Programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. Understanding the treatment-related adverse events of these drugs is ...critical for clinical practice.
To evaluate the incidences of treatment-related adverse events of PD-1 and PD-L1 inhibitors and the differences between different drugs and cancer types.
PubMed, Web of Science, Embase, and Scopus were searched from October 1, 2017, through December 15, 2018.
Published clinical trials on single-agent PD-1 and PD-L1 inhibitors with tabulated data on treatment-related adverse events were included.
Trial name, phase, cancer type, PD-1 and PD-L1 inhibitor used, dose escalation, dosing schedule, number of patients, number of all adverse events, and criteria for adverse event reporting data were extracted from each included study, and bayesian multilevel regression models were applied for data analysis.
Incidences of treatment-related adverse events and differences between different drugs and cancer types.
This systematic review and meta-analysis included 125 clinical trials involving 20 128 patients; 12 277 (66.0%) of 18 610 patients from 106 studies developed at least 1 adverse event of any grade (severity), and 2627 (14.0%) of 18 715 patients from 110 studies developed at least 1 adverse event of grade 3 or higher severity. The most common all-grade adverse events were fatigue (18.26%; 95% CI, 16.49%-20.11%), pruritus (10.61%; 95% CI, 9.46%-11.83%), and diarrhea (9.47%; 95% CI, 8.43%-10.58%). The most common grade 3 or higher adverse events were fatigue (0.89%; 95% CI, 0.69%-1.14%), anemia (0.78%; 95% CI, 0.59%-1.02%), and aspartate aminotransferase increase (0.75%; 95% CI, 0.56%-0.99%). Hypothyroidism (6.07%; 95% CI, 5.35%-6.85%) and hyperthyroidism (2.82%; 95% CI, 2.40%-3.29%) were the most frequent all-grade endocrine immune-related adverse events. Nivolumab was associated with higher mean incidences of all-grade adverse events compared with pembrolizumab (odds ratio OR, 1.28; 95% CI, 0.97-1.79) and grade 3 or higher adverse events (OR, 1.30; 95% CI, 0.89-2.00). PD-1 inhibitors were associated with a higher mean incidence of grade 3 or higher adverse events compared with PD-L1 inhibitors (OR, 1.58; 95% CI, 1.00-2.54).
Different PD-1 and PD-L1 inhibitors appear to have varying treatment-related adverse events; a comprehensive summary of the incidences of treatment-related adverse events in clinical trials provides an important guide for clinicians.
Abstract
Background: Early phase trials (EPCT) provide significant value by evaluating the possible benefits of new agents. The eligibility criteria in EPCT are usually rigorous and may exclude many ...patients (pts) commonly seen in clinical practice. Our objective was to identify the most common comorbidities excluded in EPCT for NSCLC.
Methods: ClinicalTrials.gov was queried on August 1st of 2016. 299 interventional drug trials were extracted from 2010 to 2016. We studied the trial characteristics including: experimental therapy, location, funding and eligibility criteria. Exclusion of CNS metastasis was treated as a binary variable (strict exclusion vs. allowed). Logistic regressions were used for statistical analysis.
Results: Of the 299 trials, 164 (55%) were phase II, 81 (27%) phase I and 54 (18%) phase Ib/II. 164 (55%) were conducted in the United States (US), 45 (15%) in Asia, 39 (13%) in Europe and 51 (17%) were international. 171 (57%) trials were funded by the industry, 54 (18%) by government agencies and 74 (25%) were investigator initiated. Survival was an end-point in 97 (32%) trials. 70 (23%) trials required a repeat lung biopsy. 54 (18%) trials excluded pts >75 years of age. 99 (33%) trials required creatinine levels <1.5 mg/dl, 132 (44%) liver enzymes <2.5 and total bilirubin <1.5 of the upper limit of normal. 88 (29%) trials required Hgb>9 g/dl and 141 (47%) excluded pts with platelets <100,000/dl. In terms of comorbidities, 84 (28%) trials excluded pts with atrial fibrillation, 94 (31%) with any anticoagulation therapy and 120 (40%) HIV positive pts. CNS involvement was a significant exclusion factor, 123 (41%) trials excluded pts with CNS metastasis. On univariate analysis, the odds of CNS metastasis exclusion were significantly higher in immunotherapy trials (OR 1.72, 95%CI 1.2-2.4, p<0.01) and lower in European trials (OR 0.76, 95%CI 0.6-0.9, p<0.005). In multivariate analysis, US based trials had higher odds of exclusion of CNS metastasis (OR: 3.2, 95%CI 1.4-7.5, p<0.05).
