We sought to test and validate the predictive utility of trichotomous tumor response (TriTR; complete response CR or partial response PR v stable disease SD v progressive disease PD), disease control ...rate (DCR; CR/PR/SD v PD), and dichotomous tumor response (DiTR; CR/PR v others) metrics using alternate cut points for PR and PD. The data warehouse assembled to guide the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was used.
Data from 13 trials (5,480 patients with metastatic breast cancer, non-small-cell lung cancer, or colorectal cancer) were randomly split (60:40) into training and validation data sets. In all, 27 pairs of cut points for PR and PD were considered: PR (10% to 50% decrease by 5% increments) and PD (10% to 20% increase by 5% increments), for which 30% and 20% correspond to the RECIST categorization. Cox proportional hazards models with landmark analyses at 12 and 24 weeks stratified by study and number of lesions (fewer than three v three or more) and adjusted for average baseline tumor size were used to assess the impact of each metric on overall survival (OS). Model discrimination was assessed by using the concordance index (c-index).
Standard RECIST cut points demonstrated predictive ability similar to the alternate PR and PD cut points. Regardless of tumor type, the TriTR, DiTR, and DCR metrics had similar predictive performance. The 24-week metrics (albeit with higher c-index point estimate) were not meaningfully better than the 12-week metrics. None of the metrics did particularly well for breast cancer.
Alternative cut points to RECIST standards provided no meaningful improvement in OS prediction. Metrics assessed at 12 weeks have good predictive performance.
We sought to develop and validate clinically relevant, early assessment continuous tumor measurement-based metrics for predicting overall survival (OS) using the Response Evaluation Criteria in Solid ...Tumors (RECIST) 1.1 data warehouse.
Data from 13 trials representing 2096 patients with breast cancer, non-small cell lung cancer (NSCLC), or colorectal cancer were used in a complete case analysis. Tumor measurements from weeks 0-6-12 assessments were used to evaluate the ability of slope (absolute change in tumor size from 0-6 and 6-12 weeks) and percent change (relative change in tumor size from 0-6 and 6-12 weeks) metrics to predict OS using Cox models, adjusted for average baseline tumor size. Metrics were evaluated by discrimination (via concordance or c-index), calibration (goodness-of-fit type statistics), association (hazard ratios), and likelihood (Bayesian Information Criteria), with primary focus on the c-index. All statistical tests were two-sided.
Comparison of c-indices suggests slight improvement in predictive ability for the continuous tumor measurement-based metrics vs categorical RECIST response metrics, with slope metrics performing better than percent change metrics for breast cancer and NSCLC. However, these differences were not statistically significant. The goodness-of-fit statistics for the RECIST metrics were as good as or better than those for the continuous metrics. In general, all the metrics performed poorly in breast cancer, compared with NSCLC and colorectal cancer.
Absolute and relative change in tumor measurements do not demonstrate convincingly improved overall survival predictive ability over the RECIST model. Continued work is necessary to address issues of missing tumor measurements and model selection in identifying improved tumor measurement-based metrics.
Emerging technologies and progress in data processing allowed for new insights on gene expression, genomics and epigenomics, and mechanisms of cancer genesis and progression. The development of new ...therapeutic strategies should therefore be triggered by the understanding of the underlying biology through sophisticated clinical trials. Therefore, the methodology and the design of cancer clinical trials as well as the methods of their implementation are under profound changes. Targeting specific pathways has open the hope of a more focused and personalized medicine which has the potential to bring more efficient and tailored treatments to patients. It has been questioned therefore whether clinical trials traditionally designed for specific tumor types could not re-visited towards trials gathering patients based on molecular features rather than pure pathology criteria. The complexity of the cancer biology being the result of so many different interactive mechanisms whether driving or not the process of cancer cells is an additional level of complexity to approach more inclusive clinical trial access. Nevertheless, a number of innovative solutions to address biological challenges across histologies have been initiated and the question of whether histology agnostic trials could be conceived is a logical next question. This paper questions the advantages and the limits of clinical trials performed across tumor types bearing similar selected molecular features and looks further into the feasibility of such histology agnostic trials.
