Effect of tumor burden and radical surgery on survival difference between upfront, early interval or delayed cytoreductive surgery in ovarian cancer

Procediments quirúrgics de citoreducció; Teràpia neoadjuvant; Neoplàsies d'ovariProcedimientos quirúrgicos de citorreducción; Terapia neoadyuvante; Neoplasias de ovarioCytoreduction Surgical Procedures; Neoadjuvant Therapy; Ovarian NeoplasmsObjective We sought to evaluate the impact on survival of tumor burden and surgical complexity in relation to the number of cycles of neoadjuvant chemotherapy (NACT) in patients with advanced ovarian cancer (OC) with minimal (CC-1) or no residual disease (CC-0). Methods This retrospective study included patients with International Federation of Gynaecology and Obstetrics IIIC–IV stage OC who underwent debulking surgery at 4 high-volume institutions between January 2008 and December 2015. We assessed the overall survival (OS) of primary debulking surgery (PDS group), early interval debulking surgery after 3–4 cycles of NACT (early IDS group) and delayed debulking surgery after 6 cycles (DDS group) with CC-0 or CC-1 according to peritoneal cancer index (PCI) and Aletti score. Results Five hundred forty-nine women were included: 175 (31.9%) had PDS, 224 (40.8%) early IDS and 150 (27.3%) DDS. Regardless of Aletti score, median OS after PDS was significantly higher than after early IDS or DDS, but the survival difference was higher in women with an Aletti score 10, there were no differences between PDS and early IDS, but DDS was associated with decreased OS. Conclusion The benefit of complete PDS compared with NACT was maximal in patients with a low complexity score. In patients with low tumor burden, there was a survival benefit of PDS over early IDS or DDS. In women with high tumor load, DDS impaired the oncological outcome.The project that gave rise to these results received the support of a fellowship from “la Caixa” Foundation (ID 100010434). The fellowship code is LCF/BQ/EU18/11650038

Risk Factors for Pharyngocutaneous Fistula After Total Pharyngolaryngectomy

Purpose:To evaluate the risk factors of pharyngocutaneous fistula after total pharyngolaryngectomy (TPL) in orderto reduce theirincidence and propose a perioperative rehabilitation protocol.Materials and Methods:This was a multicenter retrospectivestudy based on 456 patients operated for squamous cell carcinoma by total laryngectomy or TPL. Sociodemographic, medical,surgical, carcinologic, and biological risk factors were studied. Reactive C protein was evaluated on post-op day 5. Patients weredivided into a learning population and a validation population with patients who underwent surgery between 2006 and 2013 andbetween 2014 and 2016, respectively. A risk score of occurrence of salivary fistula was developed from the learning population dataand then applied on the validation population (temporal validation).Objective:To use a preoperative risk score in order tomodify practices and reduce the incidence of pharyngocutaneous fistula.Results:Four hundred fifty-six patients were included,328 in the learning population and 128 in the validation population. The combination of active smoking over 20 pack-years, ahistory of cervical radiotherapy, mucosal closure in separate stitches instead of running sutures, and the placement of a pedicleflap instead of a free flap led to a maximum risk of post-op pharyngocutaneous fistula after TPL. The risk score was discriminantwith an area under the receiver operating characteristic curve of 0.66 (95% confidence interval [CI]¼0.59-0.73) and 0.70 (95% CI¼0.60-0.81) for the learning population and the validation population, respectively.Conclusion:A preoperative risk score couldbe used to reduce the rate of pharyngocutaneous fistula after TPL by removing 1 or more of the 4 identified risk factors

Taking into account the heterogeneity of the elderly population in the design of phase II clinical trials in geriatric oncologye

