Tailored recommendation for adjuvant chemotherapy in breast cancer patients is of great importance. This survey assessed agreement among oncologists on risk assessment and chemotherapy ...recommendation, the impact of adding the 70-gene signature to clinical-pathological characteristics, and changes over time.
A survey consisting of 37 discordant patient cases from the MINDACT trial (T1-3N0-1M0) was sent to European breast cancer specialists for assessment of risk (high or low) and chemotherapy administration (yes or no). In 2015 the survey was sent twice (survey 1 and 2), several weeks apart, and in 2021 a third time (survey 3). Only the second and third surveys included the 70-gene signature result.
41 breast cancer specialists participated in all three surveys. Overall agreement between respondents decreased slightly between survey 1 and 2, but increased again in survey 3. Over time there was an increase in agreement with the 70-gene signature result on risk assessment, 23% in survey 2 versus 1 and 11% in survey 3 versus 2. With information available indicating a low risk 70-gene signature (n = 25 cases), 20% of risk assessments changed from high to low and 19% of recommendations changed from yes to no chemotherapy in survey 2 versus 1, further increasing with 18% and 21%, respectively, in survey 3 versus 2.
There is a variability in risk assessment of early breast cancer patients among breast cancer specialists. The 70-gene signature provided valuable information, resulting in fewer patients being assessed as high risk and fewer recommendations for chemotherapy, increasing over time.
•Risk assessment of early breast cancer patients varies among breast specialists.•The 70-gene signature provides valuable information for risk assessment.•Information on the 70-gene signature resulted in fewer high risk assessments.•Information on the 70-gene signature resulted in fewer chemotherapy recommendations.•Agreement with the 70-gene signature result increased over time.
Summary Background The gold standard endpoint in randomised trials of locally advanced head and neck squamous-cell carcinoma (HNSCC) is overall survival. Our objective was to study whether duration ...of locoregional control or event-free survival (EFS) could be considered as surrogate endpoints to estimate the effect of radiotherapy and chemotherapy on overall survival. This would allow a reduction in the duration and cost of the development of new treatments. Methods Individual patient data from 104 trials (22 744 patients), with 116 treatment–control comparisons, from four meta-analyses on hyperfractionated or accelerated radiotherapy and concomitant, induction, or adjuvant chemotherapy were analysed. Duration of locoregional control was defined as the time from randomisation to the first locoregional event and EFS as the time to any first event (ie, locoregional relapse, distant recurrence, or death). At the individual level, a rank correlation coefficient between the surrogate endpoint and overall survival was used to assess surrogacy; at the trial level, a correlation coefficient R between treatment effects was used. Findings At the individual level, overall survival was more strongly correlated with EFS (range of correlations 0·82–0·90) than with locoregional control (0·65–0·76). For radiotherapy, treatment effects on both locoregional control and EFS were strongly correlated with those on overall survival (R=0·94 and 0·98, respectively). For chemotherapy, the correlations between treatment effects on EFS and overall survival were stronger than those between locoregional control and overall survival (range of R 0·79–0·93 vs 0·53–0·84, respectively). Interpretation EFS is a better correlate with overall survival than locoregional control and could be used as a surrogate for overall survival to assess the treatment effect of radiotherapy and chemotherapy in randomised trials of locally advanced HNSCC. Funding Programme Hospitalier de Recherche Clinique, the Association pour la Recherche sur le Cancer, the Ligue Nationale Contre le Cancer, and Sanofi-Aventis.
The increasing number of drugs targeting specific proteins implicated in tumourigenesis and the commercial promotion of relatively affordable genome-wide analyses has led to an increasing expectation ...among patients with cancer that they can now receive effective personalised treatment based on the often complex genomic signature of their tumour. For such approaches to work in routine practice, the development of correspondingly complex biomarker assays through an appropriate and rigorous regulatory framework will be required. It is becoming increasingly evident that a re-engineering of clinical research is necessary so that regulatory considerations and procedures facilitate the efficient translation of these required biomarker assays from the discovery setting through to clinical application. This article discusses the practical requirements and challenges of developing such new precision medicine strategies, based on leveraging complex genomic profiles, as discussed at the Innovation and Biomarkers in Cancer Drug Development meeting (8th–9th September 2016, Brussels, Belgium).
•Premature rollout of assays and technologies without proper analytical validation is often done before it is clinically appropriate.•Expensive though non-fully validated technical solutions brings no added value to the health care systems.•The current process of developing and validating biomarkers and assays needs streamlining alongside the principles developed in this paper.•In the absence of regulatory framework for biomarker development, discipline and common sense processes and guidelines must be strictly followed.
