•Current anticancer drug trial designs are often not suitable to determine an optimal efficacy threshold.•This implies potential overtreatment with unnecessary toxicities and undermines the success ...rates of trials.•De-escalation non-inferiority trials require considerable resources and time.•We propose a new Framework for Cautious Escalation for clinical trials in oncology.•The FCE may prevent overtreatment, optimize use of resources and obviate the need for de-escalation trials.
The developmental workflow of the currently performed phase 1, 2 and 3 cancer trial stages lacks essential information required for the determination of the optimal efficacy threshold of new anticancer regimens. Due to this there is a serious risk of overdosing and/or treating for an unnecessary long time, leading to excess toxicity and a higher financial burden for society. But often post-approval de-escalation trials for dose-optimization and treatment de-intensification are not performed due to failing resources and time. Therefore, the developmental workflow needs to be restructured toward cautious systemic cancer treatment escalation, in order to guarantee optimal efficacy and sustainability.
In this manuscript we discuss opportunities to produce the information needed for cautious escalation, based on models of cancer growth and cancer kill kinetics as well as exploratory biomarkers, for the purpose of designing the optimal phase 3 superiority trial. Subsequently, we compare the sample size needed for a phase 3 superiority trial, followed by a necessary de-escalation trial with the sample size needed for a multi-arm phase 3 trial with intervention arms of differing intensity. All essential items are structured within a Framework for Cautious Escalation (FCE). The discussion uses illustrations from the breast cancer setting, but aims to be applicable for all cancers.
The FCE is a promising model of clinical development in oncology to prevent overtreatment and associated issues, especially with regard to the number of repetitive treatment cycles. It will hopefully increase the relevance and success rate of clinical trials, to deliver improved patient-centric outcomes.
We established an international consortium to review and discuss relevant clinical evidence in order to develop expert consensus statements related to cancer management during the severe acute ...respiratory syndrome coronavirus 2-related disease (COVID-19) pandemic. The steering committee prepared 10 working packages addressing significant clinical questions from diagnosis to surgery. During a virtual consensus meeting of 62 global experts and one patient advocate, led by the European Society for Medical Oncology, statements were discussed, amended and voted upon. When consensus could not be reached, the panel revised statements until a consensus was reached. Overall, the expert panel agreed on 28 consensus statements that can be used to overcome many of the clinical and technical areas of uncertainty ranging from diagnosis to therapeutic planning and treatment during the COVID-19 pandemic.
Background:: Adjuvant 5-fluoruracil-based chemotherapy significantly decreases mortality among patients with stage III colon cancer, but is less prescribed with rising age. We were interested in the ...pattern of adjuvant treatment and possible effects on survival among elderly patients. Patients and methods:: All resected patients aged 65–79 with stage III colon carcinoma, diagnosed between 1995 and 2001 in the Comprehensive Cancer Centre South registry area in the Netherlands were included (n=577). We examined determinants of receipt of adjuvant chemotherapy and their relation to survival. Results:: The proportion of elderly patients receiving adjuvant chemotherapy increased from 19% in 1995 to 50% in 2001, but a large inter-hospital variation remained. In a multivariable analysis, females odds ratio (OR) 0.5, P=0.006, patients with comorbidity OR 0.5, P=0.005, and patients with a low socioeconomic status OR 0.5, P=0.02 received less adjuvant therapy. Between 1995 and 2001 survival of elderly patients improved (hazard ratio 0.8, P=0.04). Conclusion:: Although an increasing proportion of elderly patients with colon cancer are treated with adjuvant chemotherapy, many elderly patients still do not receive this treatment. As expected, receipt of adjuvant treatment decreased in the presence of comorbidity, but the clinical rationale for undertreatment of women and patients with low socioeconomic status is not clear.
Abstract Introduction Adjuvant chemotherapy still is a controversial therapy for rectal cancer patients. The aim of this study was to analyze the effect of adjuvant chemotherapy on recurrence-free ...survival (RFS) for patients with stage III rectal cancer treated in clinical practice, taking into account which neo-adjuvant treatment patients received. Methods Patients from regions in the Netherlands diagnosed between 1996 and 2013 with pathological stage III rectal cancer who received short-course radiotherapy, chemoradiation or no neo-adjuvant treatment and who underwent surgery were included. After stratification by neo-adjuvant treatment, 5-year RFS according to adjuvant chemotherapy receipt was calculated using Kaplan–Meier curves. Cox regression was used to discriminate the independent effect of adjuvant chemotherapy on the risk of recurrence/death. Results The study population consisted of 829 patients, of whom 537 (65%) patients received short-course radiotherapy, 128 (15%) patients received chemoradiation and 164 (20%) patients received no neo-adjuvant treatment. Adjuvant chemotherapy was administered to 152 (18%) patients. Adjuvant chemotherapy was associated with improved 5-year RFS for patients who received short-course radiotherapy (61% vs. 46%, p = 0.005) and for patients who did not receive any neo-adjuvant treatment (70% vs. 28%, p < 0.0001). In multivariable analyses, adjuvant chemotherapy was associated with a reduced risk of recurrence/death for patients treated with short-course radiotherapy (HR 0.65, 95% CI 0.46–0.93) and for patients without neo-adjuvant treatment (HR 0.35, 95% CI 0.18–0.71), but not for patients treated with chemoradiation (HR 1.11, 95% CI 0.51–2.41). Conclusion Among patients with stage III rectal cancer, the effect of adjuvant chemotherapy on RFS seems to vary by neo-adjuvant treatment.
