PARP inhibitors (PARPi) are standard-of-care therapy for high-grade serous ovarian cancer (HGSOC). We investigated combining cediranib (antiangiogenic) with olaparib (PARPi) at emergence of PARPi ...resistance.
The proof-of-concept EVOLVE study (NCT02681237) assessed cediranib-olaparib combination therapy after progression on a PARPi. Women with HGSOC and radiographic evidence of disease progression were enrolled into one of three cohorts: platinum sensitive after PARPi; platinum resistant after PARPi; or progression on standard chemotherapy after progression on PARPi (exploratory cohort). Patients received olaparib tablets 300 mg twice daily with cediranib 20 mg once daily until progression or unacceptable toxicity. The coprimary endpoints were objective response rate (RECIST v1.1) and progression-free survival (PFS) at 16 weeks. Archival tissue (PARPi-naïve) and baseline biopsy (post-PARPi) samples were mandatory. Genomic mechanisms of resistance were assessed by whole-exome and RNA sequencing.
Among 34 heavily pretreated patients, objective responses were observed in 0 of 11 (0%) platinum-sensitive patients, 2 of 10 (20%) platinum-resistant patients, and 1 of 13 (8%) in the exploratory cohort. Sixteen-week PFS rates were 55%, 50%, and 39%, respectively. The most common grade 3 toxicities were diarrhea (12%) and anemia (9%). Acquired genomic alterations at PARPi progression were reversion mutations in
, or
(19%);
amplification (16%);
upregulation (15%); and
downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or
upregulation had poor outcomes.
This is currently the largest post-PARPi study identifying genomic mechanisms of resistance to PARPis. In this setting, the activity of cediranib-olaparib varied according to the PARPi resistance mechanism.
Re-excision due to positive margins following breast-conserving surgery (BCS) negatively affects patient outcomes and healthcare costs. The inability to visualize margin involvement is a significant ...challenge in BCS. 5-Aminolevulinic acid hydrochloride (5-ALA HCl), a non-fluorescent oral prodrug, causes intracellular accumulation of fluorescent porphyrins in cancer cells. This single-center Phase II randomized controlled trial evaluated the safety, feasibility, and diagnostic accuracy of a prototype handheld fluorescence imaging device plus 5-ALA for intraoperative visualization of invasive breast carcinomas during BCS.
Fifty-four patients were enrolled and randomized to receive no 5-ALA or oral 5-ALA HCl (15 or 30 mg/kg). Forty-five patients (n = 15/group) were included in the analysis. Fluorescence imaging of the excised surgical specimen was performed, and biopsies were collected from within and outside the clinically demarcated tumor border of the gross specimen for blinded histopathology.
In the absence of 5-ALA, tissue autofluorescence imaging lacked tumor-specific fluorescent contrast. Both 5-ALA doses caused bright red tumor fluorescence, with improved visualization of tumor contrasted against normal tissue autofluorescence. In the 15 mg/kg 5-ALA group, the positive predictive value (PPV) for detecting breast cancer inside and outside the grossly demarcated tumor border was 100.0% and 55.6%, respectively. In the 30 mg/kg 5-ALA group, the PPV was 100.0% and 50.0% inside and outside the demarcated tumor border, respectively. No adverse events were observed, and clinical feasibility of this imaging device-5-ALA combination approach was confirmed.
This is the first known clinical report of visualization of 5-ALA-induced fluorescence in invasive breast carcinoma using a real-time handheld intraoperative fluorescence imaging device.
Clinicaltrials.gov identifier NCT01837225 . Registered 23 April 2013.
Phase 1 dose-escalation trials are crucial to drug development by providing a framework to assess the toxicity of novel agents in a stepwise and monitored fashion. Despite widely adopted, rule-based ...dose-escalation methods (such as 3 + 3) are limited in finding the maximum tolerated dose (MTD) and tend to treat a significant number of patients at subtherapeutic doses. Newer methods of dose escalation, such as model-based and model-assisted designs, have emerged and are more accurate in finding MTD. However, these designs have not yet been broadly embraced by investigators. In this review, we summarise the advantages and disadvantages of contemporary dose-escalation methods, with emphasis on model-assisted designs, including time-to-event designs and hybrid methods involving optimal biological dose (OBD). The methods reviewed include mTPI, keyboard, BOIN, and their variations. In addition, the challenges of drug development (and dose-escalation) in the era of immunotherapeutics are discussed, where many of these agents typically have a wide therapeutic window. Fictional examples of how the dose-escalation method chosen can alter the outcomes of a phase 1 study are described, including the number of patients enrolled, the trial’s timeframe, and the dose level chosen as MTD. Finally, the recent trends in dose-escalation methods applied in phase 1 trials in the immunotherapeutics era are reviewed. Among 856 phase I trials from 2014 to 2019, a trend towards the increased use of model-based and model-assisted designs over time (OR = 1.24) was detected. However, only 8% of the studies used non-rule-based dose-escalation methods. Increasing familiarity with such dose-escalation methods will likely facilitate their uptake in clinical trials.