The purpose of this correspondence is to discuss the TrialsTracker, presented by Powell-Smith and Goldacre in their article ‘TrialsTracker: Automated ongoing monitoring of failure to share clinical ...trial results by all major companies and research institutions’ (2016) as a tool to discover publication bias in clinical trial results. The findings from one specific organization (European Organization for Research and Treatment of Cancer; EORTC) are compared with the actual publication history of the trials in question. We also present shortcomings of the method being used and suggestions for improvement to the proposed algorithm.
This Review describes the work conducted by the TRANSBIG consortium in the development of the MINDACT (Microarray In Node negative Disease may Avoid ChemoTherapy) trial. The goal of the trial is to ...provide definitive evidence regarding the clinical relevance of the 70-gene prognosis signature, and to assess the performance of this signature compared with that of traditional prognostic indicators for assigning adjuvant chemotherapy to patients with node-negative breast cancer. We outline the background work and the key questions in node-negative early-stage breast cancer, and then focus on the MINDACT trial design and statistical considerations. The challenges inherent in this trial in terms of logistics, implementation and interpretation of the results are also discussed. We hope that this article will trigger further discussion about the difficulties of setting up and analyzing trials aimed at establishing the worth of new methods for better selection of patients for cancer treatment.
Abstract Background The MINDACT (Microarray In Node-negative and 1–3 node positive Disease may Avoid ChemoTherapy) trial investigates the clinical utility of the 70-gene profile (MammaPrint) for the ...selection of breast cancer patients for adjuvant chemotherapy (CT) together with standard clinicopathological criteria. We present the results of the pilot phase consisting of first 800 patients included. Methods MINDACT has enrolled 6600 patients, classified into high or low risk by MammaPrint and clinicopathological risk through Adjuvant! Online. Patients with both clinical (C) and genomic (G) high risks are offered adjuvant CT; those with both C and G low risks do not receive CT; patients with discordant risk are randomised for the decision of adjuvant CT based on C or G risk. CT randomisation of anthracycline-based versus docetaxel/capecitabine and endocrine therapy randomisation between letrozole and tamoxifen → letrozole are offered. Results During the pilot phase 46% of screened patients were enrolled. Main reasons for non-enrolment were node positivity before trial amendment, sample quality problems and failure to meet logistic settings. Among the 800 patients, 386 (48%) were C-low/G-low, 198 (24.8%) as C-high/G-high, 75 (9.4%) as C-low/G-high and 141 (17.6%) as C-high/G-low. In total 216 (27%) cases were discordant. The difference between patients with C-high (42%) and G-high risk (34%) is 8.25% (95% confidence interval (CI), 4.7–11.8%; P < .0001). Compliance with the treatment decision was high (>92%). Conclusions The logistically complex MINDACT trial is feasible in a multinational setting. The proportion of discordant patients, the potential reduction in CT by using the genomic signature and compliance to treatment assignment are in accordance with the trial hypotheses.
Summary The survival of patients diagnosed with Hodgkin lymphoma (HL) has improved from 70% to 90% in clinical trials. However, population-based data has shown lower survival. In this study, clinical ...trial data were linked with cancer registry to identify trial and non-trial participants and differences in overall survival and associated factors were assessed. In 1986-2004, 27% of HL patients aged 15-70 years participated in clinical trials. Compared to non-trial participants, trial participants were younger (median age, 31 vs. 34 years), had staging registered more accurately and had an 8% higher 20-year survival rate (73% vs. 65%). After adjusting for baseline differences, no differences in survival (hazard ratio = 0·96, 95% confidence interval 0·82-1·12), or in subgroup analysis according to stage, remained. Over time, increased administration of chemotherapy in combination with radiotherapy, together with the decreased use of radiotherapy alone was observed among the trial population. This trend was later followed in non-trial participants, coinciding with a similar 'take-up' in survival. The observed superior survival among patients with HL treated in clinical trials can be largely explained by the differences in baseline characteristics, particularly younger age. High trial participation rate and centralized expertise facilitates the implementation of trial findings to real-world practice.
