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Objectives How frequently patient-reported outcome (PRO) data are collected in commercial cancer clinical trials after treatment discontinuation and the quality of that data are poorly understood. We reviewed treatment discontinuation follow-up PRO data collection to learn about trials collecting these data and understand data quality. The review included 4 cancer types representing potential for long- (prostate cancer), medium-/long- (breast cancer), and short-term (pancreatic cancer and hepatocellular carcinoma) follow-up owing to disease trajectory. Methods We reviewed registration trials in US Food and Drug Administration databases between January 2010 and January 2019. Protocols were reviewed to determine whether PROs were collected and, if so, whether these included the follow-up phase. Clinical study reports were reviewed when follow-up PROs were collected to determine completion rates. Results were summarized using descriptive analyses. Results Of the 46 trials containing PRO data, 46% had at least 1 follow-up PRO assessment. Follow-up schedules of assessment were wide ranging; the first assessment occurred between 30 days and 6 months after stopping treatment with follow-up for as long as 3 years. PRO completion rates were reported in 57% of 21 trials; at the first follow-up assessment, completion rates for the treatment arm ranged from 38% to 91% and from 41% to 100% in the control arm. Conclusions The quality of the follow-up PRO data, based on completion rates, was variable, as was the duration of follow-up. A clear research objective should be developed for follow-up PRO data, accounting for patient burden. If PRO data are collected, monitoring should be implemented to improve completion because poor completion limits data use in the benefit-risk assessment.

On May 24, 2019, the FDA granted regular approval to alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. Approval was based on the SOLAR-1 study, a randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST v1.1 in the cohort of trial participants whose tumors had a PIK3CA mutation. The estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11 months [95% confidence interval (CI), 7.5–14.5] compared with 5.7 months (95% CI, 3.7–7.4) in the placebo plus fulvestrant arm (HR, 0.65; 95% CI, 0.50–0.85; two-sided P = 0.001). The median overall survival was not yet reached for the alpelisib plus fulvestrant arm (95% CI, 28.1–NE) and was 26.9 months (95% CI, 21.9–NE) for the fulvestrant control arm. No PFS benefit was observed in trial participants whose tumors did not have a PIK3CA mutation (HR, 0.85; 95% CI, 0.58–1.25). The most common adverse reactions, including laboratory abnormalities, on the alpelisib plus fulvestrant arm were increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, and alopecia.

Patient-reported outcome (PRO) measures describe how a patient feels or functions and are increasingly being used in benefit-risk assessments in the development of cancer drugs. However, PRO research objectives are often ill-defined in clinical cancer trials, which can lead to misleading conclusions about patient experiences. The estimand framework is a structured approach to aligning a clinical trial objective with the study design, including endpoints and analysis. The estimand framework uses a multidisciplinary approach and can improve design, analysis, and interpretation of PRO results. On the basis of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use E9(R1) addendum, we provide an overview of the estimand framework intended for a multistakeholder audience. We apply the estimand framework to a hypothetical trial for breast cancer, using physical function to develop specific PRO research objectives. This Policy Review is not an endorsement of a specific study design or outcome; rather, it is meant to show the application of principles of the estimand framework to research study design and add to ongoing discussion. Use of the estimand framework to review medical products and label PROs in oncology can improve communication between stakeholders and ultimately provide a clearer interpretation of patient experience in the development of oncological drugs.