Conclusions: Many of the EPCTs excluded pts with advanced age, cytopenias and other common comorbidities, eliminating the possibility of many of our aging pts from participation. Regarding CNS disease, our analysis suggests the type of agent and location may influence the trial design about CNS metastasis inclusion. Investigators should review whether sufficient justification exists for every exclusion criterion before their incorporation in future trial protocols.
Citation Format: Narjust Duma, Yucai Wang, Aaron Mansfield. Comorbidities limiting recruitment of non-small cell lung cancer (NSCLC) patients in early phase trials abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 766. doi:10.1158/1538-7445.AM2017-766
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Background: Gender inequalities contribute to burnout and have contributed to an ongoing exodus of women from academic oncology. Our aim was to explore the perceptions and experiences of ...oncology professionals regarding gender bias in the workplace with the hope of providing critical information to support equity initiatives. Methods: An anonymous, 22-question survey was sent via Survey Monkey to 1512 physicians with oncology-related specialties from National Cancer Institute (NCI) designated cancer centers whose emails were publicly available. Likert-scale questions (never-rarely-sometimes-often-very often) were analyzed with Kruskal-Wallis and Wilcoxon rank sum tests (percentages shown as frequency of having responded “sometimes-often-very often”). Chi-square test was used for categorical variables. Results: A total of 274 physicians completed the survey (response rate 18%): 152 (55.5%) self-identified as female (F); 112 (42%) as male (M); 7 (2.6%) as gender non-conforming or transgender; 3 (1.1%) chose not to answer. Most were White (59.9%), followed by Asian (20.4%), Middle Eastern (5.8 %), Multiracial (5.1%), Hispanic (3.6%), and Black (1.5%). The plurality (n = 103; 37.6%) were < 40 years old. Primary fields of practice included 118 (43.1%) in adult oncology, 45 (16.4%) in combined hematology/oncology, 44 (16.1%) in radiation oncology, 44 (16.1%) in adult hematology, and 23 (8.4%) in other specialties. Female gender was associated with experiencing gender bias more often than male gender in the following areas: clinical practice (80.9% F vs 20.6% M), research activities (73.0% F vs 15.2% M), having difficulty balancing work and non-work responsibilities (95.4% F vs 78.6% M), being held to higher standards compared to physicians of other genders (73.1% F vs 14.2% M), being mistaken as a non-physician (78.9% F vs 6.3% M), and being scrutinized by others while tending to childcare needs (48.8% F vs 23.2% M) (all p <.001). Female gender was associated with using techniques to navigate gender challenges more often than male gender, including wearing a white coat (55% F vs 7% M; p <.001), ensuring that “Doctor” is written on identification (33% F vs 3% M; p =.002), emphasizing a professional look (53% F vs 10% M; p =.003) and working harder to establish expertise in the field (72% F vs 18% M; p =.003). When asked about strategies to address workplace gender-related bias, 63% would like policies on gender-related discrimination, (66.4% F vs 65.2% M; p =.93), 62% would like policies that prioritize leadership representation (74.3% F vs 51.8% M; p <.001), and relatively few (37%) would prefer formal lectures/instruction for staff (38.2% F vs 37.5% M; p >.99). Conclusions: Self-identified female academic oncologists at NCI Cancer Centers reported facing gender-related challenges in daily practice at much higher rates than men. There is a clear need to identify root causes and create initiatives to promote gender equity in the field of oncology.
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Background: The internet and social media have become a common source of medical information. Previous analyses have found that YouTube videos disseminate biased cancer related information of ...low to moderate quality. We analyzed online information disseminated by NCI-designated Cancer Centers (CC) through their YouTube pages. Methods: We searched CC websites and online search engines to identify CC-specific YouTube pages. Our sample included each CC’s top 20 most-viewed videos uploaded during 2019, which were < 5 minutes long, and available in English or Spanish. We examined video content themes and speaker demographics. For patient education videos, we evaluated content understandability and quality of information using validated measures i.e., Patient Education Materials Assessment Tool (PEMAT) and DISCERN. Data was summarized using descriptive statistics. Results: A total of 31 of 64 clinical NCI-designated CC had dedicated YouTube pages. Only 6 (19%) CC had videos in languages other than English. A total of 402 videos were examined for content themes and demographic characteristics. 43% focused on patient education (n = 175), 36% research (n = 139), 24% survivorship (n = 95), and 13% clinical trials (n = 52). 32% (n = 119) of speakers were doctors and 18% (n = 65) patients. Perceived speakers’ ethnicity was 57% White (n = 229), followed by Asian (15%, n = 60), Black or African American (8%, n = 32), and Latinx (4%, n = 16). Perceived gender of speakers was 49% women (n = 197) and 51% men (n = 203). Most videos were understandable (91%, n = 159), but only 21% (n = 36) provided high quality information. Videos discussing treatments lacked discussion of risks, alternate options, and effects on quality of life. Conclusions: Most patient education videos uploaded to NCI-designated CC YouTube pages have low to moderate quality information and limited ethnic diversity of speakers. With ongoing trends of increasing misinformation spreading through social media, CC have an opportunity to create and disseminate high-quality, reliable, and comprehensive educational videos that meet the informational needs of patients with cancer and their caregivers.Table: see text
