups. Conclusions and Relevance: The findings of this study suggest that the estimation model using 6-month PFS could reliably estimate 12-month OS in ICI trials. This study could assist in better selection and prioritization of ICI agents for testing in RCTs based on phase 2 single-arm RCT results.
Assuntos
Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias , Humanos , Estadiamento de Neoplasias , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Avaliação de Resultados em Cuidados de Saúde/normas , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos TestesRESUMO
Background: Recent trials of novel agents in 'rare' molecular subtypes of non-small cell lung cancer (NSCLC) have used single-arm trial designs and benchmarked outcomes against historical controls. We assessed the consistency of historical control outcomes using docetaxel data from published NSCLC randomized controlled trials (RCTs).Material and methods: Advanced NSCLC RCTs including a docetaxel monotherapy arm were included. Heterogeneity in tumor objective response rates (ORRs), progression-free survival (PFS) and overall survival (OS), and correlations between outcomes and year of trial commencement were assessed.Results: Among 63 trials (N = 10,633) conducted between 2000 and 2017, ORR ranged from 0% to 26% (I2 = 76.1%, pheterogeneity < .0001). Mean of the median PFS was 3.0 months (range: 1.4-6.4), 3-month PFS ranged from 25% to 85% (I2 = 86.0%, pheterogeneity < .0001). Mean of the median OS was 9.1 months (range: 4.7-22.9), 9-month OS ranged from 23% to 79% (I2 = 83.0%, pheterogeneity < .0001). Each later year of trial commencement was associated with 0.3% (p = .046), 0.5% (p = .11) and 0.9% (p = .001) improvement in ORR, 3-month PFS and 9-month OS rates, respectively.Conclusions: There was significant heterogeneity and an improving trend in docetaxel outcomes across trials conducted over 20 years. Benchmarking biomarker-targeted agents against historical controls may not be a valid approach to replace RCTs. Innovative study designs involving a concurrent control arm should be considered.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Benchmarking , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Docetaxel/administração & dosagem , Feminino , Estudo Historicamente Controlado , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVES: There is uncertainty whether older patients derive a similar benefit from immune checkpoint inhibitors (ICI) as younger patients. We performed a meta-analysis of ICI trials in advanced cancers to better estimate treatment benefit in the older population. MATERIALS AND METHODS: We performed an electronic search for randomized trials of ICI, either as monotherapy or in combination with other agents. Hazard ratios (HR) for subgroups defined by different age cut-offs were extracted. Pooled overall survival (OS) treatment estimates were calculated using the inverse variance weighted method. RESULTS: In nineteen trials comparing ICI monotherapy versus non-ICI treatment, there was no significant treatment-age interaction (ageâ¯≥â¯65â¯years: Nâ¯=â¯6064, HR 0.73; ageâ¯<â¯65â¯years: Nâ¯=â¯7250, HR 0.79; P-interactionâ¯=â¯0.27). Findings were similar at older age cut-offs of 70â¯years (ageâ¯≥â¯70â¯years: Nâ¯=â¯433, HRâ¯=â¯0.93; ageâ¯<â¯70â¯years: Nâ¯=â¯169, HRâ¯=â¯0.95; P-interactionâ¯=â¯0.91) and 75â¯years (ageâ¯≥â¯75â¯years: Nâ¯=â¯139, HRâ¯=â¯0.75; ageâ¯<â¯75â¯years: Nâ¯=â¯1133, HRâ¯=â¯0.61; P-interactionâ¯=â¯0.72) respectively, and for trials of ICI combination therapy. CONCLUSION: ICI therapy improves OS in both younger and older patients with advanced cancers, and the magnitude of improvement does not depend on age. Patient selection for ICI therapy should be done based on performance status and adequate organ function independently of age.
Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Idoso , Humanos , Neoplasias/tratamento farmacológicoRESUMO
We investigate if PD-L1 expression and other clinical characteristics predict chemoimmunotherapy (CIT) benefits versus chemotherapy in advanced non-small-cell lung cancer. We performed a meta-analysis of randomized controlled trials of CIT versus chemotherapy identified through electronic searches. In seven randomized controlled trials (n = 4170), CIT prolonged progression-free survival over chemotherapy (hazard ratio [HR]: 0.62; 95% CI: 0.58-0.67; p < 0.00001). The treatment benefits differed between PD-L1-high (HR: 0.41; 95% CI: 0.34-0.49) and PD-L1 low (HR: 0.63; 95% CI: 0.55-0.72; interaction-p = 0.00002) and PD-L1-high and PD-L1-negative (HR: 0.72; 95% CI: 0.65-0.80; interaction-p < 0.00001). Similar benefits were observed regardless of gender, EGFR/ALK status and histological subtype. PD-L1 status is predictive of CIT benefit and may assist patient selection and design of future trials.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Seleção de Pacientes , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores SexuaisRESUMO
OBJECTIVE: The aim of this study was to quantify false-positive and incidental findings from annual surveillance imaging in asymptomatic, American Joint Committee on Cancer stage III melanoma patients. METHODS: This was a cohort study of patients treated at Melanoma Institute Australia (2000-2015) with baseline computed tomography (CT) or positron emission tomography (PET)/CT imaging and at least two annual surveillance scans. False-positives were defined as findings suspicious for melanoma recurrence that were not melanoma, confirmed by histopathology, subsequent imaging, or clinical follow-up, while incidental findings were defined as non-melanoma-related findings requiring further action. Outcomes of incidental findings were classified as 'benign' if they resolved spontaneously or were not seriously harmful; 'malignant' if a second malignancy was identified; or 'other' if potentially harmful. RESULTS: Among 154 patients, 1022 scans were performed (154 baseline staging, 868 surveillance) during a median follow-up of 85 months (interquartile range 56-112); 57 patients (37%) developed a recurrence. For baseline and surveillance imaging, 124 false-positive results and incidental findings were identified in 81 patients (53%). The frequency of these findings was 5-14% per year, and an additional 181 tests, procedures, and referrals were initiated to investigate these findings. The diagnosis was benign in 109 findings of 124 findings (88%). Fifteen patients with a benign finding underwent an unnecessary invasive procedure. Surveillance imaging identified distant metastases in 20 patients (13%). CONCLUSION: False-positive results and incidental findings occur in at least half of all patients undergoing annual surveillance imaging, and the additional healthcare use is substantial. These findings persist over time. Clinicians need to be aware of these risks and discuss them with patients, alongside the expected benefits of surveillance imaging.
Assuntos
Achados Incidentais , Melanoma/patologia , Recidiva Local de Neoplasia/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Reações Falso-Positivas , Feminino , Seguimentos , Humanos , Masculino , Melanoma/diagnóstico por imagem , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Estadiamento de Neoplasias , Estudos Prospectivos , Compostos RadiofarmacêuticosRESUMO
PURPOSE: Adding cyclin-dependent kinase (CDK) 4/6 inhibitor to endocrine therapy improves progression-free survival (PFS) in advanced breast cancer but the impact of ethnicity on efficacy and toxicity is unclear. We aimed to estimate the relative treatment efficacy and toxicity of endocrine therapy with and without CDK4/6 inhibitors, and compare between Asian/non-Asian subgroups. METHOD: This meta-analysis included published first-line randomized trials comparing CDK4/6 inhibitor-endocrine therapy versus endocrine monotherapy. Hazard ratios (HR) and 95% confidence intervals (CI) for the overall population and Asian/non-Asian subgroups were extracted. The inverse-variance-weighted method was used to pool treatment estimates of PFS. RESULTS: Four trials (N = 2499) were included. Patients received combination CDK4/6 inhibitor-endocrine therapy (N = 1441; ribociclib, [46.4%]; palbociclib, [30.8%]; or abemaciclib, [22.8%]) versus endocrine monotherapy (N = 1058). CDK4/6 inhibitor-endocrine therapy was associated with prolonged PFS compared with endocrine monotherapy (HR 0.56; 95% CI 