RESUMO
Advances in genomics have enabled anticancer therapies to be tailored to target specific genomic alterations. Single-arm trials (SATs), including those incorporated within umbrella, basket, and platform trials, are widely adopted when it is not feasible to conduct randomized controlled trials in rare biomarker-defined subpopulations. External controls (ECs), defined as control arm data derived outside the clinical trial, have gained renewed interest as a strategy to supplement evidence generated from SATs to allow comparative analysis. There are increasing examples demonstrating the application of EC in precision oncology trials. The prospective application of EC in conducting comparative studies is associated with distinct methodological challenges, the specific considerations for EC use in biomarker-defined subpopulations have not been adequately discussed, and a formal framework is yet to be established. In this review, we present a framework for conducting a prospective comparative analysis using EC. Key steps are (1) defining the purpose of using EC to address the study question, (2) determining if the external data are fit for purpose, (3) developing a transparent study protocol and a statistical analysis plan, and (iv) interpreting results and drawing conclusions on the basis of a prespecified hypothesis. We specify the considerations required for the biomarker-defined subpopulations, which include (1) specifying the comparator and biomarker status of the comparator group, (2) defining lines of treatment, (3) assessment of the biomarker testing panels used, and (4) assessment of cohort stratification in tumor-agnostic studies. We further discuss novel clinical trial designs and statistical techniques leveraging EC to propose future directions to advance evidence generation and facilitate drug development in precision oncology.
Assuntos
Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Medicina de Precisão , Oncologia , Resultado do Tratamento , BiomarcadoresRESUMO
PURPOSE: Cancer antigen-125 (CA-125) is recommended by treatment guidelines and widely used to diagnose ovarian cancer recurrence. The value of CA-125 as a surrogate for disease progression (PD) and its concordance with radiologic progression are unclear, particularly for women with platinum-sensitive relapsed ovarian cancer (PSROC) who have responded to chemotherapy and treated with maintenance poly(ADP-ribose) polymerase inhibitor (PARPi). METHODS: In this pooled analysis of four randomized trials of maintenance PARPi or placebo (Study 19, SOLO2, ARIEL3, and NOVA), we extracted data on CA-125 PD as defined by Gynecologic Cancer InterGroup criteria and RECIST v1.1. We evaluated the concordance between CA-125 and RECIST PD and reported on the negative predictive value (NPV) and positive predictive value (PPV). RESULTS: Of 1,262 participants (n = 818 PARPi, n = 444 placebo), 403 (32%) had CA-125 PD, and of these, 366 had concordant RECIST PD (PPV, 91% [95% CI, 88 to 93]). However, of 859 (68%) without CA-125 PD, 382 also did not have RECIST PD (NPV, 44% [95% CI, 41 to 48]). Within the treatment arms, PPV remained high (PARPi, 91% [95% CI, 86 to 94]; placebo, 91% [95% CI, 86 to 95]) but NPV was lower on placebo (PARPi, 53% [95% CI, 49 to 57]; placebo, 25% [95% CI, 20 to 31]). Of 477 with RECIST-only PD, most (95%) had a normal CA-125 at the start of maintenance therapy and the majority (n = 304, 64%) had CA-125 that remained within normal range. Solid organ recurrence without peritoneal disease was more common in those with RECIST-only PD than in those with CA-125 and RECIST PD (36% v 24%; P < .001). CONCLUSION: In patients with PSROC treated with maintenance PARPi, almost half with RECIST PD did not have CA-125 PD, challenging current guidelines. Periodic computed tomography imaging should be considered as part of surveillance, particularly in those with a normal CA-125 at the start of maintenance therapy and on treatment.