•Model-based/assisted methods have not been broadly adopted despite favourable features.•Model-assisted methods combine features of both model-based and rule-based designs.•Dose-escalation methods can affect the duration and sample size of phase I trials.•From 2014 to 2019, only 8% of phase I trials used non-ruled based methods.•IO agents should be risk stratified based on therapeutic range and toxicity potential.
Objectives
To identify combined clinical, radiomic, and delta-radiomic features in metastatic gastroesophageal adenocarcinomas (GEAs) that may predict survival outcomes.
Methods
A total of 166 ...patients with metastatic GEAs on palliative chemotherapy with baseline and treatment/follow-up (8–12 weeks) contrast-enhanced CT were retrospectively identified. Demographic and clinical data were collected. Three-dimensional whole-lesional radiomic analysis was performed on the treatment/follow-up scans. “Delta” radiomic features were calculated based on the change in radiomic parameters compared to the baseline. The univariable analysis (UVA) Cox proportional hazards model was used to select clinical variables predictive of overall survival (OS) and progression-free survival (PFS) (p-value <0.05). The radiomic and “delta” features were then assessed in a multivariable analysis (MVA) Cox model in combination with clinical features identified on UVA. Features with a p-value <0.01 in the MVA models were selected to assess their pairwise correlation. Only non-highly correlated features (Pearson’s correlation coefficient <0.7) were included in the final model. Leave-one-out cross-validation method was used, and the 1-year area under the receiver operating characteristic curve (AUC) was calculated for PFS and OS.
Results
Of the 166 patients (median age of 59.8 years), 114 (69%) were male, 139 (84%) were non-Asian, and 147 (89%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. The median PFS and OS on treatment were 3.6 months (95% CI 2.86, 4.63) and 9 months (95% CI 7.49, 11.04), respectively. On UVA, the number of chemotherapy cycles and number of lesions at the end of treatment were associated with both PFS and OS (p < 0.001). ECOG status was associated with OS (p = 0.0063), but not PFS (p = 0.054). Of the delta-radiomic features, delta conventional HUmin, delta gray-level zone length matrix (GLZLM) GLNU, and delta GLZLM LGZE were incorporated into the model for PFS, and delta shape compacity was incorporated in the model for OS. Of the treatment/follow-up radiomic features, shape compacity and neighborhood gray-level dependence matrix (NGLDM) contrast were used in both models. The combined 1-year AUC (Kaplan–Meier estimator) was 0.82 and 0.81 for PFS and OS, respectively.
Conclusions
A combination of clinical, radiomics, and delta-radiomic features may predict PFS and OS in GEAs with reasonable accuracy.
Anal adenocarcinoma is a rare clinical entity for which the optimal management is not defined.
This study aimed to describe the multidisciplinary management and outcomes of patients with anal ...adenocarcinoma.
This is a retrospective cohort study.
This study was conducted at a quaternary cancer center.
Men and women with anal adenocarcinoma treated between 1995 and 2016 were selected.
Fifty-two patients were treated with either chemoradiotherapy or trimodality therapy including radiation therapy, chemotherapy, and surgical resection.
Local failure, regional failure, and distant metastasis rates were estimated using the cumulative incidence method. The Kaplan-Meier method was used to estimate progression-free survival and overall survival. The multivariable Cox proportional hazards model was used to evaluate the clinical predictors of outcome.