0.50-0.62). In Asians (N = 492), PFS HR was 0.39 (95% CI 0.29-0.51, P < 0.0001). In non-Asians (N = 2007), PFS HR was 0.62 (95% CI 0.54-0.71, P < 0.0001). There was a significant treatment-by-ethnicity interaction (P = 0.002). Toxicity data by ethnic subgroup were only available from two trials (n = 1334) with no convincing evidence that the risk of toxicity between CDK4/6 inhibitor-endocrine therapy and endocrine monotherapy varied by ethnicity. CONCLUSION: Adding CDK4/6 inhibitor to endocrine therapy prolongs PFS compared to endocrine therapy alone as first-line treatment in advanced breast cancer. The magnitude of PFS benefit is ethnicity-dependent but there is no interethnic differences in relative treatment-related toxicities. These findings may assist in the design and interpretation of trials, inform economic analyses, and stimulate pharmacogenomic research.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/etnologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Povo Asiático , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Neoplasias da Mama/mortalidade , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Intervalo Livre de Progressão , Purinas/administração & dosagem , Purinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversosRESUMO
INTRODUCTION: Traditionally, marked tumor shrinkage has been assumed to portend better outcome. We investigated whether depth of tumor response was associated with improved survival outcomes in advanced EGFR-mutant NCLC. METHODS: Individual patient data from randomized trials (EURTAC, IPASS, ENSURE, LUX-Lung 3, and LUX-Lung 6) were used. The association of depth of response with progression-free survival (PFS) and overall survival was examined using landmark analyses. Depth of response based on radiologic assessments at 6 weeks and 12 weeks was calculated as the relative changes in the sum of the longest diameters of the target lesions from baseline. RESULTS: Of 1081 evaluable patients at 6 weeks with no disease progression, 71.2% achieved Response Evaluation Criteria in Solid Tumors response. Using a landmark analysis, EGFR-TKI was more effective than chemotherapy (PFS hazard ratio = 0.36, p < .0001); and was associated with greater mean tumor shrinkage than chemotherapy (35.1% versus 18.5%, p < .0001). However, there was no significant difference in the relative PFS benefit between treatment groups across the entire spectrum of tumor shrinkage (p = .18 for test of interaction between treatment and continuously measured depth of response). Depth of response at 6 weeks was not associated with PFS when adjusted for treatment effect (hazard ratio = 0.96, p = .78). Similar results were obtained for 12-week landmark analysis and for OS outcome. CONCLUSIONS: The PFS advantage of EGFR-TKI over chemotherapy in advanced EGFR mutant NCLC is not explained by depth of response at 6 or 12 weeks. It should not be used as a surrogate of benefit in future trials or routine clinical decision making.
Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Intervalo Livre de Doença , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
IMPORTANCE: Checkpoint inhibitors have a unique mechanism of action that differs from chemotherapy or targeted therapies. The validity of objective response rate (ORR) as a surrogate for progression-free survival (PFS) and overall survival (OS) in checkpoint-inhibitor trials is uncertain. OBJECTIVE: To determine the types of primary end points used in phase 2 checkpoint-inhibitor trials, and to assess the strength of associations for ORR with PFS and OS. DATA SOURCES: Trials listed in electronic databases from 2000 to 2017 (PREMEDLINE, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials). STUDY SELECTION: Advanced solid cancers in phase 2 and phase 3 trials. DATA EXTRACTION AND SYNTHESIS: Correlations between ORR odds ratios and hazard ratios (HRs) for PFS and OS were examined for randomized comparisons. Within checkpoint-inhibitor treatment arms, correlations for ORR with 6-month PFS and 12-month OS rates were examined. All analyses were weighted by trial size. Multivariable models to predict 6-month PFS and 12-month OS rates from ORR were developed and their performance validated in an independent sample of trials. MAIN OUTCOMES AND MEASURES: Correlation coefficient (r) of ORR with PFS and OS. RESULTS: Of 87 phase 2 trials identified, ORR was the most common (52 [60%]) primary end point. Twenty randomized clinical trials with 25 treatment comparisons were identified. Checkpoint-inhibitor therapy was associated with pooled ORR of 24% (95% CI, 