Assuntos
Antineoplásicos , Neoplasias Ovarianas , Humanos , Feminino , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Antígeno Ca-125/uso terapêutico , Critérios de Avaliação de Resposta em Tumores Sólidos , Recidiva Local de Neoplasia/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/tratamento farmacológico , Carcinoma Epitelial do Ovário/tratamento farmacológicoRESUMO
BACKGROUND: We investigated differences in cumulative incidence of first distant recurrence (DR) following non-metastatic breast cancer over a time period when new adjuvant therapies became available in Australia. METHODS: We conducted a health record linkage study of females with localized (T1-3N0) or regional (T4 or N+) breast cancer in the New South Wales Cancer Registry in 2001 to 2002 and 2006 to 2007. We linked cancer registry records with administrative records from hospitals, dispensed medicines, radiotherapy services, and death registrations to estimate the 9-year cumulative incidence of DR and describe use of adjuvant treatment. RESULTS: The study included 13,170 women (2001-2002 n = 6,338, 2006-2007 n = 6,832). The 9-year cumulative incidence of DR was 3.6% [95% confidence interval (CI), 2.3%-4.9%] lower for 2006-2007 diagnoses (15.0%) than 2001-2002 (18.6%). Differences in the annual hazard of DR between cohorts were largest in year two. DR incidence declined for localized and regional disease. Decline was largest for ages <40 years (absolute difference, 14.4%; 95% CI, 8.3%-20.6%), whereas their use of adjuvant chemotherapy (2001-2002 49%, 2006-2007 75%) and HER2-targeted therapy (2001-2002 0%, 2006-2007 16%) increased. DR did not decline for ages ≥70 years (absolute difference, 0.9%; 95% CI, -3.6%-1.8%) who had low use of adjuvant chemotherapy and HER2-targeted therapy. CONCLUSIONS: This whole-of-population study suggests that DR incidence declined over time. Decline was largest for younger ages, coinciding with changes to adjuvant breast cancer therapy. IMPACT: Study findings support the need for trials addressing questions relevant to older people and cancer registry surveillance of DR to inform cancer control programs.
Assuntos
Neoplasias da Mama , Feminino , Humanos , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/terapia , Neoplasias da Mama/patologia , Incidência , Austrália/epidemiologia , New South Wales/epidemiologia , Quimioterapia Adjuvante , Recidiva Local de Neoplasia/patologiaRESUMO
AIM: To assess population-level characteristics and post-metastasis survival of people with recurrent metastatic breast cancer (rMBC) during a period when new publicly-subsidised adjuvant and metastatic systemic therapies became available. METHODS: Record linkage study of females in NSW Cancer Registry (NSWCR) diagnosed with non-metastatic breast cancer (BC) in 2001-2002 (C1) and 2006-2007 (C2). We identified first rMBC from NSWCR, administrative hospital records, dispensed medicines and radiotherapy services (2001-2016). We used death registrations to estimate cumulative incidence of BC death. RESULTS: The analysis included 2267 women with rMBC (C1:1210, C2:1057). Compared to C1, C2 had access to adjuvant HER2-targeted therapy and were more likely to have received adjuvant chemotherapy (C1:38%, C2:47%) and aromatase inhibitors (C1:52%, C2:73%, of those dispensed endocrine therapy). Five-year probability of BC death was 65% (95%CI:62-68%) in C1 and 63% (95%CI:60-66%) in C2. Regional disease (T4 or N + ) at initial BC diagnosis (C1:62%, C2:68%), and age ≥ 70 years at first metastasis (C1:27%, C2:31%) were more common in C2 and had poorer prognosis. Five-year probability of BC death was lower in C2 than C1 for treatment-defined HER2-positive BC (C1:72% 95%CI:63-79%; C2:52% 95%CI 45-60%) and those dispensed chemotherapy alone (C1:76% 95%CI:69-82, C2:67% 95%CI:59-74%, p = 0.01), but not treatment-defined hormone receptor-positive HER2-negative BC (C1:60% 95%CI 56-63%, C2:64% 95%CI 60-68%). CONCLUSIONS: Despite less favourable prognostic characteristics in C2, BC-related survival following rMBC was similar between the two cohorts; and improved for women with HER2-positive tumours. These findings support the real-world benefits of newer treatments for rMBC.
