Mortality due to cancer treatment delay: systematic review and meta-analysis.

OBJECTIVE: To quantify the association of cancer treatment delay and mortality for each four week increase in delay to inform cancer treatment pathways. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Published studies in Medline from 1 January 2000 to 10 April 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Curative, neoadjuvant, and adjuvant indications for surgery, systemic treatment, or radiotherapy for cancers of the bladder, breast, colon, rectum, lung, cervix, and head and neck were included. The main outcome measure was the hazard ratio for overall survival for each four week delay for each indication. Delay was measured from diagnosis to first treatment, or from the completion of one treatment to the start of the next. The primary analysis only included high validity studies controlling for major prognostic factors. Hazard ratios were assumed to be log linear in relation to overall survival and were converted to an effect for each four week delay. Pooled effects were estimated using DerSimonian and Laird random effect models. RESULTS: The review included 34 studies for 17 indications (n=1 272 681 patients). No high validity data were found for five of the radiotherapy indications or for cervical cancer surgery. The association between delay and increased mortality was significant (P<0.05) for 13 of 17 indications. Surgery findings were consistent, with a mortality risk for each four week delay of 1.06-1.08 (eg, colectomy 1.06, 95% confidence interval 1.01 to 1.12; breast surgery 1.08, 1.03 to 1.13). Estimates for systemic treatment varied (hazard ratio range 1.01-1.28). Radiotherapy estimates were for radical radiotherapy for head and neck cancer (hazard ratio 1.09, 95% confidence interval 1.05 to 1.14), adjuvant radiotherapy after breast conserving surgery (0.98, 0.88 to 1.09), and cervix cancer adjuvant radiotherapy (1.23, 1.00 to 1.50). A sensitivity analysis of studies that had been excluded because of lack of information on comorbidities or functional status did not change the findings. CONCLUSIONS: Cancer treatment delay is a problem in health systems worldwide. The impact of delay on mortality can now be quantified for prioritisation and modelling. Even a four week delay of cancer treatment is associated with increased mortality across surgical, systemic treatment, and radiotherapy indications for seven cancers. Policies focused on minimising system level delays to cancer treatment initiation could improve population level survival outcomes

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Trends and disparities in the treatment of older adults with colon cancer.

e18776 Background: Adults aged ≥70 years represent approximately half of all patients diagnosed with colon cancer (CC), but undertreatment in this population persists. Recent guidelines have aimed to reduce age-related biases in the treatment of CC and emphasized the importance of personalizing management with comprehensive geriatric assessments (CGAs). Therefore, we hypothesized that age-related disparities in the curative-intent treatment of CC would improve over time. Methods: This was a retrospective, population-based cohort study of adults diagnosed with CC between 2010 and 2018 in Alberta, Canada. The study data included patient demographics and clinical characteristics collected through the Alberta Cancer Registry and electronic medical records. Patients were stratified by age: &lt; 70 and ≥70 years. Cox proportional hazard models (CPHM) were generated to evaluate the associations and interaction between age groups and treatment status on disease-specific survival (DSS), after adjusting for important covariates. Multivariable logistic regression was used to identify time trends and predictors of treatment receipt. Results: A total of 10,838 patients were included, of whom 5,176 (48%) were aged ≥70 years and 2,468 (23%) had stage IV CC at initial diagnosis. Older age was associated with greater comorbidity and less advanced disease ( p &lt; 0.001, standardized mean difference &gt; 0.1 for both). The vast majority (87%) of patients in the overall cohort received surgery while 34% received systemic therapy. In multivariable CPHM, older age was associated with lower DSS (HR 1.42, 95%CI 1.31-1.54, p &lt; 0.001) while surgery and systemic therapy were each associated with higher DSS (HR 0.30, 95%CI 0.27-0.33, p &lt; 0.001; HR 0.40, 95%CI 0.37-0.43, p &lt; 0.001; respectively). However, the interaction between age and treatment status was not statistically significant ( p = 0.78 for surgery; p = 0.17 for systemic therapy). Compared to the younger age group, the odds of receiving surgery and systemic therapy were 3 and 5 times lower, respectively, among older patients (OR 0.27, 95%CI 0.18-0.40, p &lt; 0.001; OR 0.18, 95%CI 0.16-0.20, p &lt; 0.001; respectively). In addition to younger age, predictors of surgery receipt included less comorbidity and stage II/III vs I disease, whereas predictors of systemic therapy receipt included male sex, southern residence, higher neighbourhood income, less comorbidity, and stage III vs IV disease ( p &lt; 0.05 for all). There were no statistically significant correlations between year of diagnosis and treatment receipt ( ptrend = 0.07 for surgery; ptrend = 0.26 for systemic therapy). Conclusions: Surgery and systemic therapy continue to improve CC outcomes regardless of age. However, rates of curative-intent treatment for CC were consistently lower in patients aged ≥70 years, with minimal changes over time. Better integration of CGAs into routine care may be needed to reduce persistent age-related treatment disparities. </jats:p