18%-31%). For randomized comparisons, r between ORR odds ratio and PFS HR was 0.63 (95% CI, 0.35-0.89), ORR odds ratio and OS HR was 0.57 (95% CI, 0.23-0.89), and between PFS HR and OS HR was 0.42 (95% CI, 0.04-0.81). Within the checkpoint-inhibitor arms, r correlation coefficients between ORR with 6-month PFS, ORR with 12-month OS, and 6-month PFS with 12-month OS were 0.37 (95% CI, -0.06 to 0.95), 0.08 (95% CI, -0.17 to 0.70), and 0.74 (95% CI, 0.57-0.92), respectively. In validation, when 6-month PFS was used to predict 12-month OS, there was a good calibration between actual and predicted 12-month OS. When ORR was used to predict 6-month PFS and 12-month OS rates, respectively, the actual vs predicted rates calibrated poorly. CONCLUSIONS AND RELEVANCE: In checkpoint-inhibitor trials, ORR correlated poorly with OS. For future phase 2 studies, 6-month PFS rate is recommended as an end point.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Farmacológicos/análise , Biomarcadores Tumorais/análise , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Biomarcadores Tumorais/isolamento & purificação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Progressão da Doença , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias/mortalidade , Neoplasias/patologia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: We performed a meta-analysis to quantify toxic death, adverse events (AEs) and treatment discontinuation due to AEs from checkpoint inhibitors (CI). METHODS: We searched for randomized trials with adequate reporting for toxicity outcomes. Pooled risk ratios were estimated for CI versus chemotherapy or different combinations of these agents. RESULTS: Twenty trials of five different cancers with 10 794 patients with performance status 0 or 1 were identified. Toxic deaths from CI were infrequent (0.6%). Treatment discontinuations were less frequent for programmed-death-1 (PD-1) or PD-ligand-1 (PD-L1) inhibitors (5.8% vs 13.3%, P < 0.001) and cytotoxic-T-lymphocyte-associated-antigen-4 (CTLA-4) inhibitors (6.2% vs 11.4%, P = 0.002) than chemotherapy. PD-1/PD-L1 inhibitors had less grade 3, 4, and 5 (G3/4/5) AEs than chemotherapy (13.8% vs 39.8%, P < 0.001) or CTLA-4 inhibitors (13.4% vs 22.8%, P < 0.001). Combination CI had higher discontinuation (37.8% vs 11.6%, P < 0.001) and higher G3/4/5 AEs (55.3% vs 21.9%, P < 0.001) than CI monotherapy. Endocrinopathy (11.2% vs 0.9%), rash (10.1% vs 4.3%) and pneumonitis (3.1% vs 0.7%) were associated with CI, and alopecia (25.9% vs 1.0%), neutropenia (16.6% vs 0.6%) and neuropathy (7.6% vs 3.0%) with chemotherapy. CONCLUSIONS: CI inhibitors have different toxicity profiles to chemotherapy. These findings are useful for patient counselling and planning of future trials.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Humanos , Neoplasias/patologiaRESUMO
BACKGROUND: Leak rates of over 5% following anastomoses between the ileum and colon continue to be reported in large series and are associated with substantial morbidity and with mortality rates of 10-20%. In 1994, we began performing circumferentially oversewn inverted stapled anastomoses in patients undergoing ileo-colic anastomoses or ileostomy closure. It has become increasingly apparent that this method is associated with a low risk of leakage, which we should report. METHODS: The anastomotic technique described was used in all patients undergoing ileo-colic anastomosis or closure of ileostomy by surgeon 1 (1994-2015) and in all ileo-colic anastomoses by surgeon 2 (2007-2015). All patients had a widely patent anastomosis constructed by two firings of a linear cutting stapler, as previously described. Additionally, the entire staple line was carefully oversewn with interrupted, inverting 4/0 polydioxanone sutures. Anastomotic leak was defined as a patient requiring re-operation or radiological drainage. RESULTS: One thousand and twelve patients underwent ileo-colic anastomosis and 685 patients underwent closure of ileostomy by surgeon 1, and 165 patients underwent ileo-colic anastomosis by surgeon 2. None of the 1862 patients required re-operation or radiological drainage for a leak (event rate 0%, 95% confidence interval 0-0.2%). However, there were three possible contained leaks treated successfully conservatively. The time taken to perform the actual anastomosis was measured in the last 30 ileo-colic resections. The median time was 42 min. CONCLUSION: While this method may well be too slow to gain widespread adoption, we hope this report encourages increased research into finding techniques with similar low leak rates.