Assuntos
Neoplasias da Mama , Idoso , Feminino , Humanos , Inibidores da Aromatase/uso terapêutico , Austrália/epidemiologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Prognóstico , Receptor ErbB-2 , Metástase NeoplásicaRESUMO
Background: Next-generation sequencing is used to increase targeted treatment opportunities, particularly for patients who have exhausted standard options. Where randomized controlled trial evidence for a targeted therapy is available for molecular alterations in one tumor type, the dilemma for the clinician is whether 'matching' targeted agents should be recommended off-label for the same molecular alterations detected in other tumor types, for which no trial data are available to guide practice. To judge the likely benefits, it may be possible to extrapolate evidence from cancers where treatment benefits have been established. Methods: We present a framework for assessing the appropriateness of extrapolation using trastuzumab, an anti-HER2 antibody, for HER2-amplified tumors where trastuzumab use would be off-label as an illustrative example. Results: The following should be considered for the tumor type where trastuzumab would be off-label: (a) reliability of the NGS assay for detecting HER2 amplification; (b) criteria for defining HER2 positivity; (c) strength of evidence supporting the actionability of HER2 amplification and trastuzumab; (d) whether better clinical outcomes with trastuzumab are due to a more favorable natural history rather than trastuzumab effect; (e) signals of trastuzumab activity and whether it translates to clinically meaningful benefit; (f) whether the safety profile of trastuzumab differs from established indications; and (g) discussion points for shared decision making (SDM) to facilitate informed consent. Conclusion: We present a systematic approach for appraising evidence to support extrapolating trastuzumab benefits from established indications to off-label applications. Extrapolation criteria and areas of uncertainty to inform SDM are outlined. This framework is potentially generalizable to other tumor-agnostic biomarker-targeted therapy scenarios. It is a practical approach for clinicians to apply in routine practice and should be considered by molecular tumor boards who make off-label recommendations.
RESUMO
OBJECTIVES: Cancer is increasingly classified according to biomarkers that drive tumour growth and therapies developed to target them. In rare biomarker-defined cancers, randomised controlled trials to adequately assess targeted therapies may be infeasible. Extrapolating existing evidence of targeted therapy from common cancers to rare cancers sharing the same biomarker may reduce evidence requirements for regulatory approval in rare cancers. It is unclear whether guidelines exist for extrapolation. We sought to identify methodological guidance for extrapolating evidence from targeted therapies used for common cancers to rare biomarker-defined cancers. DESIGN: Scoping review. DATA SOURCES: Websites of health technology assessment agencies, regulatory bodies, research groups, scientific societies and industry. EBM Reviews-Cochrane Methodology Register and Health Technology Assessment, Embase and MEDLINE databases (1946 to 11 May 2022). ELIGIBILITY CRITERIA: Papers proposing a framework or recommendations for extrapolating evidence for rare cancers, small populations and biomarker-defined cancers. DATA EXTRACTION AND SYNTHESIS: We extracted framework details where available and guidance for components of extrapolation. We used these components to structure and summarise recommendations. RESULTS: We identified 23 papers. One paper provided an extrapolation framework but was not cancer specific. Extrapolation recommendations addressed six distinct components: strategies for grouping cancers as the same biomarker-defined disease; analytical validation requirements of a biomarker test to use across cancer types; strategies to generate control data when a randomised concurrent control arm is infeasible; sources to inform biomarker clinical utility assessment in the absence of prospective clinical evidence; requirements for surrogate endpoints chosen for the rare cancer; and assessing and augmenting safety data in the rare cancer. CONCLUSIONS: In the absence of an established framework, our recommendations for components of extrapolation can be used to guide discussions about interpreting evidence to support extrapolation. The review can inform the development of an extrapolation framework for biomarker-targeted therapies in rare cancers.