Background: Patient reports of expected treatment side effects are increasingly collected as part of the assessment of patient experience in clinical trials. A global side effect item that is patient-reported has the potential to inform overall tolerability. Therefore, the aim of this study was to examine the completion and distribution of such a global single-item measure of side effect burden in five cancer clinical trials. Methods: Data from five trials from internal Food and Drug Administration databases that included the Functional Assessment of Cancer Therapy–General single-item measure of overall side effect burden (i.e. impact on degree of bother) were analyzed. Completion rates for the side effect bother item, items adjacent to this item, and two non-adjacent items on the Functional Assessment of Cancer Therapy–General that are related to health-related quality of life were calculated at the baseline assessment and at the 3-month assessment. To evaluate the distribution, the percentage of patients reporting high levels (quite a bit or very much bother) of side effect bother at baseline and 3 months was assessed. Results: Completion rates for all items were at least 80% regardless of time point or trial population. However, in three of the five trials, completion rates for the side effect bother item were lower at baseline compared to adjacent and non-adjacent items. This difference was not observed at 3 months. Up to 9.4% of patients reported high levels of side effect bother at baseline. Conclusion: Patients may enter trials already reporting some bother from side effects. This can make interpretation of results with respect to the investigational agent under study challenging. Patients may skip an item evaluating side effect bother at baseline, suggesting some difficulty with interpretation of what is being asked. Further study of the wording and utility of a baseline side effect bother assessment is warranted.

Human activities like urbanization and agriculture affect spatial biodiversity patterns. The presence and activities of humans richly benefit alien species, but native species usually decline in human-impacted areas. Considering that the richness of alien and native species are inter-related, we explored the effect of human population density, human-related land uses (agricultural and urban), and natural land area on avian (alien and native) species richness of Massachusetts for two time periods using Generalized Additive Models. Avian alien species richness increased with native species richness in both time periods. Despite the predominant role of native species richness as a major driver of alien species richness, human activities play an important additional role in shaping species richness patterns of established aliens. Human-related land uses (urban and agricultural) and human population favored alien species richness in both time periods. Counter to expectations, human activities were also positively associated to native avian species richness. Possible explanations of these patterns may include habitat heterogeneity, increased availability of resources, and reduced predation risk.

Understanding the ecological mechanisms behind biological invasions remains a major focus of conservation biology and ecosystem management. Several hypotheses highlight that different facets of native biodiversity affect the establishment and spread of alien species. Here, we approach this question by examining the spatiotemporal relationship between alien bird species richness and different facets of biodiversity (taxonomic, functional, and phylogenetic) using breeding bird atlases for three U.S. states and for two time periods in each state. We associated native species richness, and functional and phylogenetic diversity with alien species richness, using generalized least squares models. Our results show that, consistently, across the three states and two time periods examined, alien species richness is positively associated with native diversity, and particularly with phylogenetic diversity. The relative importance of biodiversity metrics reflecting the functional or phylogenetic range occupied by the assemblage seems to advocate in favor of the importance of resource diversity as a main driver of both native and alien diversity. The secondary importance of biodiversity facets reflecting species functional or phylogenetic similarity, along with the lack of importance of functional or phylogenetic clustering or overdispersion, implies that if this relationship is shaped by biotic interactions, then biotic interactions facilitating coexistence (including even processes like predator‐mediated coexistence) are far more important than adversarial interactions like competition, at least at the scale of our analysis. Finally, the dominance of phylogenetic metrics over functional ones highlights the adaptive potential of a community accumulated over long lineage history may play an additional role as a source of information on evolutionary processes driving diversity patterns.

Biliary obstruction is common in pancreatobiliary malignancies and has a negative impact on the patient’s quality of life, postoperative complications, and survival rates. Particularly in the last decade, there has been enormous progress regarding the diagnostic and therapeutic options in patients with malignant biliary obstruction. Endoscopy has given a new insight in this direction and novel techniques have been developed for the better characterization and treatment of malignant strictures. We herein summarize the available data on the different endoscopic techniques, and clarify their role in the diagnosis and treatment of malignant biliary obstructive disease. Finally, we propose an algorithm that can facilitate management decisions in these patients.

