Oncologist最新文献

Background: Microsatellite instable (MSI) gastric cancers exhibit reduced lymph node (LN) metastasis and improved survival compared to microsatellite stable (MSS) counterparts. However, to our longstanding observation, clinical N-staging (cN) is frequently overestimated in MSI cases. The clinical implications and underlying mechanisms of this discrepancy warrant further investigation.

Materials and methods: We conducted a comprehensive review of clinicopathological data from a 141 MSI and 1119 MSS gastric cancer patients. Expression of vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 were assessed using qPCR and immunohistochemistry. High-parameter flow cytometry was employed to analyze subsets of CD8+ T cells within the tumors.

Results: Multivariate analysis revealed that MSI status was an independent prognostic factor, alongside the LN ratio and AJCC8 pathology staging. MSI gastric cancers exhibited a reduced LN ratio, particularly at advanced T-staging, compared to MSS counterparts, while maintaining an equivalent LN yield. Overestimation of cN by computed tomography preoperatively was frequent in MSI gastric cancers but was more commonly underestimated in MSS counterparts. VEGF-C and VEGFR-3 expression were lower in MSI tumors. MSI gastric cancers showed an increased total number of CD8+ T cells, albeit with a lower proportion of effector memory cells expressing CD45RA (EMRA) and CD8+ CXCR4+ T cells, compared to MSS counterparts.

Conclusion: Frequent overestimation of clinical N-staging in MSI gastric cancers is associated with VEGF-C signaling and CD8+ T-cell dynamics and should be cautiously interpreted, as it might misguide therapeutic options.

Introduction: The initial SARS-CoV-2 pandemic wave in Spain in 2020 precipitated significant paradigm shifts in gastrointestinal oncology patient management. This study captures the "Zeitgeist" of this period by analyzing adaptive strategies, treatment modifications, and survival outcomes, leveraging a 3-year follow-up perspective to extract insights from this unprecedented experience.

Methods: We conducted a multicenter, retrospective cohort study utilizing the RETUD-TTD registry, encompassing 703 patients across 19 Spanish centers in April 2020. We evaluated alterations in clinical practice, therapeutic approaches, coronavirus disease 2019 (COVID-19)-related impacts, and patient survival. A Bayesian hierarchical model was employed to identify potential regional-specific frailties.

Results: The peak of the pandemic in April 2020 catalyzed substantial shifts in oncological care delivery. Outpatient consultations decreased by 13%, with a notable selection bias toward cases with more favorable prognostic indicators. Multidisciplinary tumor board discussions were significantly curtailed (eg, mean monthly colorectal cancer cases discussed was reduced from 40 to 23), compromising qualitative care measures. This occurred concurrently with an average of over 3 oncologists per center on medical leave. Contrary to initial concerns, the healthcare system demonstrated remarkable resilience. The majority of patients received standard-of-care therapies with regulatory approval, albeit with regimen modifications in 15% of cases. These adaptations included extended dosing intervals, dose intensity modulations, and transitions to oral formulations while maintaining unexpectedly stable long-term survival outcomes. The Bayesian frailty model detected minimal unmeasured prognostic factors related to geographic location, and the type of pandemic-induced adaptation did not significantly impact survival. The model revealed that coronavirus disease 2019's impact was less pronounced than other core prognostic variables.

Conclusions: The decentralized Spanish healthcare system exhibited substantial robustness in managing pre-pandemic diagnosed gastrointestinal malignancies, despite asymmetrical, and occasionally severe organizational disruptions. The insights gleaned from this experience could inform future crisis preparedness strategies and optimize care provision during subsequent public health emergencies.

Background: Disitamab vedotin (RC48-ADC), an antibody-drug conjugate (ADC), combines specific antibody disitamab with cytotoxicity monomethyl auristatin E to effectively target the human epidermal growth factor receptor 2 (HER2) protein on tumor cells for precise elimination. Recent studies have demonstrated that RC48-ADC offers therapeutic benefits for patients with HER2-positive and HER2-low-expression breast cancer (BC). However, a thorough exploration of its efficacy and safety in real-world settings for patients with metastatic breast cancer (mBC) is currently lacking.