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Background: A cancer diagnosis can pose a significant financial burden to patients and their families, both during and after treatment. Financial toxicity has long-term consequences, with cancer ...being the most commonly cited reason for medical cost-associated bankruptcy in the United States. We used nationally representative survey data to assess financial toxicity in cancer survivors, with a focus on Hispanic patients given known disparities in socioeconomic and cancer outcomes. Methods: 2013-2018 data from the National Health Interview Survey (NHIS) was used to select individuals aged 18 years old and older who reported any previous diagnosis of cancer. Financial toxicity was defined as unmet healthcare need, health care unaffordability, and/or general financial stress. Individuals were disaggregated by race/ethnicity, and patients who self-identified as Hispanic were further classified by country of origin. Survey-adjusted percentages characterize the cohort. Multivariable logistic regression generated adjusted odds ratios (aORs) with 95% CI for each category of financial toxicity, with non-Hispanic White (NHW) used as reference. Results: Hispanic patients in aggregate had the highest prevalence of all 3 categories of financial toxicity when compared to other racial/ethnicity groups (35% unmet healthcare need, 61% healthcare unaffordability, 61% financial stress). Mexican (aOR: 2.53 95%CI: 1.82–3.52), Cuban/Cuban-American (aOR: 1.97 95%CI: 1.17–3.34), and patients of Central/South American heritage (aOR: 2.61 95%CI: 1.67–4.10) were more likely to have healthcare unaffordability. Unmet healthcare needs were higher in Mexican patients (aOR: 1.43 95%CI: 1.03-1.99) and patients of Cuban descent (aOR: 1.96 95%CI: 1.07-3.58). Financial stress was highest among patients of Central/South American heritage (aOR: 4.20 95%CI: 2.50-7.05) and Mexican patients (aOR: 1.84 95%CI: 1.27-2.66). Mediator analyses further revealed that disparities persisted even after adjusting for socioeconomic status in Mexican patients (healthcare unaffordability - aOR: 1.65 95%CI: 1.14-2.40) and patients of Central/South American heritage (healthcare unaffordability – aOR: 1.99 95%CI: 1.23-3.21; general financial stress – aOR: 2.97 95%CI: 1.71 – 5.17). Conclusions: Our study highlights significant disparities in the financial impact of cancer treatments on Hispanic patients. Disaggregation by Hispanic country of origin illustrates differences within the Hispanic and Hispanic-American population and reveals specific groups that may be at particular risk of financial harm. Targeted interventions to improve health care access and affordability are needed to increase equity and improve outcomes.
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Background: Disparities persist in the recruitment and enrollment of diverse populations to cancer clinical trials (CT). Barriers to CT participation are numerous and include structural ...inequities that limit access, stringent eligibility criteria, financial barriers, provider bias, and patient knowledge. While national societies recommend patient educational materials should be written ≤6th grade reading level, most CT online information available is complex. We evaluated the accessibility, readability, and content of patient-specific CT information from NCI-designated cancer center websites (CCW). Methods: We conducted a qualitative review of CT information in 64 clinical NCI CCW. We reviewed each CCW’s patient-specific CT information to evaluate content, reading level, and navigation. Readability was evaluated using validated measures i.e., Flesch-Kincaid Grade Level (FKGL), Gunning Fog Index (GFI), Coleman-Liau Index (CLI), and Simple Measure of Gobbledygook (SMOG) Grade Level and an average readability score. Data was summarized using descriptive statistics. Results: Most CCW made CT information easily accessible, 62 had a CT-specific website of which 61% required only 1-click from the homepage and 5% required ≥3 clicks. Common patient-specific information included definition of CT (89%), CT phases (66%), guidance on how to decide if you should enroll in a CT (59%), risks and benefits of participation (53%), informed consent (48%), and financial considerations (30%). Only 16% of CCW contained CT information for patients with limited or no English proficiency (14% Spanish, 8% Chinese). CT educational content required a reading level of ≥10
th
grade (Table). 44% of websites included links to outside educational resources, such as the NCI. None of the websites included CT-specific supportive resources (i.e., transportation, navigation, financial assistance, etc.). Most CCW included a CT search bar (77%), yet when searching for a specific cancer type (i.e., breast cancer) 53% yielded a top search result that was disease agnostic or for a different cancer type. 72% included CT descriptions, 58% their eligibility criteria, and 29% included pre-screening forms or links to CT-specific inquiries. Conclusions: Most NCI designated CCW contain CT information at a high literacy level with suboptimal search options and very limited resources/information in other languages. Our findings highlight missed opportunities to develop and advertise CT-specific supportive services and to disseminate CT education materials that meet the literacy and language needs of the increasingly diverse US population.Table: see text
The use of race and ethnicity in biomedical research has been a subject of debate for the past three decades. Initially the two major race categories were: White and Black, leaving other minorities ...uncounted or inappropriately misclassified. As the science of health disparities evolves, more sophisticated and detailed information has been added to large databases. Despite the addition of new racial classifications, including multiracial denominations, the quality of the data is limited to the data collection process and other social misconceptions. Although race is viewed as an imposed or ascribed status, ethnicity is an achieved status, making it a more challenging variable to include in biomedical research. Ambiguity between race and ethnicity often exists, ultimately affecting the value of both variables. To better understand specific health outcomes or disparities of groups, it is necessary to collect subgroup-specific data. Cultural perceptions and practices, health experiences, and susceptibility to disease vary greatly among broad racial-ethnic groups and requires the collection of nuanced data to understand. Here, we provide an overview of the classification of race and ethnicity in the United States over time, the existing challenges in using race and ethnicity in biomedical research and future research directions.