There was a higher 5-year rate of local failure in patients treated with chemoradiotherapy compared with trimodality therapy (53% vs 10%; p < 0.01). The 5-year incidence of distant metastases was 29% (trimodality therapy) versus 30% (chemoradiotherapy; p = 0.9); adjuvant chemotherapy did not reduce the incidence of distant metastases (p = 0.8). Five-year overall survival was 73% (trimodality therapy) versus 49.4% (chemoradiotherapy; p = 0.1). On multivariable analysis, factors associated with worse overall survival were treatment with chemoradiotherapy, cT3-4 category disease, and node-positive disease.
This study is limited by its small sample size and retrospective nature.
Although treatment may continue to be tailored to individual patients, better outcomes with a trimodality therapy approach were observed. See Video Abstract at http://links.lww.com/DCR/B708.ADENOCARCINOMA ANAL: UNA ENTIDAD POCO FRECUENTE EN NECESIDAD DE UN MANEJO MULTIDISCIPLINARIO.
El adenocarcinoma anal es una entidad clínica poco frecuente por lo que aún no se define el manejo óptimo.
Describir el manejo multidisciplinario y los resultados de los pacientes con adenocarcinoma anal.
Estudio de cohorte retrospectivo.
Centro de cáncer cuaternario.
Hombres y mujeres con adenocarcinoma anal tratados entre 1995 y 2016.
Cincuenta y dos pacientes fueron tratados con quimiorradioterapia o terapia trimodal que incluyó: radioterapia, quimioterapia y resección quirúrgica.
Se estimaron las tasas de falla local, falla regional y metástasis a distancia mediante el método de incidencia acumulada. Se utilizó el método de Kaplan-Meier para estimar la supervivencia libre de progresión y la supervivencia global. Los riesgos proporcionales de multivariable Cox se utilizaron para evaluar los predictores clínicos de los resultados.
Hubo una mayor tasa de falla local a cinco años en pacientes tratados con quimiorradioterapia en comparación con terapia trimodal (53% vs 10%; p < 0,01). La incidencia a cinco años de metástasis a distancia fue del 29% (terapia trimodal) versus 30% (quimiorradioterapia) (p = 0,9); la quimioterapia adyuvante no redujo la incidencia de metástasis a distancia (p = 0,8). La supervivencia global a cinco años fue del 73% (terapia trimodal) versus 49,4% (quimiorradioterapia); p = 0,1. En el análisis multivariable, los factores asociados con una peor supervivencia general fueron el tratamiento con quimiorradioterapia, enfermedad de categoría cT3-4 y enfermedad con ganglios positivos.
Este estudio está limitado por su pequeño tamaño de muestra y su naturaleza retrospectiva.
Aunque el tratamiento puede seguir adaptándose a pacientes individuales, se observaron mejores resultados con un enfoque TTM. Conslute Video Resumen en http://links.lww.com/DCR/B708. (Traducción- Dr. Francisco M. Abarca-Rendon).
The coronavirus disease 2019 (COVID-19) pandemic has burdened health care resources and disrupted care of patients with cancer. Virtual care (VC) represents a potential solution. However, few ...quantitative data support its rapid implementation and positive associations with service capacity and quality.
To examine the outcomes of a cancer center-wide virtual care program in response to the COVID-19 pandemic.
This cohort study applied a hospitalwide agile service design to map gaps and develop a customized digital solution to enable at-scale VC across a publicly funded comprehensive cancer center. Data were collected from a high-volume cancer center in Ontario, Canada, from March 23 to May 22, 2020.
Outcome measures were care delivery volumes, quality of care, patient and practitioner experiences, and cost savings to patients.
The VC solution was developed and launched 12 days after the declaration of the COVID-19 pandemic. A total of 22 085 VC visits (mean, 514 visits per day) were conducted, comprising 68.4% (range, 18.8%-100%) of daily visits compared with 0.8% before launch (P < .001). Ambulatory clinic volumes recovered a month after deployment (3714-4091 patients per week), whereas chemotherapy and radiotherapy caseloads (1943-2461 patients per week) remained stable throughout. No changes in institutional or provincial quality-of-care indexes were observed. A total of 3791 surveys (3507 patients and 284 practitioners) were completed; 2207 patients (82%) and 92 practitioners (72%) indicated overall satisfaction with VC. The direct cost of this initiative was CAD$ 202 537, and displacement-related cost savings to patients totaled CAD$ 3 155 946.
These findings suggest that implementation of VC at scale at a high-volume cancer center may be feasible. An agile service design approach was able to preserve outpatient caseloads and maintain care quality, while rendering high patient and practitioner satisfaction. These findings may help guide the transformation of telemedicine in the post COVID-19 era.