Le cancer du sujet âgé est un réel problème de santé publique. L’incidence du cancer augmentant avec l’âge couplée au vieillissement général de la population font que plus de la moitié des tumeurs diagnostiquées aujourd’hui le sont chez des patients de plus de 65 ans. Cependant, cette population hétérogène a longtemps été exclue des essais cliniques et le manque de données prospectives rend difficile la prise en charge de ces patients. Plusieurs publications soulignent l’importance et la complexité de réaliser des essais cliniques dans cette population. Les schémas classiques ne prenant pas en compte l’hétérogénéité, les essais de phase II spécifiques aux sujets âgés sont rares et généralement stratifiés en sous-groupes définis selon un critère gériatrique ce qui augmente le nombre de patients à inclure et donc diminue la faisabilité. L’objectif de cette thèse est de présenter, comparer et développer des schémas de phase II adaptatifs stratifiés permettant de prendre en compte l’hétérogénéité de la population âgée. L’utilisation de ce type d’approche permet de réduire le nombre de patients à inclure tout en maintenant la puissance statistique et en contrôlant le risque d’erreur de type I. Ce qui implique une diminution du coût et de la durée de l’étude et donc une augmentation de la faisabilité. Afin d’améliorer l’efficacité de la recherche clinique en oncogériatrie, il est donc primordial d’utiliser des schémas adaptatifs stratifiés prenant en compte l’hétérogénéité de la population et permettant d’identifier un sous-groupe d’intérêt susceptible de pouvoir bénéficier (ou non) de la nouvelle thérapeutique.Elderly cancer is a real public health problem. With the overall aging population and the increased incidence of cancer, more than half of all tumors diagnosed today are in patients aged 65 years or older. However, this heterogeneous population has long been excluded from clinical trials and the lack from prospective data makes it difficult managing these patients. Many publications highlight the importance and the complexity of conducting clinical trials in this population. As classical phase II designs do not take into account the heterogeneity, elderly specific phase II clinical trials are very uncommon and generally conducted in specific subgroups defined by geriatric criteria which increases the number of patients to be included and thus reduces the feasibility. The objective of this thesis is to present, compare and develop stratified adaptive designs that address the heterogeneity of the elderly population. The use of this methodology can minimize the number of patients to be included while maintaining statistical power and controlling the type I error risk. This implies a reduction in the cost and duration of the study and thus increases the feasibility. In order to improve the efficiency of clinical research in geriatric oncology, it is essential to use stratified adaptive designs that take into account the heterogeneity of the population and make it possible to identify a subgroup of interest that might benefit (or not) from the new therapeutic

Prise en compte de l'hétérogénéité de la population âgée dans le schéma des essais cliniques de phase II en oncogériatrie

Le cancer du sujet âgé est un réel problème de santé publique. L’incidence du cancer augmentant avec l’âge couplée au vieillissement général de la population font que plus de la moitié des tumeurs diagnostiquées aujourd’hui le sont chez des patients de plus de 65 ans. Cependant, cette population hétérogène a longtemps été exclue des essais cliniques et le manque de données prospectives rend difficile la prise en charge de ces patients. Plusieurs publications soulignent l’importance et la complexité de réaliser des essais cliniques dans cette population. Les schémas classiques ne prenant pas en compte l’hétérogénéité, les essais de phase II spécifiques aux sujets âgés sont rares et généralement stratifiés en sous-groupes définis selon un critère gériatrique ce qui augmente le nombre de patients à inclure et donc diminue la faisabilité. L’objectif de cette thèse est de présenter, comparer et développer des schémas de phase II adaptatifs stratifiés permettant de prendre en compte l’hétérogénéité de la population âgée. L’utilisation de ce type d’approche permet de réduire le nombre de patients à inclure tout en maintenant la puissance statistique et en contrôlant le risque d’erreur de type I. Ce qui implique une diminution du coût et de la durée de l’étude et donc une augmentation de la faisabilité. Afin d’améliorer l’efficacité de la recherche clinique en oncogériatrie, il est donc primordial d’utiliser des schémas adaptatifs stratifiés prenant en compte l’hétérogénéité de la population et permettant d’identifier un sous-groupe d’intérêt susceptible de pouvoir bénéficier (ou non) de la nouvelle thérapeutique.Elderly cancer is a real public health problem. With the overall aging population and the increased incidence of cancer, more than half of all tumors diagnosed today are in patients aged 65 years or older. However, this heterogeneous population has long been excluded from clinical trials and the lack from prospective data makes it difficult managing these patients. Many publications highlight the importance and the complexity of conducting clinical trials in this population. As classical phase II designs do not take into account the heterogeneity, elderly specific phase II clinical trials are very uncommon and generally conducted in specific subgroups defined by geriatric criteria which increases the number of patients to be included and thus reduces the feasibility. The objective of this thesis is to present, compare and develop stratified adaptive designs that address the heterogeneity of the elderly population. The use of this methodology can minimize the number of patients to be included while maintaining statistical power and controlling the type I error risk. This implies a reduction in the cost and duration of the study and thus increases the feasibility. In order to improve the efficiency of clinical research in geriatric oncology, it is essential to use stratified adaptive designs that take into account the heterogeneity of the population and make it possible to identify a subgroup of interest that might benefit (or not) from the new therapeutic