Methods: This retrospective, multicenter, real-world study included patients with mBC who received RC48-ADC from September 2021 to March 2024. These patients include HER2-positive BC and HER2-low-expression BC. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), restricted mean survival time, objective response rate (ORR), and disease control rate (DCR). Factors affecting efficacy and the occurrence of treatment-related adverse events (TRAE) were evaluated.

Results: The study included a cohort of 89 patients with mBC, with 48 of those being identified as HER2-positive. As of March 2024, 22 deaths were recorded, with an immature median OS. Total PFS varied from 1.0 to 31.2 months, with a median of 5.5 months (95% CI, 4.368-6.632). HER2-positive patients exhibited prolonged PFS compared with HER2-low-expression patients (6.6 months vs 4.1 months, P = .023). The overall ORR stood at 25.8% (95% CI, 0.178-0.358), with higher rates observed in HER2-positive patients compared with HER2-low-expression patients (31.3% vs 19.5%). Similarly, the overall DCR was 78.7% (95% CI, 0.691-0.859), with HER2-positive patients demonstrating superior DCR compared with HER2-low-expression patients (83.3% vs 73.2%). Notably, HER2 expression emerged as the primary determinant of RC48-ADC efficacy. The most prevalent TRAE among all patients included leukopenia (21.3%) and alopecia (20.2%).

Conclusion: RC48-ADC showcases promising efficacy and manageable safety in patients with both HER2-positive and HER2-low-expression mBC.

Background: Many FDA-approved cancer therapies, whether as a multiagent combination or as a single agent, have demonstrated only modest clinical benefit. To investigate the drug development landscape, this analysis focuses on whether newly approved drugs are added to existing standards as combination therapy or replace a former drug as monotherapy.

Methods: A retrospective analysis of package inserts and corresponding trials for the treatment of nonhematology solid tumor malignancies from January 2011 to December 2023 was conducted to categorize an approval as monotherapy or combination therapy. Drug characteristics, treatment indications, study design, approval history, and efficacy results were compared between the 2 cohorts.

Results: Among the 292 approval entries and 110 drugs, 193 (66.1%) were monotherapies and 99 (33.9%) were combinations. Combinations, when compared with monotherapies, were more frequently approved as regular than accelerated approval (85 [85.9%] vs 132 [68.4%], P <.01), in the first-line setting (66 [66.7%] vs 69 [35.8%], P <.01), and with overall survival as the criteria (49 [49.5%] vs 40 [20.7%], P <.01). Monotherapies were more likely to be novel drugs compared with combinations (80 [41.5%] vs 14 [14.1%] P <.01). Monotherapies were more likely to be small molecule targeted agents, while combinations were more likely to be immunotherapies (P <.02). There was no difference comparing the time-to-event endpoints and validated clinical benefit scale, but the median response rate of combinations (46%) was higher than monotherapies (34%, P <.01).

Discussion: Given that clinical benefit appears limited in combination therapy compared with monotherapy, drug development could focus on simplifying cancer therapies toward patient-centered paradigms.

Introduction: Non-small cell lung cancer (NSCLC) patients with large brain metastases (BrM) defined as >2 cm in diameter historically face grim prognoses. With immunotherapy emerging as a promising avenue for BrM management and being commonly used in NSCLC, its application in addressing large BrM remains underexplored.

Methods: This retrospective study conducted across the MedStar Georgetown Cancer Network aimed to assess the efficacy of immunotherapy in non-biomarker driven NSCLC patients with large BrM following initial treatment.

Results: Thirty-six patients were included, all of whom underwent neurosurgery and/or radiation before commencing immunotherapy. The median intracranial progression-free survival (PFS) was 9.2 months and the median overall survival (OS) reached 31 months. Utilizing multivariable Cox penalized regression, the intracranial PFS hazard ratio (HR) was 0.07 (95% confidence interval (CI), 0.02-0.26) for patients who received at least 90 days of immunotherapy compared to those who did not. Each additional 30 days of immunotherapy was associated with an OS HR 0.77 (95% CI, 0.67-0.90).

Conclusion: This real-world data highlights the potential of immunotherapy in large BrM NSCLC patients, a population often excluded from clinical trials. This study contributes insights that can inform future treatment approaches, emphasizing the need for further exploration of immunotherapy's role in enhancing outcomes for this challenging patient population.

