Introduction Timeliness in colorectal cancer diagnosis and treatment is crucial, however recommendations are often not evidence based. This study aimed to assess associations between the length of diagnostic and treatment interval and overall survival and stage of disease in colorectal cancer using Australian data. Patients and Methods Data from multiple sources were probabilistically linked to ensure coverage across the healthcare system. Data sources included two general practice electronic medical record databases, a hospital-based colorectal cancer clinical registry from three health services, and health service administrative data from three hospitals. Key events were extracted, and the length of diagnostic and treatment intervals determined. Overall survival was assessed using multivariable Cox proportional hazards regression models; risk of advanced stage was assessed using multivariable logistic regression. Restricted cubic splines were used to allow for non-linear associations. Results Six discrete intervals could be assessed, and four had sufficient samples for analyses of colorectal cancer-related outcomes (range 87 – 9,049). Three models, assessing the diagnostic (between first presentation and diagnosis) and the treatment (between diagnosis and treatment) intervals showed a non-linear association with both very short and long intervals associated with poorer outcomes. The nadir of these curves was approximately 150 days for the diagnostic interval for survival and risk of advanced stage, and 28 days for the treatment interval for survival. Conclusion There is an association between time taken to diagnose and treat colorectal cancer and poorer outcomes, consistent with international studies using similar analytic methods to account for non-linear associations. The U-shaped association between time and outcomes can be used to guide maximum waiting time targets and confirms the need for early detection interventions as a strategy to improve outcomes.
Purpose Pancreatic adenocarcinoma is a devastating disease for which there are limited treatment options. Identification of novel agents to enhance the activity of existing regimens are much in need. We hypothesized that the disruption of the DNA damage response by AZD1775, an oral Wee1 inhibitor, added to the nab-paclitaxel and gemcitabine chemotherapy backbone would be safe and effective. Methods A phase I trial to evaluate the dose limiting toxicities and maximum tolerated dose of AZD1775 in combination with nab-paclitaxel and gemcitabine was conducted in patients with metastatic or locally advanced, unresectable pancreatic adenocarcinoma (NCT02194829). A total of 7 patients received nab-paclitaxel and gemcitabine intravenously on days 1, 8 and 15 of a 28-day treatment cycle along with AZD1775 by mouth on days 1, 2, 8, 9, 15 and 16. Toxicities were assessed using CTCAE version 4 criteria. Results Two patients were treated at the initial dose level of nab-paclitaxel, gemcitabine and AZD1775 and both experienced dose limiting toxicities (dehydration, elevated bilirubin, oral mucositis, increased AST and candida intertrigo). Under a revised study design, five patients were treated and two of them also developed dose limiting toxicities (anemia, thrombocytopenia, neutropenia, hyponatremia and febrile neutropenia). Progression-free survival (PFS) and overall survival (OS) among these seven patients was 5.26 months (95% CI [2.73, 12.16]) and 5.29 months (95% CI [2.73, 20.17]) respectively. Conclusion The combination of nab-paclitaxel, gemcitabine and AZD1775 was determined to be too toxic when administered in patients with metastatic or locally advanced, unresectable pancreatic adenocarcinoma.
Background The BRAF V600E mutation in metastatic colorectal cancer (mCRC) is associated with a poor prognosis when treated with conventional chemotherapy regimens. Recent advances in research have shown promise in using combined BRAF inhibitor and EGFR inhibitor to treat BRAF V600E mutated mCRC, with international guidelines recommending this combination for patients who have progressed after chemotherapy. However, there is limited real-world evidence evaluating the uptake and outcomes of this regimen. Hence, we sought to evaluate the baseline characteristics, treatment patterns, outcomes, and health-care resource utilization (HCRU) of BRAF V600E mutated stage IV mCRC patients receiving encorafenib (BRAFi) plus panitumumab (EGFRi) in Alberta, Canada. Materials and Methods We conducted an observational study retrospectively analyzing population-level secondary data supplemented with chart review data from Alberta, Canada. Results We identified a total of 43 patients with stage IV mCRC who received encorafenib plus panitumumab in Alberta, Canada between 2018 and 2023. Median overall survival (OS) was 13.0 months while real-world progression free survival was 5.6 months for this cohort. Dose reductions for panitumumab occurred in 2 patients, and 12 patients had a dose reduction of encorafenib. Healthcare utilization for patients receiving this regimen was low, as the mean number of hospital visits and emergency visits within the first year of treatment was 5.2 and 3.4 visits, respectively. Conclusion Encorafenib and panitumumab can be effectively combined to treat stage IV mCRC in patients with BRAF V600E mutation. Real world outcomes indicate that the combination is tolerated with meaningful clinical efficacy.