Multiple myeloma (MM) occurs in all races, but the incidence in non‐Hispanic black patients (NHBs) is two to three times higher than in non‐Hispanic white patients (NHWs). We determined the ...representation of minorities and elderly patients in MM clinical trials. Enrollment data from all therapeutic trials reported in ClinicalTrials.gov from 2000 to 2016 were analyzed. Enrollment fraction (EF) was defined as the number of trial enrollees divided by the 2014 MM prevalence. Participation in MM clinical trials varied significantly across racial and ethnic groups; NHWs were more likely to be enrolled in clinical trials (EF 0.18%) than NHBs (EF 0.06%, p < .0001) and Hispanic patients (EF 0.04%, p < .0001). The median age of trial participants was 62 years, with 7,956 participants (66%) being less than 65 years of age. Collaborations between investigators, sponsors, and the community are necessary to increase access to clinical trials to our minority and elderly patients.
Studies have documented underrepresentation of minorities and elderly in oncology clinical trials; however, this issue has not been addressed for some of the most common hematologic malignancies. This article focuses on the representation of minorities and the elderly with multiple myeloma clinical trials over the past 16 years.
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Background: Survivorship care plans (SCPs) is recommended as a tool for communication between oncologists and primary care physicians. According to the Institute of Medicine, it ...is necessary to lead a cultural shift to provide SCPs to all cancer survivors to improve the transition from the oncology clinic to primary care practices. Studies suggest residency training curriculums for internal medicine (IM) are lacking education about cancer survivorship and SCPs. We aimed to assess the awareness of trainees toward SCPs. Methods: A survey was distributed to IM trainees in an outpatient setting. We stratified the descriptive analyses by program type (transitional TY and categorical CT trainees) and year of training. Differences in the proportions were tested appropriately. Analyses were conducted in R v3.6.2. Results: 37 trainees were interviewed; 32.4% were TY and 67.6% CT trainees. A 54% were PGY-1, 21.6% PGY-2, and 24.3% PGY-3. None of the trainees reported following a SCP for cancer-free patients nor to use SCP as a source to obtain cancer-related information. 78.3% and 92.6% reported that they were not taught during residency or medical school about SCPs, respectively. 84.8% informed that cancer-related information was inaccessible during the encounter with patients; sources cancer diagnosis and treatment information included: patients/family members (97.3%), outside records (83.8%), and oncology notes (86.5%). By program type, there was a statistically significant difference between TY v. CT groups (p = 0.017) regarding how often cancer-related issues were discussed with patients; the TY group mainly reported ‘Not at all’ whether CT were more likely to engage in discussion about cancer. Differences in the trainees’ comfort level answering patients concerns about cancer recurrence were observed between TY v. CT trainees but was not statistically significant (p = 0.864). Most common barriers to discuss cancer history and/or SCP were insufficient information from patients (83.8%), perceived inaccuracy from patients’ information (81.1%), unclear if patient has a SCP (81.1%), lack of SCP in medical record (75.7%), and trainees’ low medical knowledge about side effects of cancer therapies (70.3%). Conclusions: The awareness of cancer SCP among the IM trainees is limited, and many have not accessed or received training in SCPs. Efforts intended to facilitate SCP use and educate residents about cancer survivorship may be effective to increase the comfort level of trainees managing the growing number of survivors and improve transition from oncology to primary care clinics.Table: see text
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