Integrative epigenetic and genetic pan-cancer somatic alteration portraits

Genetic and epigenetic alterations are required for carcinogenesis and the mutation burden across tumor types has been investigated. Here, we investigate epigenetic alterations with a novel measure of global DNA methylation dysregulation, the methylation dysregulation index (MDI), across 14 cancer types in The Cancer Genome Atlas (TCGA) database. DNA methylation data—obtained using Illumina HumanMethylation450 BeadChip—was accessed from TCGA. We calculated the MDI in 14 tumor types (n = 5,592 tumors), using adjacent normal tissues (n = 701) from each tumor site. Copy number alteration, and mutation burden were retrieved from cBioportal (n = 5,152). We tested the relation of subject MDI across tumors and with age, gender, tumor stage, estimated tumor purity, and copy number alterations for both overall MDI and genomic-context-specific MDI. We also investigated the top most dysregulated loci shared across tumor types. There was a broad range of extent in methylation dysregulation across tumor types (P < 2.2E-16). However, a consistent pattern of methylation dysregulation stratified by genomic context was observed across tumor types where the highest dysregulation occurred at non-CpG island regions. Considering other summary measures of somatic alteration, MDI was correlated with copy number alterations but not with mutation burden. Using the top dysregulated CpG sites in common across tumors, 4 classes of cancer types were observed, and the functional consequences of these alterations to gene expression were confirmed. This work identified the global DNA methylation dysregulation patterns across 14 cancer types showing a higher impact for the non-CpG island areas. The most dysregulated loci across cancer types identified common clusters across cancer types that may have implications for future treatment and prevention measures

Patient-Reported Symptom Burden and Supportive Care Needs of Patients With Stage II-III Colorectal Cancer During and After Adjuvant Systemic Treatment: A Real-World Evidence Study

PURPOSE: Patients with colorectal cancer (CRC) experience a range of physical and psychologic symptoms, and supportive care needs throughout the illness trajectory. We used patient-reported outcomes and administrative health data to describe symptom burden and supportive care needs during and after adjuvant treatment and determine factors associated with changes to symptom burden. METHODS: A retrospective population-based cohort study of patients who were newly diagnosed with stage II-III CRC in Alberta, Canada, between January 1, 2016, and January 31, 2019. Adults age 18 years or older who completed a patient-reported outcomes survey (Edmonton Symptom Assessment System) and supportive care needs (Canadian Problem Checklist) within 3 months after starting adjuvant treatment (during treatment) and &gt; 7 months after starting treatment (after treatment) were included. Changes to symptom severity were stratified as stable, improved, or deteriorated. Multivariable logistic regression was used to evaluate factors associated with these changes. RESULTS: We included 303 patients (median age 60 years, 62% male, 84.5% stage III, 51.2% rectal v colon). Prevalent symptoms included tiredness (80.5%), pain (50.8%), and poor well-being (50%) during treatment, and tiredness (71.3%), pain (44.2%), and poor well-being (62.1%) after treatment. The results were heterogeneous with respect to improvements, stability, or deterioration. Pain worsened for 25% of the cohort, tiredness for 28%, and depression, anxiety, and well-being for 21%, 22%, and 31%, respectively. Deterioration of some symptoms was associated with older age, stage II, comorbidities, rural setting, and higher income. CONCLUSION: We demonstrated symptom severity was generally low and most symptoms remained stable or improved after treatment. Particular groups of patients were at greater risk for more severe and/or more persistent symptoms. Ongoing assessments and interventions to address physical and psychologic symptoms, and supportive care needs in patients with CRC during and after treatment are needed. </jats:sec

Detailed incidence and mortality trends of early-onset colorectal cancer in Canada.