Assuntos
Terapia de Alvo Molecular , Neoplasias , Biomarcadores , Humanos , Neoplasias/tratamento farmacológico , Estudos Prospectivos , Avaliação da Tecnologia BiomédicaRESUMO
BACKGROUND: Maintenance treatment is standard of care for front-line (FL) and platinum-sensitive recurrent ovarian cancer (PSROC) following response to chemotherapy. Adverse events (AEs) on maintenance therapies are common and usually attributable to investigational treatments but could also be unrelated. Randomised controlled trial (RCT) with blinded placebo design is the gold standard for determining the relative differences in efficacy and AEs between treatment arms. We performed a meta-analysis to quantify AE rates in placebo arms of RCTs to determine AEs not due to investigational agents. METHODS: We performed an electronic search to identify eligible RCTs in FL and PSROC settings. Data from placebo arms were extracted and pooled using the inverse variance method to determine the risk of any AE, overall and specific grade 3 or higher (G ≥ 3) AEs, and AE-related treatment delay, reduction and discontinuation. RESULTS: We identified 13 eligible RCTs (FL, N = 8; PSROC, N = 5) with 2224 patients who received placebo (FL, N = 1541; PSROC, N = 683). The majority experienced an AE of any grade (FL, 93.0%; PSROC, 95.2%). Substantial proportions experienced G ≥ 3 AEs (FL, 14.6%; PSROC, 18.2%). In the FL setting, AEs led to treatment delay in 14.4%, dose reduction in 4.1% and discontinuation in 2.6%. Findings were similar for PSROC: 8.4%, 5.5% and 2.1%, respectively. CONCLUSIONS: AEs not due to investigational agents are common in ovarian cancer patients in maintenance therapy RCTs. Potential explanations include the nocebo effect, residual toxicities from previous treatment or underlying disease. Further research is required to identify better approaches to assessing AEs in this population.
Assuntos
Efeito Nocebo , Neoplasias Ovarianas , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológicoRESUMO
OBJECTIVE: To estimate the cost-effectiveness of three surveillance imaging strategies using whole-body positron emission tomography (PET) with computed tomography (CT) (PET/CT) in a follow-up program for adults with resected stage III melanoma. METHODS: An analytic decision model was constructed to estimate the costs and benefits of PET/CT surveillance imaging performed 3-monthly, 6-monthly, or 12-monthly compared with no surveillance imaging. RESULTS: At 5 years, 3-monthly PET/CT surveillance imaging incurred a total cost of AUD 88,387 per patient, versus AUD 77,998 for 6-monthly, AUD 52,560 for 12-monthly imaging, and AUD 51,149 for no surveillance imaging. When compared with no surveillance imaging, 12-monthly PET/CT imaging was associated with a 4% increase in correctly diagnosed and treated distant disease; a 0.5% increase with 6-monthly imaging and 1% increase with 3-monthly imaging. The incremental cost-effectiveness ratio (ICER) of 12-monthly PET/CT surveillance imaging was AUD 34,362 for each additional distant recurrence correctly diagnosed and treated, compared with no surveillance imaging. For the outcome of cost per diagnostic error avoided, the no surveillance imaging strategy was the least costly and most effective. CONCLUSION: With the ICER for this strategy less than AUD 50,000 per unit of health benefit, the 12-monthly surveillance imaging strategy is considered good value for money.
Assuntos
Melanoma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adulto , Análise Custo-Benefício , Humanos , Melanoma/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnóstico por imagem , Estadiamento de Neoplasias , Tomografia por Emissão de PósitronsRESUMO
Background: In metastatic non-small-cell lung cancer (mNSCLC), PD-L1 expression is associated with benefit from immune checkpoint inhibitor (ICI) therapy. However, the significance of PD-L1 expression in chemotherapy-treated patients is uncertain. Methods: Using the chemotherapy control arm of first-line randomized trials, a meta-analysis of the association between efficacy outcomes and PD-L1 status was performed, stratified by assay due to inter-assay differences. Results: Across 12 trials and 4378 patients, overall survival (OS) was superior in high PD-L1 versus negative tumors and low versus negative according to 22C3/28-8 assays. When classified by SP142 assay, no significant difference in response or survival was seen between PD-L1 groups. Conclusion: In mNSCLC, high PD-L1-expressing tumors are associated with longer OS and improved objective rate when treated with chemotherapy. Inter-assay variability impacts outcome results.