Designing phase II clinical trials to target subgroup of interest in a heterogeneous population: A case study using an R package

International audiencePhase II trials that evaluate target therapies based on a biomarker must be well designed in order to assess anti-tumor activity as well as clinical utility of the biomarker. Classical phase II designs do not deal with this molecular heterogeneity and can lead to an erroneous conclusion in the whole population, whereas a subgroup of patients may well benefit from the new therapy. Moreover, the target population to be evaluated in a phase III trial may be incorrectly specified. Alternative approaches are proposed in the literature that make it possible to include two subgroups according to biomarker status (negative/positive) in the same study. Jones, Parashar and Tournoux et al. propose different stratified adaptive two-stage designs to identify a subgroup of interest in a heterogeneous population that could possibly benefit from the experimental treatment at the end of the first or second stage. Nevertheless, these designs are rarely used in oncology research. After introducing these stratified adaptive designs, we present an R package (ph2hetero) implementing these methods. A case study is provided to illustrate both the designs and the use of the R package. These stratified adaptive designs provide a useful alternative to classical two-stage designs and may also provide options in contexts other than biomarker studies

Focus on an infrequently used quantity in the context of competing risks: The conditional probability function

International audienceIn clinical studies of hematologic and oncologic diseases, the outcomes of interest are generally composite time to event endpoints which are usually defined by occurrence of different event types. Nonetheless, clinicians are interested in studying only one event type, which leads to a competing risks situation. In this context, Pepe and Mori presented a quantity directly derived from the cumulative incidence: the conditional probability. This function defines the probability that a given event occurs, conditionally on not having had a competing event by that time. The objective of this paper is to present this conditional cumulative incidence function and to compare its use to the cumulative incidence in different data sets. Different scenarios highlight the importance of the competing event on the interpretation of the conditional probability. Conditional probability needs to be interpreted jointly with the cumulative incidence. This quantity can be of interest especially when the risk of the competing event is large, strongly precludes the risk of the event of interest and provides useful additional information

A stratified adaptive two-stage design with co-primary endpoints for phase II clinical oncology trials

Background: Given the inherent challenges of conducting randomized phase III trials in older cancer patients, single-arm phase II trials which assess the feasibility of a treatment that has already been shown to be effective in a younger population may provide a compelling alternative. Such an approach would need to evaluate treatment feasibility based on a composite endpoint that combines multiple clinical dimensions and to stratify older patients as fit or frail to account for the heterogeneity of the study population to recommend an appropriate treatment approach. In this context, stratified adaptive two-stage designs for binary or composite endpoints, initially developed for biomarker studies, allow to include two subgroups whilst maintaining competitive statistical performances. In practice, heterogeneity may indeed affect more than one dimension and incorporating co-primary endpoints, which independently assess each individual clinical dimension, would therefore appear quite pertinent. The current paper presents a novel phase II design for co-primary endpoints which takes into account the heterogeneity of a population. Methods: We developed a stratified adaptive Bryant & Day design based on the Jones et al. and Parashar et al. algorithm. This two-stage design allows to jointly assess two dimensions (e.g. activity and toxicity) in two different subgroups. The operating characteristics of this new design were evaluated using examples and simulation comparisons with the Bryant & Day design in the context where the study population is stratified according to a pre-defined criterion. Results: Simulation results demonstrated that the new design minimized the expected and maximum sample sizes as compared to parallel Bryant & Day designs (one in each subgroup), whilst controlling type I error rates and maintaining a competitive statistical power as well as a high probability of detecting heterogeneity. Conclusions: In a heterogeneous population, this two-stage stratified adaptive phase II design provides a useful alternative to classical one and allows to identify a subgroup of interest without dramatically increasing sample size. As heterogeneity is not limited to older populations, this new design may also be relevant to other study populations such as children or adolescents and young adults or the development of targeted therapies based on a biomarker

Prognostic impact of celiac lymph node involvement in patients after frontline treatment for advanced ovarian cancer

International audienceCompleteness of cytoreduction is the most important prognostic factor in patients with advanced ovarian cancer (OC). Extensive upper abdominal surgery has allowed to increase the rate complete cytoreduction and the feasibility of resection of celiac lymph nodes (CLN) and porta hepatis disease in these patients has been demonstrated. The aim of our study was to assess the prognostic impact of CLN involvement in patients with primary advanced OC undergoing a complete cytoreductive surgery (CRS)