Assessing the methodological quality of quality-of-life analyses in first-line non-small cell lung cancer trials: A systematic review.

BACKGROUND: Non-cytotoxic therapy has changed the treatment paradigm for advanced non-small cell lung cancer (NSCLC) patients. With unique mechanisms of action, these agents have decidedly improved survival and have demonstrated an improved toxicity profile. However, the real-life experience of the patient, which is commonly assessed by health-related quality of life (HRQoL) measurement, is not clearly established with this new generation of lung cancer treatments. The heterogeneity created by specific patient subgroups and different therapeutics calls for a tailored-approach to analyzing patient-reported outcomes. The objective of this systematic review was to assess the methodological quality of HRQoL analysis in Randomized Clinical Trials (RCTs) involving biologic agents to treat NSCLC. METHODS: A systematic literature search was performed using Medline, Embase, and Web of Science databases to identify NSCLC RCTs published between January 1st, 2000 and January 1st, 2020 reporting HRQoL measures. Only RCTs that both enrolled previously untreated patients with advanced NSCLC and had HRQoL analysis were included. RESULTS: 4203 abstracts were screened, of which only 85 RCTs met inclusion and exclusion criteria for analysis. The most applied HRQoL assessment tools were the EORTC-QLQ-C30 (47, 55.3 %), and EORTC-QLQ-LC13 (35, 41.2 %). The median number of verified CONSORT-PRO Extension criteria in the included trials was 3, and only in 10 (11.8 %) trials were all criteria well-documented. Notably, only 21 (24.7 %) RCTs performed subgroup analyses to specifically evaluate HRQoL in different patient populations. CONCLUSION: QoL reporting in clinical trials is inconsistent and the quality of QoL measures adopted in a majority of trials is suboptimal. Considering the fact that NSCLC is a biologically diverse disease and that the treatments differ based on patient and tumor-specifics, efforts should be pursued to tailor QoL measures for different subsets of this patient population in addition to mandating QoL reporting in clinical trials. We believe that this is necessary to understand the real-life experience of lung cancer patients in the era of personalized medicine.

Analysis of adverse events attribution and reporting in cancer clinical trials: A systematic review.

We systematically reviewed the quality of AEs reports in published oncology trials analyzing also the bias in the attribution process. We searched MEDLINE, PubMed (2000-2019) selecting randomized, double-blind, placebo-controlled, and phase 3 cancer trials using exclusively targeted therapy or immunotherapy-related drugs. The proportion of publications with complete AE reports (including both all-cause and drug-related AE data) and the AEs attribution ratio (patients with drug-related over all-cause AE) were investigated. Among 60 trials (38,174 patients) included, 40 (66.6 %) presented an incomplete report of AEs attribution. Journals with the lowest impact factor were significantly associated with deficient reports of grade 3-4 AEs (p = 0.02). Under placebo administration, the median incidence of all-grade drug-related AEs was 49 % (IQR 39-56). The median attribution ratio for all-grade AEs in the active and placebo arms was 88.9 % (IQR 79.8-93) and 53.9 % (IQR 43.4-60.9), respectively. The AEs reporting and attribution process appear to be more unreliable than expected.

Incidence of Placebo Adverse Events in Randomized Clinical Trials of Targeted and Immunotherapy Cancer Drugs in the Adjuvant Setting: A Systematic Review and Meta-analysis.