During the European Society for Medical Oncology (ESMO) Congress 2022, outcome data of a great number of clinical trials were presented. For the attending medical oncologist, it is important to ...structure these data in a way that facilitates a trade-off between treatment burden and benefit.
To illustrate this, we carried out a narrative non-systematic review of 12 selected oral presentations with potential impact on future daily practice, focusing on trial methodology, possible study flaws, reported clinical benefit and implementability.
The selected presentations encompassed 10 phase III trials, 1 randomized phase II trial and 1 phase II trial. In 7 out of 12 trials, quality of life and/or patient-reported outcomes had been evaluated. None of the trials, which reported progression-free survival (PFS) data, provided information, which could exclude informative censoring bias. In none of the trials reporting overall survival (OS) data, potential flaws due to undesirable crossover and imbalance between study groups regarding post-progression treatments were addressed. For the 11 reviewed randomized trials, the ESMO-Magnitude of Clinical Benefit Scale (MCBS) grade achieved with the new intervention was calculated based on the presented data. The MCBS grade varied from 1 to 5.
Our review confirms the high-quality standard of current cancer research and the clinical relevance of the research questions answered. However, during presentation of PFS and/or OS data, factors known to affect PFS and OS analysis should be structurally addressed. In order to keep cancer care affordable and sustainable, it could be considered to include an ESMO-MCBS threshold in the drug appraisal process of regulatory authorities.
•During the ESMO Congress 2022 outcome data of a great number of trials were presented.•Data appraisal requires a trade-off between treatment burden and benefit.•To illustrate this we carried out a narrative non-systematic review of 12 selected oral presentations.•Factors known to affect PFS and OS analysis were not structurally addressed.•Selection of only fit patients in later-line advanced cancer trials may limit generalizability.
The European Society for Medical Oncology (ESMO) 2021 conference provided a high number of randomized phase III trial reports, many of which were claimed to be practice changing. Given the short time ...available for conference presentations, results and conclusions tend to have greatest priority with less time remaining for study background and study methodology.
On behalf of the ESMO Practicing Oncologists Working Group, 11 potentially practice-changing reports were selected and screened for three main questions: (i) Did the investigators provide sufficient details with regard to Patients and Methods to make the results comprehensible? (ii) Were there any reasons to consider bias? (iii) To which extent did the results presented translate to clinical benefit?
In 2 out of 11 trials, the study design presented differed considerably from the study design described at ClinicalTrials.gov. Allocation concealment was not carried out in 6 out of 11 trials. In none of the trials reporting progression-free survival was informative censoring considered an issue. In none of the trials reporting overall survival was desirable crossover considered an issue. Defined trial outcome measures depicted at ClinicalTrials.gov, which could boost or weaken the ESMO-Magnitude of Clinical Benefit Scale score, were often lacking in the presentation. Study success was claimed in a heterogeneous manner, which was often not clearly linked to overall clinical benefit.
ESMO conference presentations can inform the scientific community and catalyze further research but cannot replace the full papers in peer-reviewed journals, which are needed to estimate the thoroughness of the results, the overall impact on clinical benefit and the consequences for future treatment guidelines.
•An oncological peer-reviewed paper is lengthy and well structured.•An oncological conference presentation is short and less structured, but its impact can be high.•ESMO 2021 conference encompassed many possibly practice-shaping phase III trial reports.•A survey of 11 selected reports to ascertain if the conclusions made were adequately underlined by the provided information.
We examine how differences in language models, learned by different data-driven systems performing the same NLP task, can be exploited to yield a higher accuracy than the best individual system. We ...do this by means of experiments involving the task of morphosyntactic word class tagging, on the basis of three different tagged corpora. Four well-known tagger generators (hidden Markov model, memory-based, transformation rules, and maximum entropy) are trained on the same corpus data. After comparison, their outputs are combined using several voting strategies and second-stage classifiers. All combination taggers outperform their best component. The reduction in error rate varies with the material in question, but can be as high as 24.3% with the LOB corpus.
A review-based hypothesis is presented on the energy flow in cancer patients. This hypothesis centres on the hypoxic condition of tumours, the essential metabolic consequences, especially the ...gluconeogenesis, the adaptation of the body, and the pathogenesis of cancer cachexia.
In growing tumours the O
2 concentration is critically low. Mammalian cells need O
2 for the efficient oxidative dissimilation of sugars and fatty acids, which gives 38 and 128 moles of ATP per mole glucose and palmitic acid, respectively. In the absence of sufficient O
2 they have to switch to anaerobic dissimilation, with only 2 moles of ATP and 2 moles of lactic acid from 1 mole of glucose. Since mammalian cells cannot ferment fatty acids, in vivo tumour cells completely depend on glucose fermentation. Therefore, growth of these tumour cells will require about 40 times more glucose than it should require in the presence of sufficient O
2.
Since lactic acid lowers the intracellular pH, it decreases the activity of pyruvate dehydrogenase, stimulates fermentation, and thus amplifies its own fermentative production. Compensatory glucose is provided by hepatic gluconeogenesis from lactic acid. However, the liver must invest 3 times more energy to synthesize glucose than can be extracted by tumour cells in an anaerobic way. The liver extracts the required energy from amino acids and especially from fatty acids in an oxidative way. This may account for weight loss, even when food intake seems adequate.
In the liver 6 moles of ATP are invested in the gluconeogenesis of one mole of glucose. The energy content of 4 out of these 6 moles of ATP is dissipated as heat. This may account for the elevated body temperature and sweating experience by cancer patients.
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