Delivery of health services in the province of Ontario is organized into 14 Local Health Integration Networks (LHINs), and further into 76 LHIN subregions, making these a natural unit of comparing ...the regional differences in palliative care receipt among decedents who were identified as having palliative care needs.
To assess the presence and magnitude of the remaining regional variation in palliative care receipt in Ontario after accounting for demographic and socioeconomic differences between the LHIN subregions, and therefore to assess whether the standardized proportion of palliative care receipt as a performance indicator can capture potential performance-related issues.
A retrospective cohort study based on Ontario administrative data sources.
Ontario residents who died between April 1, 2015 and March 31, 2016 and were identified as having palliative care needs.
Date of death, diagnostic codes used for determining palliative care needs, and services receipt in last year of life were identified from multiple administrative databases. Demographic and socioeconomic information were derived from linking decedents' postal codes to Statistics Canada Census data and Ontario Marginalization Index.
Statistically significant variation ranging from 63% to 75% in palliative care receipt exists between Ontario subregions even after accounting for demographic and socioeconomic differences, including age, sex, rurality, income quintile, and the four dimensions of the Ontario Marginalization Index.
Annual directly standardized proportion of palliative care receipt can be used as a performance indicator to detect regional differences in service receipt while adjusting for regional differences in the characteristics of the decedent populations. The factors to be adjusted for can be chosen based on the comparison of interest.
Maintaining and improving quality of life (QOL) are important goals of anal cancer management. This disease is generally curable, with many long-term survivors.
Long-term QOL after chemoradiation for ...patients with anal cancer was evaluated.
This was a prospective cohort study.
This study used data from a prospective study of patients with anal cancer who were treated with chemoradiation between 2008 and 2013.
Patients with anal cancer who were treated with image-guided intensity-modulated radiation therapy were included.
English-speaking patients completed European Organization for Research and Treatment of Cancer cancer-specific (C30) and site-specific (CR29) QOL questionnaires at baseline, at end of radiation, at 3 and 6 months, and then annually.
Long-term QOL was evaluated clinically (a change in score of ≥10 points was considered clinically significant) and statistically (using repeated-measurement analysis) by comparing the subscale scores at 1, 2, and 3 years with baseline scores. Subanalysis compared patients who received a radiation dose of 45 to 54 Gy versus 63 Gy.
Ninety-six patients were included (median follow-up of 56.5 months). The symptom and functional scales showed a clinically significant decline at the end of treatment with improvement by 3 months after treatment. There was a long-term statistically significant decline in dyspnea, body image, bowel embarrassment, fecal incontinence, and hair loss, and there was long-term statistically and clinically significant worsening of impotence. Higher radiation dose (63 Gy) was not associated with significantly worse QOL.
Limitations included single-institution, single-arm study design, and lack of dose reconstruction (ie, analyses were based on prescribed, rather than delivered, dose).
Patients with anal cancer treated with chemoradiation reported recovery of overall QOL to baseline levels. Specific symptoms remained bothersome, emphasizing the need to address and manage the chemoradiation-induced symptoms, during treatment and in the long term. See Video Abstract at http://links.lww.com/DCR/B905.