Biomarkers are naturally occurring cancer traits that can predict certain events. PD-L1 expression is a biomarker used in advanced lung cancer to predict benefit from immunotherapy. However, the association between PD-L1expression and chemotherapy is unclear. The authors analyzed data from 14 large clinical trials and found that PD-L1 expression could also be used to define a type of lung cancer that responds better to chemotherapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , PrognósticoRESUMO
BACKGROUND: It is not known whether there is a survival benefit associated with more frequent surveillance imaging in patients with resected American Joint Committee on Cancer stage III melanoma. OBJECTIVE: The aim of this study was to investigate distant disease-free survival (DDFS), melanoma-specific survival (MSS), post distant recurrence MSS (dMSS), and overall survival for patients with resected stage III melanoma undergoing regular computed tomography (CT) or positron emission tomography (PET)/CT surveillance imaging at different intervals. PATIENTS AND METHODS: A closely followed longitudinal cohort of patients with resected stage IIIA-D disease treated at a tertiary referral center underwent 3- to 4-monthly, 6-monthly, or 12-monthly surveillance imaging between 2000 and 2017. Survival outcomes were estimated using the Kaplan-Meier method, and log-rank tests assessed the significance of survival differences between imaging frequency groups. RESULTS: Of 473 patients (IIIA, 19%; IIIB, 31%; IIIC, 49%; IIID, 1%) 30% underwent 3- to 4-monthly imaging, 10% underwent 6-monthly imaging, and 60% underwent 12-monthly imaging. After a median follow-up of 6.2 years, distant recurrence was recorded in 252 patients (53%), with 40% detected by surveillance CT or PET/CT, 43% detected clinically, and 17% with another imaging modality. Median DDFS was 5.1 years (95% confidence interval 3.9-6.6). Among 139 IIIC patients who developed distant disease, the median dMSS was 4.4 months shorter in those who underwent 3- to 4-monthly imaging than those who underwent 12-monthly imaging. CONCLUSION: Selecting patients at higher risk of distant recurrence for more frequent surveillance imaging yields a higher proportion of imaging-detected distant recurrences but is not associated with improved survival. A randomized comparison of low versus high frequency imaging is needed.
Assuntos
Melanoma , Neoplasias Cutâneas , Doença Crônica , Humanos , Melanoma/diagnóstico por imagem , Melanoma/cirurgia , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/cirurgia , Melanoma Maligno CutâneoRESUMO
BACKGROUND: The survival outcomes of patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) are variable. This study investigated whether pre- and on-treatment lactate dehydrogenase (LDH) could better prognosticate and select patients for ICI therapy. METHODS: Using data from the POPLAR and OAK trials of atezolizumab versus docetaxel in previously treated advanced NSCLC, the authors assessed the prognostic and predictive value of pretreatment LDH (less than or equal to vs greater than the upper limit of normal). They further examined changes in on-treatment LDH by performing landmark analyses and estimated overall survival (OS) distributions according to the LDH level stratified by the response category (complete response [CR]/partial response [PR] vs stable disease [SD]). They repeated pretreatment analyses in subgroups defined by the programmed death ligand 1 (PD-L1) status. RESULTS: This study included 1327 patients with available pretreatment LDH. Elevated pretreatment LDH was associated with an adverse prognosis regardless of treatment (hazard ratio [HR] for atezolizumab OS, 1.49; P = .0001; HR for docetaxel OS, 1.30; P = .004; P for treatment by LDH interaction = .28). Findings for elevated pretreatment LDH were similar for patients with positive PD-L1 expression treated with atezolizumab. Persistently elevated on-treatment LDH was associated with a 1.3- to 2.8-fold increased risk of death at weeks 6, 12, 18, and 24 regardless of treatment. Elevated LDH at 6 weeks was associated with significantly shorter OS regardless of radiological response (HR for CR/PR, 2.10; P = .04; HR for SD, 1.50; P < .01), with similar findings observed at 12 weeks. CONCLUSIONS: In previously treated advanced NSCLC, elevated pretreatment LDH is an independent adverse prognostic marker. There is no evidence that pretreatment LDH predicts ICI benefit. Persistently elevated on-treatment LDH is associated with worse OS despite radiologic response.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , L-Lactato Desidrogenase , Neoplasias Pulmonares/tratamento farmacológico , PrognósticoRESUMO
BACKGROUND: The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients. METHODS: The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib. RESULTS: The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3-11.3), 5.4 (4.8-5.8) and 2.9 (2.8-4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1-22.4) and 8.3 (7.1-10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot). CONCLUSIONS: This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies.