e15539 Background: There has been a consistent increase in the incidence of early-onset colorectal cancer (eoCRC), under the age of 50, in Canada since the late 1990s. Questions remain surrounding how these trends vary by topography, histology, and stage, and related trends with CRC-specific mortality. Methods: CRC incidence data were obtained from the Canadian Cancer Registry and CRC-specific mortality data from the Canadian Vital Statistics – Death Database for the years 2000 to 2017. Age-specific average annual percent changes (AAPC) in the incidence (by topography and histology) and mortality rates of CRC were estimated using the National Cancer Institute’s Joinpoint Regression Program. To determine age-specific differences (5-year age groups) in CRC diagnosis at late stage (III and IV) for years 2011 to 2017 combined, a logistic regression model adjusting for sex with the 50-54 age group as the referent was conducted. Results: AAPCs and 95% confidence intervals in the rates of incidence (topography and histology) and mortality of eoCRC from 2000 to 2017 in Canada are presented in Table. Different trends in topography were observed across sexes with the largest increases in the distal colon (splenic flexure, descending, and sigmoid) and rectum among males and rectum only among females. Significant increases were observed for non-mucinous adenocarcinomas, while significant decreases were observed for mucinous adenocarcinomas among the 40-49 age group. Compared to the 50-54 age group, only the 45-49 group had a significantly higher odds of developing late-stage colon cancer, while men and adults 25-49 had a higher odds of developing late stage rectal cancer. Despite increases in the incidence of eoCRC there has only been a significant increase in mortality for men aged 20-39. Trends in mortality vary by site, with significant decreases observed for colon cancer-specific mortality among the 40-49 age group and increases in rectal cancer-specific mortality for adults aged 20-49. Conclusions: These results indicate that the largest increases in incidence and mortality for eoCRC have occurred in the rectum and trends have varied by sex. Further research on the etiology and treatment outcomes of eoCRC patients are warranted for this patient population.[Table: see text] </jats:p

Understanding patient characteristics, treatment patterns, and clinical outcomes for advanced and recurrent endometrial cancer in Alberta, Canada.

e17624 Background: Endometrial cancer (EC) incidence in Canada is steadily increasing and a paucity of real-world data exists. This study aimed to examine treatment (tx) patterns and clinical outcomes for patients (pts) with advanced and recurrent (A/R) EC in Canada. Methods: A retrospective observational cohort study was conducted among pts with primary advanced EC (de novo stage IIIB, IIIC, IV) or recurrent EC (progression from de novo stage I, II, IIIA) between 2010 and 2018 in Alberta, Canada. Health administrative data were used to describe baseline characteristics, time to next tx (TTNT), and overall survival (OS). Using Kaplan-Meier methods, TTNT was defined from tx initiation to initiation of subsequent tx or death from any cause, and OS was examined from tx initiation until death from any cause. Outcomes were stratified by pt type (A/R) and tx. Results: 1,053 pts were included: 620 (58.9%) advanced and 433 (41.1%) recurrent pts. 713 (67.7%) pts received first-line (1L) systemic therapy; this differed by pt type (75.2% of advanced and 57.0% of recurrent pts). Advanced pts who received chemotherapy were more likely to have prior surgery (p &lt; 0.001), radiotherapy (p = 0.01), were younger (p &lt; 0.001), and had fewer comorbidities (p &lt; 0.001) than those without chemotherapy. Platinum-based chemotherapy (PBCT) was the most common 1L regimen (78.6%), differing by pt type (96.1% for advanced and 45.4% for recurrent pts). Hormone therapy in 1L was higher for recurrent compared to advanced pts (27.9% vs 3.2%). Median TTNT and OS from 1L systemic therapy was 19.9 months (95% confidence interval [CI]: 17.5–23.5) and 35.9 months (95% CI: 31.5–53.5), differing by therapy (p &lt; 0.05). Median OS from 1L ranged from 8.5 months (95% CI: 6.2–20.0; platinum monotherapy) to 62.5 months (95% CI: 59.2–NA; hormone therapy). 257 pts received second-line (2L) chemotherapy, with a median TTNT of 7.0 months (95% CI: 6.1–8.2) and median OS of 12.6 months (95% CI: 10.0–14.6). Outcomes differed by tx (p &lt; 0.05), with median OS ranging from 8.0 months (95% CI: 5.9–13.2; non-platinum monotherapy) to 17.1 months (95% CI: 12.7–NA; non-platinum combination). Among pts who received a 1L PBCT, median OS from 2L chemotherapy (N = 187) was 10.4 months (95% CI: 8.9–13.3) and was significantly higher for those rechallenged with PBCT compared to no rechallenge (13.3 months [95% CI: 11.2–20.9] vs 6.4 months [95% CI: 4.6–10.4]). Median OS in third-line (N = 71) and fourth-line (N = 26) chemotherapy was 11.0 months (95% CI: 8.2–13.5) and 12.0 months (95% CI: 7.5–NA), respectively. Outcomes did not differ significantly by pt type (A/R; p≥0.05). Conclusions: Outcomes for pts with A/R EC in Alberta, Canada are poor, particularly following 1L therapy where tx options are limited. Novel therapies with proven efficacy could address this unmet need and improve pt outcomes. Funding: GSK (216962; [email protected]). </jats:p