Abstract Aims BI 2536 is a selective and potent small-molecule inhibitor of polo-like kinase 1. We performed a multi-centre, multi-tumour phase II trial to investigate the efficacy, safety and ...pharmacokinetics of BI 2536 in five solid tumour types. Patients and methods Patients with advanced head and neck, breast and ovarian cancer, soft tissue sarcoma and melanoma were selected according to protocol-defined general and tumour-specific criteria. They were ⩾18 years old, had a good performance status, adequate bone marrow, renal and liver function, measurable progressive disease and had completed other relevant systemic treatments >4 weeks ago. BI 2536 200–250 mg was given intravenously on day 1 every 3 weeks until intolerance, progression or refusal. The study was based on a Simon two-stage design, with 12 patients entering in stage 1 and additional 25 patients to be entered in case of at least one response in the first stage. The rate of objective responses (RECIST criteria) was chosen as primary end-point. Results Seventy six patients were included, 71 started treatment and received a median number of two cycles (four in ovarian cancer). Frequent grade 3–4 adverse events were neutropaenia (81.6%), thrombocytopaenia (19.7%), febrile neutropaenia (19.7%), anaemia (15.5%) and pain (9.9%). We did not observe confirmed objective responses. All cohorts were closed after the entry of 14–15 eligible non-responding patients. Pharmacokinetic analyses revealed multi-compartmental behaviour and a rapid distribution of BI 2536. Conclusions BI 2536 showed limited antitumour activity according to the design of this trial in five different tumour types. Derivatives of BI 2536 with a more favourable pharmacological profile are currently explored further in prospective studies.
Abstract Background Preclinical data suggest that epidermal growth factor receptor (EGFR) inhibitors (e.g. gefitinib) can delay endocrine resistance in breast cancer. A double-blind, ...placebo-controlled, phase II trial investigated whether adding gefitinib (G) to anastrozole (A) would improve outcome in advanced breast cancer (ABC). Methods Postmenopausal pre-treated hormone receptor-positive ABC patients (locally recurrent or metastatic) were 1:1 randomized to A (1 mg/d) plus G 250 mg/d or plus placebo (P). Patients who had prior treatment with an aromatase inhibitor in metastatic setting or with trastuzumab, anti-EGFR or anti-VEGF agents were excluded. Treatment was given until disease progression, unacceptable toxicity or patient withdrawal. Progression-free survival (PFS) rate at 1 year was assessed according to Response Evaluation Criteria in Solid Tumours, version 1.0. Results Of 108 planned patients, 71 were recruited (36 in A/G and 35 in A/P). The trial closed prematurely due to slow recruitment; 31 patients had prior chemotherapy and 53 prior endocrine therapy (all except one received tamoxifen); 60% in adjuvant and 16% in metastatic setting received tamoxifen; 59 patients had visceral disease. Median follow-up was 18 months. PFS rate at 1 year was 35% for A/G and 32% for A/P arm. Objective responses were six (22%) in the A/G and nine (28%) in the A/P arm. Median duration of response was 13.8 and 18.6 months in the A/G and A/P arms, respectively. Fatigue (35%), diarrhoea (31%), rash (32%), dry skin (27%), and arthralgia/myalgia (27%) were the commonest adverse events in the A/G arm. Conclusions This phase II study, although prematurely closed, did not show a signal that adding G to A improves PFS at 1 year and its use is not supported. Gastrointestinal and skin toxicities were more pronounced with G resulting in premature therapy interruption in almost 1 in 3 patients ( ClinicalTrials.gov number, NCT00066378 ).
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