Background Accurate preoperative staging is essential for risk stratification and treatment planning in localized colon cancer (lCC), particularly in the context of emerging neoadjuvant strategies. However, the reproducibility of CT-based classification and its concordance with pathology remain incompletely defined. Patients and Methods We analyzed 175 patients with lCC who underwent baseline contrast-enhanced CT followed by curative-intent surgery. Two independent radiologists assessed clinical tumor (cT) and nodal (cN) stages, with discrepancies resolved by consensus. Interobserver agreement was evaluated using Cohen’s kappa. Radiological-Pathological (R–P) concordance was assessed for T, N, and overall stage. Multivariable logistic regression analyses was performed to identify predictors of concordance. Results Interobserver agreement was good for cT classification (κ = 0.77) and excellent for cN classification (κ = 0.94), with overall concordance of 82.9%. R–P concordance was achieved in 78.3% for T staging and 73.7% for N staging, while overall concordance was 57.1%. Most discrepancies reflected adjacent misclassification (29.3%), whereas gross errors were rare (2.3%). CT showed moderate diagnostic performance for T stage (sensitivity 75.7%, specificity 81.6%) and lower sensitivity for nodal involvement (sensitivity 52.3%, specificity 87.3%). Performance varied by tumor location, with higher accuracy in left-sided tumors. Lymphovascular invasion was associated with lower interobserver agreement (OR 0.34; p=0.014), while advanced cT stage predicted reduced R–P concordance for T staging (OR 0.04; p=0.004). Conclusion CT classification demonstrates high interobserver reproducibility but only moderate concordance with pathology in lCC. Misclassification may impact clinical decision-making, underscoring the need for improved staging strategies and multidisciplinary integration.
Background Neoadjuvant immunotherapy has shown remarkable efficacy in mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) locally advanced rectal cancer (LARC), whereas mismatch repair-proficient/microsatellite stable (pMMR/MSS) tumors have historically been resistant because of an immunosuppressive tumor microenvironment. Recently, immune checkpoint inhibitor (ICI)-based combinations with chemoradiotherapy or total neoadjuvant therapy have shown encouraging activity in pMMR/MSS LARC, though their efficacy, safety, and optimal design remain unclear. Methods PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and major conference proceedings were searched for trials evaluating neoadjuvant ICI-based therapy in pMMR/MSS LARC. The primary endpoint was pathological complete response (pCR), with major pathological response (MPR), clinical complete response (cCR), sphincter-preserving surgery (SPS), and adverse events as secondary endpoints. Data were synthesized using single-arm, pairwise, and network meta-analytical approaches to evaluate the efficacy, safety and relative treatment rankings. Results Twenty-nine studies (1,865 patients) were included. Pooled pCR, MPR, cCR, and SPS rates were 34%, 62%, 32%, and 80%, respectively, while grade ≥ 3 treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) occurred in 19% and 4% of patients. Subgroup analyses indicated higher pCR with short-course radiotherapy (SCRT) and higher MPR and SPS with concurrent radioimmunotherapy. Compared with non-ICI controls, ICI-based regimens significantly improved pCR (OR 2.12) and MPR (OR 2.03) without increasing severe toxicity. The network meta-analysis ranked SCRT plus chemoimmunotherapy highest for achieving pCR (P-score = 0.95). Conclusions ICI-based neoadjuvant therapy, particularly SCRT plus chemoimmunotherapy, shows promising efficacy without a significant increase in severe toxicity in pMMR/MSS LARC, warranting validation in large-scale trials.