ANTECEDENTES:Mantener y mejorar la calidad de vida son objetivos importantes del tratamiento del cáncer anal, ya que esta enfermedad generalmente es curable, con muchos sobrevivientes a largo plazo.OBJETIVO:Se evaluó la calidad de vida a largo plazo después de la quimiorradiación en pacientes con cáncer anal.DISEÑO:Este fue un estudio de cohorte prospectivo.ENTORNO CLINICO:Utilizamos datos de un estudio prospectivo en pacientes con cáncer anal tratados con quimiorradiación entre 2008-2013.PACIENTES:Los pacientes con cáncer anal fueron tratados con radioterapia de intensidad modulada guiada por imágenes.INTERVENCIONES:Los pacientes de habla inglesa completaron los cuestionarios de calidad de vida específicos de cáncer (C30) y específicos del sitio (CR29) de la Organización Europea para la Investigación y el Tratamiento del Cáncer al inicio, al final de la radiación, 3 y 6 meses, y luego anualmente.PRINCIPALES MEDIDAS DE RESULTADOS:Se evaluó a largo plazo la calidad de vida clínicamente (un cambio en la puntuación de ≥10 puntos se consideraron clínicamente significativo) y estadísticamente (usando análisis de medición repetida) comparando las subescalas de puntuación al 1, 2, y 3 años. Con puntuaciones de referencia. El subanálisis comparó pacientes que recibieron 45-54 Gy versus 63 Gy.RESULTADOS:Se incluyeron un total de 96 pacientes (mediana de seguimiento: 56,5 meses). La mayoría de las escalas funcionales y de síntomas mostraron una disminución clínicamente significativa al final del tratamiento con una mejoría a los 3 meses posteriores al tratamiento. Hubo una disminución estadísticamente significativa a largo plazo en disnea, imagen corporal, vergüenza intestinal, incontinencia fecal y pérdida de cabello; y hubo un empeoramiento a largo plazo estadística y clínicamente significativo en impotencia. La dosis de radiación más alta (63 Gy) no se asoció con una calidad de vida significativamente peor.LIMITACIONES:Institución única, diseño de estudio de un solo brazo y falta de recomposición de la dosis (es decir, los análisis se basan en la dosis prescrita, en lugar de la administrada).CONCLUSIÓNES:Los pacientes con cáncer anal tratados con quimiorradiación reportaron una recuperación de la QOL en general a los niveles de base. Síntomas específicos siguieron siendo molestos, lo que enfatiza la necesidad de resolver y tartar los síntomas inducidos por la quimiorradiación no solo durante el tratamiento, sino a largo plazo. Consulte Video Resumen en http://links.lww.com/DCR/B905. (Traducción- Dr. Francisco M. Abarca-Rendon).
Virtual care (VC) visits (telephone or video) and email-based patient communication have been rapidly adopted to facilitate cancer care during the COVID-19 pandemic. Inequities in access and patient ...experience may arise as these digital health tools become prevalent. We aimed to characterize inequities in access and patient-reported experience following adoption of digital health tools at a tertiary cancer center during the COVID-19 pandemic. We designed a cross-sectional study of outpatients with visits from September to December 2020. Patient characteristics and responses to an email-based patient-experience survey were collated. Inequities in access were assessed across three pairs of comparison groups: (1) patients with VC and in-person visits, (2) patients with and without documented email addresses, and (3) responders and nonresponders to the survey. Inequities in patient-reported experience were assessed among survey responders. Demographics were mapped to area-level averages from national census data. Socioeconomic status was mapped to area-level dimensions of the Canadian Index of Multiple Deprivation. Covariate balance between comparison groups was assessed using standardized mean differences (SMDs), with SMD≥0.2 indicating differences between groups. Associations between patient experience satisfaction scores and covariates were assessed using multivariable analyses, with P<.05 indicating statistical significance. Among the 42,194 patients who had outpatient visits, 62.65% (n=26,435) had at least one VC visit and 31.15% (n=13,144) were emailable. Access to VC and email was similar across demographic and socioeconomic indices (SMD<0.2). Among emailable patients, 21.84% (2870/13,144) responded to the survey. Survey responsiveness was similar across indices, aside from a small difference by age (SMD=0.24). Among responders, 24.4% received VC and were similar to in-person responders across indices (SMD<0.2). VC and in-person responders had similar satisfaction levels with all care domains surveyed (all P>.05). Regardless of visit type, patients had variable satisfaction with care domains across demographic and socioeconomic indices. Patients with higher ethnocultural composition scores were less satisfied with the cultural appropriateness of their care (odds ratio OR 0.70, 95% CI 0.57-0.86). Patients with higher situational vulnerability scores were less satisfied with discussion of physical symptoms (OR 0.67, 95% CI 0.48-0.93). Patients with higher residential instability scores were less satisfied with discussion of both physical (OR 0.81, 95% CI 0.68-0.97) and emotional (OR 0.86, 95% CI 0.77-0.96) symptoms, and also with the duration of their visit (OR 0.85, 95% CI 0.74-0.98; P=.02). Male patients were more satisfied with how their health care provider had listened to them (OR 1.64, 95% CI 1.11-2.44; P=.01). Adoption of VC and email can equitably maintain access and patient-reported experience in cancer care across demographics and socioeconomic indices. Existing health inequities among structurally marginalized patients must continue to be addressed to improve their care experience.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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