Assuntos
Genes BRCA1 , Genes BRCA2 , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Nomogramas , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/toxicidade , Piperazinas/toxicidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Prognóstico , Intervalo Livre de ProgressãoRESUMO
PURPOSE: We aim to describe the treatment patterns and overall survival (OS) outcomes in patients receiving trastuzumab emtansine (T-DM1) for HER2-positive metastatic breast cancer (HER2+MBC) in routine clinical care. METHODS: Retrospective, whole-of-population cohort study of people initiating T-DM1 for HER2+MBC between October 2015 and May 2019 in Australia. We used dispensing claims to estimate time-to-T-DM1 initiation, duration of treatment, and treatments administered prior to and following T-DM1 therapy. We estimated OS from T-DM1 initiation and stratified results based on whether patients received first- or second-line T-DM1 treatment. We benchmarked outcomes to those reported in the pivotal, EMILIA trial. RESULTS: 345 patients initiated T-DM1: 309 as second-line therapy for HER2+MBC and 36 as first-line therapy. 51% of patients had received endocrine therapy and 98% of second-line patients received pertuzumab prior to starting T-DM1. The median age was 57 years (53 in EMILIA); median time-to-T-DM1 initiation from start of HER2-targeted therapy for HER2+MBC was 11.6 months (IQR: 7.9-16.6); median duration of T-DM1 treatment was 6.5 months (3.1-13.5; 7.6 months in EMILIA), and median OS was 19.3 months (7.9-29.5; 29.9 months in EMILIA). CONCLUSIONS: Our findings highlight differences in patient characteristics (older, more previous pertuzumab therapy) and outcomes (shorter OS) from the T-DM1 pivotal trial and provide real-world estimates that can inform patient, clinician and policy, decisions around the use of HER2-targeted therapies in routine clinical care.
Assuntos
Neoplasias da Mama , Maitansina , Ado-Trastuzumab Emtansina , Protocolos de Quimioterapia Combinada Antineoplásica , Austrália , Neoplasias da Mama/tratamento farmacológico , Estudos de Coortes , Feminino , Humanos , Maitansina/uso terapêutico , Pessoa de Meia-Idade , Receptor ErbB-2 , Estudos Retrospectivos , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: Clinical trials report adverse events (AEs) in a dense table focusing on the frequency of 'worst grade' AEs experienced over the duration of treatment. There is usually no granular information provided on the timing and trajectory of AEs or whether they are likely to worsen, improve, or remain constant over time. PATIENTS AND METHODS: Non-hematologic (NH) AE data was extracted from the CALYPSO trial comparing carboplatin with pegylated liposomal doxorubicin (CD) to carboplatin with paclitaxel (CP) in recurrent ovarian cancer (ROC). Generalised estimating equations (GEE) were used to assess the risk and trajectory of combined Grade 2 or higher (G2+) AE and of each specific AE. The risk of G2+AE was also compared between treatment arms. RESULTS: The study included 976 patients and AE were reported for the duration of treatment. Most patients experienced at least one G2+NHAE (CP:CD, 96.0%:80.6%). Risk of combined G2+AE increased with CP (4.1% per-cycle) but decreased with CD (0.8%, P <0.01). When alopecia and sensory neuropathy were excluded, risk of G2+ AE decreased by 2.7% per-cycle, with no significant difference between treatment arms. G2+ nausea improved (15.2% per-cycle, P <0.01). G2+ sensory neuropathy worsened (29.3% per-cycle, P <0.01). Fatigue was stable (17% per-cycle, P =0.06) whilst G2+ pain decreased over time (13.4% per-cycle, P <0.01), with no difference between treatment arms. CONCLUSION: Existing trial data can be used to provide AE trajectories as illustrated here for ROC. These trajectories have utility in guiding treatment choice and potentially optimising AE management with novel therapies and treatment combinations.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Carboplatina/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Seguimentos , Humanos , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Polietilenoglicóis/administração & dosagem , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: Follow-up for patients with resected stage IIIA-D melanoma may include computed tomography (CT) or positron emission tomography (PET)/CT imaging to identify distant metastases. The aim of this study was to evaluate the test performance over follow-up time, of structured 6- and 12-monthly follow-up imaging schedules in these patients. METHODS: We conducted a retrospective analysis of consecutive resected stage IIIA-D melanoma patients from Melanoma Institute Australia (2000-2017). Patients were followed until a confirmed diagnosis of distant metastasis, end of follow-up schedule, or death. Test accuracy was evaluated by cross-classifying the results of the test against a composite reference standard of histopathology, cytology, radiologic imaging, and/or clinical follow-up, and then quantified longitudinally using logistic regression models with random effects. RESULTS: In total, 1373 imaging tests were performed among 332 patients. Distant metastases were detected in 110 (33%) patients during a median follow-up of 61 months (interquartile range 38-86), and first detected by imaging in 86 (78%) patients. 152 (68%) patients had at least one false-positive result. Sensitivity of the schedule over 5 years was 79% [95% confidence interval (CI) 70-86%] and specificity was 88% (95% CI 86-90%). There was no evidence of a significant difference in test performance over follow-up time or by American Joint Committee on Cancer (AJCC) substage. The positive predictive value ranged between 33 and 48% over follow-up time, reflecting a ratio of 1:2 false-positives per true-positive finding. CONCLUSIONS: Regular 6- or 12-monthly surveillance imaging using CT or PET/CT has reasonable and consistent sensitivity and specificity over 5-year follow-up for resected stage IIIA-D melanoma patients. These data are useful when discussing the risks and benefits of long-term follow-up.