On May 3, 2019, the FDA granted regular approval to ado-trastuzumab emtansine (KADCYLA), for the adjuvant treatment of patients with HER2-positive early-breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane-based chemotherapy and trastuzumab-based treatment. Approval was based on data from the KATHERINE trial, which randomized patients to receive ado-trastuzumab emtansine or trastuzumab. At 3 years, the event-free rate for invasive disease-free survival in the ado-trastuzumab emtansine arm was 88.3% [95% confidence interval (CI), 85.8–90.7] compared with 77.0% (95% CI, 73.8–80.7) in the trastuzumab arm, (HR, 0.50; 95% CI, 0.39–0.64; P < 0.0001). Results from secondary endpoints, subgroup analyses, and sensitivity analyses generally supported the primary efficacy endpoint results. Common adverse reactions (>25% and higher incidence in ado-trastuzumab emtansine arm) with ado-trastuzumab emtansine were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia. Ado-trastuzumab emtansine is the first drug approved for the treatment of patients with residual disease after neoadjuvant treatment and surgery. This article summarizes the FDA review and the data supporting the approval of ado-trastuzumab emtansine as a component of treatment for patients with HER2-positive EBC with residual disease.

Older adults with lung cancer often have comorbidities that may increase risk of symptomatic adverse events (AEs) and physical function decline. The objective of this study was to examine age-related differences in patient-reported symptoms and functional domains in patients with advanced lung cancer receiving immunotherapy drugs.Three randomized controlled trials of anti-programmed death receptor-1/programmed death-ligand 1 therapy in patients with advanced non-small cell lung cancer that included patient-reported outcomes (PROs) were identified. Baseline PRO data were pooled for treatment arms from 2 trials that included the same PRO tools. Age-related differences in baseline mean scores for each of the health-related quality of life functional and symptom scales were assessed for patients ≥70 years and70 years. Mean change from Baseline at 3 months was also calculated and plotted for each age group. The adequacy of PRO assessments was assessed by comparing clinician-reported AE data in the 3 trials to the item content of the PRO tools included.Across the 3 trials, 75 of patients were under 70 and 26% patients were 70 and older. Comparing baseline scores in the 2 trials with the same PRO tool, older adults reported small differences including lower physical functioning, less pain, insomnia and financial difficulties, and higher social functioning than younger patients at baseline. No large differences in the distributions of mean change from baseline in function or symptom were identified. Several common clinician-reported symptomatic AEs were not assessed by the PRO strategy employed in the 3 trials. Three clinician-reported symptomatic AEs (rash, fever, and pruritus) that were commonly reported in the safety data (9%-19%) were not assessed using the PRO tools employed.While several small differences were seen, there did not appear to be large differences at baseline or in the distributions of change from baseline in PRO functional domains between younger and older patients with lung cancer undergoing anti-programmed death receptor -1/programmed death-ligand 1 therapy. Relevant symptomatic side effects were not assessed by PRO measures in these trials, and this is a limitation of current PRO assessment strategies.

Background Little is known on the impact of emerging treatments for advanced melanoma (stages III and IV) on patients’ functioning and well-being. The objective of this study was to describe the patient-reported treatment-related symptom (TRS) burden in advanced melanoma. Method Twenty-nine in-depth, qualitative interviews were conducted among adult patients with advanced melanoma in Canada using a semi-structured interview method. Interviews were transcribed verbatim, and key concepts were identified using a grounded theory analytic approach. Results The 29 patients reported 13 unique treatment journeys involving the following drug therapy categories: cytotoxic chemotherapies, CTLA-4 inhibitors, BRAF or MEK inhibitors, and PD-1 inhibitors. Patients typically underwent multiple treatment episodes over time. Common TRSs included nausea, fatigue, diarrhea or constipation, and skin rashes. Patients described these as impacting their physical functioning, ability to perform activities of daily living, social functioning, and overall quality of life. Conclusion Our findings provide a description of the patient’s experience with treatment for advanced melanoma. Our sample included patients typically diagnosed in mid-life, facing an urgent sequence of medical procedures and a pharmacological treatment journey that was burdensome. There is a need for less toxic and more efficacious treatments earlier in the patient journey to alleviate the impact of advanced melanoma treatment on patients’ health-related quality of life.