Abstract Objective This phase I study assessed the pharmacokinetic (PK), tolerability, safety and preliminary clinical activity of tamoxifen (T) and lapatinib (L) in patients with metastatic breast ...cancer (MBC). Methods Patients (pts) with hormone receptor positive MBC, irrespective of HER-2 status, were randomly assigned to T → T + L group, tamoxifen in cycle 1 for 28 days then adding lapatinib on day 1 of cycle 2; or L → T + L group, lapatinib in cycle 1 for 14 days, then adding tamoxifen on day 1 of cycle 2 to evaluate the potential drug–drug PK interaction at steady-state. The dose of tamoxifen was 20 mg/day and lapatinib 1500 mg/day. Results Twenty-five pts were enrolled of which 23 started treatment, five (22%) of them were HER-2 positive. Median age was 59 years and 96% had PS ≤1. Eleven (91.7%) pts in the T → T + L group and 10 (76.9%) in L → T + L group received at least 2 cycles of treatment. The most frequently reported drug-related adverse events (>25% of patients) were diarrhoea (62%), anaemia (56%), rash (52%), fatigue (52%), dermatology other (34%) and leukopenia (28%). Grade 3–4 drug-related toxicities were infrequent (<10%). No cardiotoxicity was observed. T plasma concentrations did not appeared to be affected by the presence of lapatinib. L steady-state plasma concentrations were 20% lower after 28 days of co-administration with T. Eight (36.4%) patients experienced stable disease and median progression free survival was 2.7 months. Conclusions The combination of L and T was safe and clinically active. T affected L plasma concentrations, which remained within the therapeutic index.
New effective chemotherapy is needed to improve the outcome of patients with advanced non-small-cell lung cancer (NSCLC). Paclitaxel administered as a single agent or in combination with cisplatin ...has been shown to be a potentially new useful agent for the treatment of NSCLC.
Between January 1995 and April 1996, 414 patients with stage IIIB or IV NSCLC were randomized to received either a control arm of high-dose cisplatin (100 mg/m(2)) or a combination of paclitaxel (175 mg/m(2), 3-hour infusion) and cisplatin (80 mg/m(2)) every 21 days.
Compared with the cisplatin-only arm, there was a 9% improvement (95% confidence interval, 0% to 19%) in overall response rate for the paclitaxel/cisplatin arm (17% v 26%, respectively; P=.028). Median time to progression was 2.7 and 4.1 months in the control and paclitaxel/cisplatin arm, respectively (P=.026). The study, however, failed to show a significant improvement in median survival for the paclitaxel/cisplatin arm (8.6 months in the control arm v 8.1 months in the paclitaxel/cisplatin arm, P=.862). There was more hematotoxicity, peripheral neuropathy, and arthralgia/myalgia on the paclitaxel/cisplatin arm, whereas the high-dose cisplatin arm produced more ototoxicity, nausea, vomiting, and nephrotoxicity. Quality of life (QOL) was similar overall between the two arms.
This large randomized phase III trial failed to show a significant improvement in survival for the paclitaxel/cisplatin combination compared with high-dose cisplatin in patients with advanced NSCLC. However, the paclitaxel/cisplatin combination did produce a better clinical response, resulting in an increased time to progression while providing a similar QOL.
To describe the attitudes of healthcare professionals and drug regulators about progression-free survival (PFS) as efficacy endpoint in clinical trials with patients with advanced cancer and to ...explore to what extent these attitudes influence the willingness to trade between PFS and toxicity.
Cross-sectional survey with regulators from the European Medicines Agency (EMA), and healthcare professionals (HCP) from the "Stichting Hemato-Oncologie voor Volwassenen Nederland" (HOVON) collaborative group and the European Organisation for Research and Treatment of Cancer (EORTC). Attitudes towards PFS were elicited using 5-point Likert items. The respondents' willingness to trade between PFS and grade 3 or 4 (G34) toxicity was assessed using the threshold technique and quantified in terms of their maximum acceptable risk (MAR).
Responses were collected from 287 HCPs and 64 regulators with mainly clinical expertise. Attitudes towards PFS were often spread out in both groups and related to beliefs about PFS being a likely surrogate for clinical benefit, being an intrinsic benefit to be distinguished from OS, or on the importance given to OS. Being a regulator or holding stronger beliefs about PFS being a likely surrogate or an intrinsic benefit were associated with a higher MAR. Presence of a supportive trend in OS was stated as important but was not associated with MAR. There was agreement on the need to address bias in the adjudication of PFS and the need for improving communication to patients about meaning, strengths, and limitations of improvements in PFS.