Assuntos
Melanoma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Austrália , Fluordesoxiglucose F18 , Humanos , Melanoma/diagnóstico por imagem , Melanoma/patologia , Melanoma/cirurgia , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios XRESUMO
INTRODUCTION: In the new era of effective systemic therapies for advanced melanoma, early detection of lower volume recurrent disease using surveillance imaging can improve survival. However, intensive imaging follow-up strategies are likely to increase costs to health systems and may pose risks to patients. The objective of this study is to estimate from the Australian health system perspective the cost-effectiveness of four follow-up strategies in resected stage III melanoma over a 5-year period following surgical treatment with curative intent. METHODS AND ANALYSIS: A decision-analytic model will be built to estimate the costs and benefits of (1) 12 monthly, (2) 6 monthly, (3) 3-4 monthly positron emission tomography/CT imaging for 5 years, compared with (4) no imaging follow-up. The model will be populated with probabilities of disease recurrence, test performance measures using data from >1000 consecutive resected stage III melanoma patients from Melanoma Institute Australia diagnosed between 2000 and 2017. Healthcare resource use, including surveillance imaging, doctor's visits, subsequent tests and procedures to investigate suspicious findings, will be quantified from detailed patient records and valued using Australian reference pricing. Economic outcomes include cost per new distant melanoma recurrence detected and cost per diagnostic error avoided, for no imaging compared with the other strategies.Deterministic sensitivity analyses will examine the robustness of model results. ETHICS AND DISSEMINATION: This study was approved by the Sydney Local Health District, Sydney Local Health District Ethics Review Committee (RPAH Zone), AU/1/830638 and the Australian Institute of Health and Welfare (EO2019-1-454). The results of this study will be published in peer-reviewed medical and health economics journals and will inform melanoma management guidelines.
Assuntos
Melanoma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adolescente , Austrália , Análise Custo-Benefício , Humanos , Melanoma/diagnóstico por imagem , Melanoma/cirurgia , Recidiva Local de Neoplasia/diagnóstico por imagem , Estadiamento de Neoplasias , RecidivaRESUMO
BACKGROUND: Limited evidence exists to support CA-125 as a valid surrogate biomarker for progression in patients with ovarian cancer on maintenance PARP inhibitor (PARPi) therapy. We aimed to assess the concordance between CA-125 and Response Evaluation Criteria in Solid Tumours (RECIST) criteria for progression in patients with BRCA mutations on maintenance PARPi or placebo. METHODS: We extracted data on progression as defined by Gynecologic Cancer InterGroup CA-125, investigator- and independent central-assessed RECIST from the SOLO2/ENGOT-ov21(NCT01874353) trial. We excluded those with progression other than by RECIST, progression on date of randomisation, and no repeat CA-125 beyond baseline. We evaluated the concordance between CA-125 progression and RECIST progression, and assessed the negative (NPV) and positive predictive value (PPV). RESULTS: Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included. 171 patients had investigator-assessed RECIST progression. Of 80 patients with CA-125 progression, 77 had concordant RECIST progression (PPV 96%, 95% confidence interval 90-99%). Of 195 patients without CA-125 progression, 94 had RECIST progression (NPV 52%, 45-59%). Within treatment arms, PPV was similar (olaparib: 95% [84-99%], placebo: 97% [87-100%]) but NPV was lower in patients on placebo (olaparib: 60% [52-68%], placebo: 30% [20-44%]). Of 94 patients with RECIST but without CA-125 progression, 64 (68%) had CA-125 that remained within normal range. We observed similar findings using independent-assessed RECIST. CONCLUSIONS: Almost half the patients without CA-125 progression had RECIST progression, and most of these had CA-125 within the normal range. Regular computed tomography imaging should be considered as part of surveillance in patients treated with or without maintenance olaparib rather than relying on CA-125 alone.