Monitoring of habitat types conservation status is an essential task in the frame of the European policy for biodiversity conservation. The parameters to be assessed for the purposes of habitat types’ conservation status assessment are described in several European documents, but the methodology for their determination has not yet been standardized or optimized. This study presents methods for the assessment of the actual status and the future prospects of structure and functions of habitat types. Specifically, it presents a bottom–up approach for the assessment of these two parameters at different spatial scales. In the proposed method, conservation status assessment is based on a classification of habitat types to subtypes, with the latter representing the basic monitoring entities. The conservation status is assessed by recording: (i) the presence/absence of specific indicators of structure and functions per habitat type, and (ii) the presence/absence, abundance, and vitality of the typical species of the habitat subtypes. The typical species are determined objectively using algorithms and fidelity coefficient values. The conservation status and future prospects of structure and functions (including the typical species) are estimated quantitatively with the help of numerical methods and algorithms, but their assignment to conservation status classes is based on thresholds defined by experts. Assessments are made at the local scale, but can be upscaled to coarser ones (up to the national level). The proposed methods have been applied in Greece and were effective both in terms of results obtained and costs needed.

Background Metastatic melanoma is a highly aggressive cancer, often striking in the prime of life. This study provides new information directly from advanced melanoma (stage III and IV) patients on how their disease impacts their health-related quality of life (HRQL). Methods Twenty-nine in-depth, qualitative interviews were conducted with adult patients with advanced melanoma in Canada. A semi-structured interview guide was used. Interviews were transcribed verbatim and key concepts were identified using a grounded theory analytic approach. Results Many patients’ journeys began with the startling diagnosis of an invasive disease and a vastly shortened life expectancy. By the time they reached an advanced stage of melanoma, these patients’ overall functioning and quality of life had been greatly diminished by this quickly progressing cancer. The impact was described in terms of physical pain and disability, emotional distress, diminished interactions with friends and family, and burden on caregivers. Conclusion Our findings provide evidence of signs, symptoms, and functional impacts of advanced melanoma. Signs and symptoms reported (physical, mental, and social) confirm and expand on those reported in the existing clinical literature. Primary care physicians should be better trained to identify melanomas early. Oncology care teams can improve on their current approaches for helping patients navigate treatment options, with information about ancillary services to mitigate disease impacts on HRQL, such as mental health and social supports, as well as employment or financial support services.

Europe’s Natura 2000 network (N2K), based on the EU Birds and Habitat Directives, has rapidly expanded protected areas targeting species and habitat types. In Greece, 52.4% of native freshwater fish are considered as species of EU community interest within the Habitats Directive (HD). However, 31.3% of all threatened fish species at a global level and 32.0% at a national level, are not included in the Habitat Directives Annex lists. Fishes in Greece’s rivers are understudied, precise knowledge of their distributions is poor for most species. We utilize a large set of site-based electrofishing samples to explore the coverage of these species by the country’s Natura 2000 sites. Field surveys recorded 102 species inhabiting rivers within 645 sampling sites. Although the majority of the HD listed, threatened and endemic freshwater fish species exist within the current N2K network, important gaps are evident and four HD species were not found within any Natura 2000 sites. In analyzing fish densities from field sampling, only two upland-stream species, Salmo farioides and Barbus strumicae, show significantly higher abundance inside N2K sites. Applying a Combined Index utilizing IUCN vulnerability status, species rarity and richness, we identified 161 hotspot sites for riverine fishes; 50.9 % of all hotspots are located outside of N2K network, especially in lowland areas. Unprotected areas with a high concentration of hotspots are mapped; the river basins with the highest number of such unprotected hotspots belong to the Strymonas, Pinios, Evrotas and Aoos rivers. With concern for the EU’s revised biodiversity conservation strategy, our screening level assessment provides insights for unmet conservation needs and the method is readily transferable to other states and protected area jurisdictions.