Assuntos
Fístula Anastomótica/prevenção & controle , Colo/cirurgia , Íleo/cirurgia , Grampeamento Cirúrgico/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastomose Cirúrgica/métodos , Fístula Anastomótica/epidemiologia , Humanos , Ileostomia , Pessoa de Meia-Idade , Estudos Retrospectivos , Suturas , Adulto JovemRESUMO
IMPORTANCE: Checkpoint inhibitors have replaced docetaxel as the new standard second-line therapy in advanced non-small cell lung carcinoma (NSCLC), but little is known about the potential predictive value of clinical and molecular characteristics. OBJECTIVE: To estimate the relative efficacy of checkpoint inhibitor vs docetaxel overall and in subgroups defined by clinicopathological characteristics. DATA SOURCES: This systematic review and meta-analysis searched MEDLINE, Embase, PubMed, and the Cochrane Central Register of Controlled Trials for randomized clinical trials published in the English language between January 1, 1996, and January 30, 2017. STUDY SELECTION: Randomized clinical trials that compared a checkpoint inhibitor (nivolumab, pembrolizumab, or atezolizumab) with docetaxel. For each trial included in this study, the trial name, year of publication or conference presentation, patients' clinicopathological characteristics, type of chemotherapy, and type of checkpoint inhibitor were extracted. Data collection for this study took place from February 1 to March 31, 2017. DATA EXTRACTION AND SYNTHESIS: Two reviewers performed study selection, data abstraction, and risk of bias assessment. Hazard ratios (HR) and 95% CIs for the overall population and subgroups were extracted. Pooled treatment estimates were calculated using the inverse-variance-weighted method. RESULTS: In total, 5 trials involving 3025 patients with advanced NSCLC were included in this meta-analysis. These patients were randomized to receive a checkpoint inhibitor (nivolumab, 427 [14.1%]; pembrolizumab, 691 [22.8%]; or atezolizumab, 569 [18.8%]) or docetaxel (1338 [44.2%]). Checkpoint inhibitors were associated with prolonged overall survival, compared with docetaxel (HR, 0.69; 95% CI, 0.63-0.75; P < .001). They prolonged overall survival in the EGFR wild-type subgroup (HR, 0.67; 95% CI, 0.60-0.75; P < .001), but not in the EGFR mutant subgroup (HR, 1.11; 95% CI, 0.80-1.53; P = .54; interaction, P = .005), and they prolonged overall survival in the KRAS mutant subgroup (HR, 0.65; 95% CI, 0.44-0.97; P = .03) but not in the KRAS wild-type subgroup (HR, 0.86; 95% CI, 0.67-1.11; P = .24; interaction, P = .24). The relative treatment benefits were similar according to smoking status (never smokers [HR, 0.79] vs ever smokers [HR, 0.69]; interaction, P = .40), performance status (0 [HR, 0.69] vs 1 [HR, 0.68]; interaction, P = .85), age (<65 years [HR, 0.71] vs ≥65 years [HR, 0.69]; interaction, P = .74), histology (squamous [HR, 0.67] vs nonsquamous [HR, 0.70]; interaction, P = .71), or sex (male [HR, 0.69] vs female [HR, 0.70]; interaction, P = .82). CONCLUSION AND RELEVANCE: Checkpoint inhibitors, compared with docetaxel, are associated with significantly prolong overall survival in second-line therapy in NSCLC. The finding of no overall survival benefit for patients with EGFR mutant tumors suggests that checkpoint inhibitors should be considered only after other effective therapies have been exhausted. The findings of this meta-analysis could also assist in the design and interpretation of future trials and in economic analyses.