Assuntos
Antineoplásicos/uso terapêutico , Antígeno Ca-125/metabolismo , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Quimioterapia de Manutenção/métodos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Compostos Organoplatínicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Critérios de Avaliação de Resposta em Tumores SólidosRESUMO
PURPOSE: Surgeons need tools to provide individualised estimates of surgical outcomes and the uncertainty surrounding these, to convey realistic expectations to the patient. This study developed and validated prognostic models for patients undergoing surgical treatment of lumbar disc herniation, to predict outcomes 1 year after surgery, and implemented these models in an online prediction tool. METHODS: Using the data of 1244 patients from a large spine unit, LASSO and linear regression models were fitted with 90% upper prediction limits, to predict scores on the Core Outcome Measures Index, and back and leg pain. Candidate predictors included sociodemographic factors, baseline symptoms, medical history, and surgeon characteristics. Temporal validation was conducted on 364 more recent patients at the same unit, by examining the proportion of observed outcomes exceeding the threshold of the 90% upper prediction limit (UPL), and by calculating mean bias and other calibration measures. RESULTS: Poorer outcome was predicted by obesity, previous spine surgery, and having basic obligatory (rather than private) insurance. In the validation data, fewer than 12% of outcomes were above the 90% UPL. Calibration plots for the model validation showed values for mean bias < 0.5 score points and regression slopes close to 1. CONCLUSION: While the model accuracy was good overall, the prediction intervals indicated considerable predictive uncertainty on the individual level. Implementation studies will assess the clinical usefulness of the online tool. Updating the models with additional predictors may improve the accuracy and precision of outcome predictions. These slides can be retrieved under Electronic Supplementary Material.
Assuntos
Descompressão Cirúrgica , Degeneração do Disco Intervertebral , Deslocamento do Disco Intervertebral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Descompressão Cirúrgica/efeitos adversos , Descompressão Cirúrgica/métodos , Feminino , Humanos , Deslocamento do Disco Intervertebral/cirurgia , Vértebras Lombares/cirurgia , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Prognóstico , Resultado do Tratamento , Adulto JovemRESUMO
Background: An elevated neutrophil-lymphocyte ratio (NLR) is associated with poor prognosis in advanced renal cell carcinoma (RCC). We examined whether the addition of NLR improves the risk reclassification of advanced RCC using current prognostic tools from the Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).Methods: Using randomised data from the COMPARZ trial of first-line pazopanib vs. sunitinib in advanced RCC, we constructed multivariable models containing MSKCC and IMDC predictor variables with and without NLR. We evaluated model discrimination using the concordance index (C-index). We computed net reclassification improvement to quantify patient reclassification into low/intermediate/poor risk groups with the addition of NLR.Results: Of 1102 patients, NLR ≥ 5 (16%) was associated with shorter survival adjusting for MSKCC variables (adjusted HR 1.89, p < .001). Adding NLR to MSKCC variables increased the C-index by 0.01. Among patients who died before 24 months (N = 415), adding NLR reclassified 8% and 2% to a higher and lower risk category, respectively. Among those alive at 24 months (N = 636), adding NLR reclassified 4% and 1% to a higher and lower risk category, respectively. This finding translates to a net benefit of eight additional patients who die within 24 months correctly identified as poor risk per 1000 patients tested. We obtained similar results when evaluating NLR with IMDC variables.Conclusions: NLR does not substantially improve risk reclassification over pre-existing prognostic tools. MSKCC and IMDC classifications remain the standard for guiding risk-directed therapy and trial stratification of patients with advanced RCC.