We studied the differentiation among plant communities of deciduous broadleaved and mountain coniferous forests in terms of functional diversity and identity at a regional scale (northern and central Greece). We asked if patterns of functional differentiation among communities are consistent between the overstorey and understorey layers and if they can be influenced by deep past environmental conditions. Functional Richness (FRic) and Functional Dispersion (FDis), as well as their standardized effect sizes, were employed to assess the multivariate functional diversity of the community types. In contrast, single-trait Community Weighted Means (CWMs) were used as surrogates of functional identity. The aforementioned indices were calculated for three datasets, namely all the vascular plant taxa found in individual vegetation plots (total community), all phanerophyte (tree and shrub) taxa (overstorey) and all non-phanerophyte vascular plant taxa (understorey). We found that community types and especially four broad forest types (beech, ravine, pine and oak forests) are well differentiated in terms of functional composition (identity), as indicated by Non-Metric Multidimensional Scaling (NMDS). After conducting an NMDS for the three datasets, functional identity based on the total floristic composition was found to be the best discriminator of the studied communities. However, contrasting patterns were found for some specific traits or their categories between overstorey and understorey layers. The patterns of functional diversity of the community types (based on multivariate indices), revealed by calculating the standardized effect sizes of FRic and FDis based on the richness null model, did not differ substantially from random expectations for most of the studied community types when the dataset of all the vascular plant taxa was analyzed. However, the patterns revealed for the overstorey layer differed from those for the understorey layer. For the latter layer, the clustered structure was revealed in many community types based on the ses.FDis metric. Indications of deep past influence on the functional composition were found for certain community types (i.e. ravine forests) based on single-trait metrics, but no indication of such influence was found based on multivariate indices. Our findings highlight the complementarity and the additive explanatory value of the simultaneous use of single- and multi-trait approaches and their application to different layers in forests.

The delineation of Quiet Areas (QAs) forms nowadays a national obligation of EU countries. Nevertheless the variable applications of QAs among Member-States have highlighted the need for an international common approach for the preservation of Quietness. The objective of this paper is to identify and thus protect QAs of EU. Our methodological design consisted of the implementation of a coarse scale distance-based methodology regarding the identification of QAs among different countries, environmental and altitudinal zones with a view to investigating the spatial pattern of QAs as well as their spatial relation to other protected areas. QAs cover 56.09% of EU territory with most of the sites comprising an area larger than 100 km 2 indicating that Quietness provides a valuable ecosystem service for human well-being. Central Europe demonstrates lower percentages of Quietness whereas Mediterranean and Scandinavian areas contain higher percentages of Quietness. Also our findings regarding the spatial overlap of QAs with Natura 2000 network suggest that QAs actually indicate sites of environmental quality, and could thus be incorporated into environmental policy initiatives.

Native-alien species relationship is one of the potential mechanisms to explain alien species' success. Most approaches have so far focused on species richness, but species-centric approaches alone are of limited explanatory ability. We utilized the breeding bird atlases of Great Britain at three time points, to examine the temporal patterns of alien bird species assemblages' richness and composition and analyze the spatio-temporal relationship between them and native species functional and phylogenetic diversity. Alien birds were successful in increasing their average local richness and range from the 1970s to the 2010s, without high values of the replacement component of β-diversity in most assemblages and with increasing richness in the majority of atlas cells. Communities with higher native diversity were positively associated with higher alien species richness and overall, our results showed that native biodiversity metrics can act as reliable predictors of alien species richness patterns. Native phylogenetic diversity emerged as an important predictor of alien species richness, whereas functional diversity was not as successful. Phylogenetic diversity may have captured native species' functional differences more effectively and/or the added layer of phylogenetic information increased phylogenetic diversity's ability to predict alien species richness patterns and may be indicative of evolutionary processes reflecting the mechanisms shaping native-alien species' relationship. If we were to predict where these alien birds may spread within the next 20 years, our results point to phylogenetically rich communities. This is likely a reflection of habitat heterogeneity and/or resource availability in these communities. In any case, a multifaceted approach is preferable, as different measures highlight different mechanisms driving communities' invasibility.