Importance: Several reports have associated the placebo effect with objective response and improvement of a clinical condition in oncology, but only a few studies have analyzed the adverse events (AEs) in the placebo groups of the clinical trials. Objective: To determine the incidence of placebo AEs reported in randomized clinical trials of modern cancer drugs in the adjuvant setting. Data Sources: Based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, a systematic literature search of English-language publications from January 1, 2000, through April 15, 2018, was performed using MEDLINE (PubMed). The following search terms were used to retrieve all trials from the PubMed library: adjuvant, maintenance, consolidation, and placebo, in addition to specific cancer type-related keywords. Study Selection: A double-blind, randomized, placebo-controlled, phase 3 design was mandatory for study inclusion. Only studies enrolling patients who had undergone macroscopically complete resections were included. No other anticancer treatments in addition to placebo were allowed in the control group. Only trials involving a targeted therapy (tyrosine kinase, BRAF, or MEK inhibitors) or immunotherapy-related drugs were included. Trials using chemotherapy, interferon, and endocrine therapy were excluded. Two authors (D.H.E. and F.D.W.) independently reviewed the studies for inclusion. Data Extraction and Synthesis: Data were extracted by investigators, and random-effects meta-analysis was performed to estimate the proportion of grade 3 to 4 placebo AEs in the included studies. Main Outcomes and Measures: Incidence of grade 3 to 4 placebo AEs in the placebo groups. Results: Of 731 studies screened, 10 eligible trials were found including 4 tumor types (melanoma, non-small cell lung cancer, gastrointestinal stromal tumor, and renal cell carcinoma). Overall, 11 143 patients (6270 [56.3%] in the treatment group with mean [SD] age of 55.6 [4.2] years and 4873 patients [43.7%] in the placebo group with mean [SD] age of 55.9 [4.3] years) were included. The mean incidence of any-grade placebo AEs was 85.1% (95% CI, 79.2%-91.0%). The most frequent (mean [SD]) grade 3 to 4 placebo AEs in patients were hypertension (2.8% [2.2%]), fatigue (1.0% [0.9%]), and diarrhea (0.8% [0.6%]). The overall, random-effects pooled incidence of grade 3 to 4 placebo AEs was 18% (95% CI, 15%-21%), with a high level of heterogeneity (I2 = 86%). Frequency of grade 3 to 4 placebo AEs was found to be correlated in the treatment and placebo groups (ρ = 0.7; P = .03). Mean study drug discontinuation owing to placebo AEs was 3.9% (95% CI, 2.7%-5.2%). Conclusions and Relevance: Placebo administration was associated with a substantial incidence of grade 3 to 4 placebo AEs in modern cancer adjuvant trials. This finding should be considered by investigators, sponsors, regulatory authorities, and patient support groups.

Neoadyuvancia en cáncer de mama. Variaciones en la expresión de receptores hormonales / Neoadyuvancia in breast cancer. Variations in the expression of hormonal receptors

El objetivo fue valorar la influencia de la quimioterapia neoadyuvante (QNA) en la modificación de la expresión de receptores de estrógeno (RE) y progesterona (RP). Mediante una revisión retrospectiva de historias clínicas fueron identificadas 52 mujeres con cáncer de mama tratadas con quimioterapia neoadyuvante en el hospital Eva Perón de San Martín, entre diciembre de 2005 y junio de 2015. Se estudió la expresión de receptores hormonales (RH) en el material de biopsia y sobre la pieza quirúrgica después del tratamiento neoadyuvante. Se realizó una valoración semicuantitativa de la intensidad de tinción para los receptores hormonales, considerándose negativas aquellas muestras con menos del 10% de las células teñidas. De las 51 pacientes, 30 de ellos presentaron respuesta parcial (RPa), 17 enfermedad estable (EE) y 4 progresión de enfermedad (PE). Si comparamos las muestras pre y post tratamiento, 32 (62.7%) no presentaron cambios en el grado histológico según el score de Nottingham, 9 (17.6%) disminuyeron su grado y 10 (19.6%) lo aumentaron. Respecto al estatus de RH hormonal, se mantuvo sin cambios en 34, 2 positivizaron los RH y 4 los negativizaron. Al valorar cada receptor de forma independiente, se aprecia positivización en 4 casos para RE y en 5 para RP. La negativización se produce en 4 casos para RE y 9 casos para RP. Se mantienen sin cambios 42 casos para RE y 37 RP. La exposición a la quimioterapia neoadyuvante se acompañó de cambios en la expresión de RH en un número reducido de casos, predominando dichos cambios en los RP (AU)

The aim was to assess the influence of neoadjuvant chemotherapy on the modification of estrogen receptors (ER) and progesterone receptors (PR). A retrospective review of clinical records identified 52 women with breast cancer treated with neoadjuvant chemotherapy at the Hospital Eva Perón de San Martin between December 2005 and June 2015. The expression of hormone receptors (HR) in the biopsy material and on the surgical specimen after neoadjuvant treatment, was studied. A semi-quantitative assessment of the intensity of staining for the hormonal receptors was performed, with negative samples being those with less than 10% of the stained cells. Of the 51 patients, 30 of them presented partial response, 17 stable disease and 4 disease progression. Comparing the pre and post treatment samples, 32 (62.7%) did not present changes in histological grade according to the Nottingham score, 9 (17.6%) decreased their grade and 10 (19.6%) increased it. Regarding HR status, it remained unchanged in 34, 2 positivized the HR and 4 negativized them. In an independent evaluation of each receptor, positivization is seen in 4 cases for RE and 5 for PR. Negativization occurs in 4 cases for RE and 9 cases for PR. Forty two cases remain unchanged for RE and 37 PR. The exposure to neoadjuvant chemotherapy was accompanied by changes in the expression of hormone receptors in a small number of cases, predominating these changes in PR (AU)