Attitudes towards PFS were spread out and were associated with individual differences in the willingness to trade between toxicity and PFS. There was agreement on the need to address bias in the adjudication of PFS and improving communication to patients.
This phase I trial investigating the vascular targeting agent NGR-hTNF aimed to determine the (a) dose-limiting toxicities, (b) maximum tolerated dose (MTD), (c) pharmacokinetics and ...pharmacodynamics, (d) vascular response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and (e) preliminary clinical activity in solid tumors.
NGR-hTNF was administered once every 3 weeks by a 20- to 60-minute i.v. infusion to cohorts of three to six patients with solid tumors in escalating doses. Pharmacokinetic and pharmacodynamic analyses in blood were done during the first four cycles. DCE-MRI was done in cycle 1 at baseline and 2 hours after the start of the infusion.
Sixty-nine patients received a total of 201 cycles of NGR-hTNF (0.2-60 microg/m(2)). Rigors and fever were the most frequently observed toxicities. Four dose-limiting toxicities were observed (at doses of 1.3, 8.1, and 60 microg/m(2)), of which three were infusion related. The MTD was 45 microg/m(2). The mean apparent terminal half-life ranged from 0.963 to 2.08 hours. DCE-MRI results of tumors showed a vascular response to NGR-hTNF. No objective responses were observed, but 27 patients showed stable disease with a median duration of 12 weeks.
NGR-hTNF was well tolerated. The MTD was 45 microg/m(2) administered in 1 hour once every 3 weeks. DCE-MRI results showed the antivascular effect of NGR-hTNF. These findings call for further research for defining the optimal biological dose and clinical activity of NGR-hTNF as a single agent or in combination with cytotoxic drugs.
In Europe, most of the cancer clinical research dedicated to therapeutic innovations aims primarily at regulatory approval. Once an anticancer drug enters the common market, each member state ...determines its real-world use based on its own criteria: pricing, reimbursement and clinical indications. Such an innovation-centred clinical research landscape might neglect patient-relevant issues in real-world setting, such as comparative effectiveness of distinct treatment options or long-term safety monitoring.
The European Organisation for Research and Treatment of Cancer (EORTC) advocates reforming the current ‘innovation-centred’ system to a truly ‘patient-centred’ paradigm with systematically coordinated applied clinical research in conjunction with drug development, featuring the following strategy:(1)An interconnected partnership among key-stakeholders involved in the care delivery system, namely patients, health professionals, academia, pharmaceutical industry, regulators, payers and policy-makers, to optimise the transition from research to clinical practice and vice versa;(2)An independent research infrastructure host and coordination ensuring independent, high quality and sustainable research.
•The limits and the consequences of the current development of anticancer therapeutic innovations in Europe.•The EORTC advocates for a paradigm shift from an ‘innovation-centred’ to a truly ‘patient-centred’ approach.•The new paradigm features interconnected partnership among stakeholders and independent research infrastructure coordination.
There is no consensus on how to estimate kidney function for the assessment of eligibility in clinical cancer trials.
We recalculated the creatinine clearance (CrCl)/glomerular filtration rate (GFR) ...at baseline in a total of 1768 patients enrolled in twelve clinical trials using the Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI 2021) and European Kidney Function Consortium (EKFC) formulas. Patients were classified as having renal impairment (RI; CrCl/GFR <60 mL/min) or no renal impairment (NRI; CrCl/GFR ≥60 mL/min) with each of the four formulas, respectively. Furthermore, we analyzed the number of adverse events (AE) per month under study treatment using measures of central tendency, variability and regression models.
Using CG, EKFC, MDRD and CKD-EPI 2021, 152 (8 %), 140 (8 %), 110 (6 %), and 61 (4 %) patients had RI respectively. Indeed, 47 (3 %) patients had RI using all 4 formulas, while 158 (9 %) had RI by at least one but not all four methods. CG showed the broadest variability and inconsistencies with other methods. All calculation methods performed similarly for excluding patients at risk of severe AE. EKFC demonstrated superior predictive ability for excluding patients at risk of renal and urinary tract AE.
This post hoc analysis highlights the importance of choosing accurate and representative methods for kidney function estimation in clinical cancer trials. CG should be replaced by newer methods. While CKD-EPI 2021 may maximize trial accrual, EKFC should be considered for treatment affecting kidney function.
•Newer methods (MDRD, CKD-EPI2021, EKFC) show more consistency than Cockcroft-Gault.•CKD-EPI2021 estimation maximizes trial accrual.•EKFC formula predicts renal and urinary tract adverse events more effectively.•"As per institutional standard" is not recommended due to differences in calculation methods.
PDF