Treatment-oriented language is used by physicians to convey to patients that treatment is available for their cancer (eg, "our usual treatment for this is…," "we can treat this," "your cancer is still treatable"). For patients who have incurable cancer, especially for patients with a poor prognosis or who are at the end of life, it is important to understand how physicians conceptualize and use this "everyday" clinical language. We conducted a qualitative interview study with a multidisciplinary group of physicians (n = 30) who may care for patients with cancer at different points in their clinical course, from diagnosis to end of life. Physicians report a wide range of reasons for using treatment-oriented language in conversations with patients who have incurable cancer. However, physicians also reported concerns that this language can be ambiguous, can convey unintended positive prognostic information, and can shift attention away from important matters such as the non-curative nature of treatment or the inevitability of death. On the basis of these concerns, physicians should (1) consider whether their aims in using treatment-oriented language can be better achieved using other evidence-based communication strategies, and (2) recognize and proactively mitigate potential adverse effects of treatment-oriented language, which may manifest much later in the patient's clinical course.

Background: The molecular characterization of early-stage (1-3) colorectal cancer (CRC) remains incomplete, as opposed to metastatic disease, where comprehensive genomic profiling (CGP) is routinely performed. This study aimed to characterize the genomics of stages 1-3 versus IV CRC, and the genomics of patients recurring within 1 year of diagnosis.

Patients and methods: Patients from a de-identified CRC clinico-genomic database who received Foundation Medicine testing (FoundationOne/FoundationOne CDx) during routine clinical care at approximately 280 US cancer clinics between March 2014 and June 2023 were included. Genomic alterations (GA) were compared by Fisher's exact test.

Results: A total of 4702 patients were included; 1902 with stages 1-3 and 2800 with stage 4 disease. Among patients with stages 1-3 disease, 546 recurred within 1 year. Patients staged 1-3 had higher prevalence of microsatellite instability (MSI-H, 11.4% vs 4.5%, P < .001), tumor mutational burden (TMB) ≥ 10 Mut/Mb (14.6% vs 6.8%, P < .001), GA in RNF43 (11.2% vs 5.7%, P < .001), MSH6 (3.9% vs 1.7%, P < .001), MLH1 (2.3% vs 0.7%, P < .001), and MSH2 (1.5% vs 0.6%, P < .01) compared to those with stage 4 disease. Patients who recurred within 1 year had higher prevalence of MSI-H (13.2% vs 4.4%, P < .001), TMB ≥ 10 Mut/Mb (16.2% vs 6.9%, P < .001), BRAF V600E (17.2% vs 7.9%, P < .003), GA in RNF43 (13.7% vs 5.3%, P < .001), MSH6 (4.2% vs 1.6%, P = .035), and BRCA1/2 (6.2% vs 3.0%, P = .030). On recurrence, more patients received targeted therapy when CGP was performed before versus after first-line therapy (43% vs 19%, P < .001).

Conclusions: Early-stage CRC patients can have distinct genomic profiles and CGP in this population can help expand access to targeted therapies.

Background: Guidelines for the management of patients with cancer of unknown primary (CUP), who have metastatic disease without an identified primary tumor site, have evolved. We sought to describe the diagnostic work-up and outcomes of patients with CUP in Canada over the last decade. We also sought to identify factors associated with improved prognosis in CUP, including primary tumor site identification, identification of "favorable subtypes," and concordance with published guidelines.

Methods: With ethics board approval, patients with histologically confirmed CUP between 2012 and 2021 in 3 Canadian cancer centers were reviewed and clinicopathological variables retrospectively collected. The primary endpoint was to describe significant trends in CUP diagnosis and management over the decade using linear regression models. Univariable (UVA) and multivariable (MVA) logistic regression analyses identified variables correlated with primary site identification and overall survival (OS). Kaplan-Meier curves with the log-rank test were used to compare OS outcomes.

Results: In total, 907 patients were included, with a median follow-up of 5.1 months. There was an increase in both 5-year survival and identification of primary tumors over the decade. Diagnostic tests including next-generation sequencing were independently associated with primary site identification on UVA. However, primary site identification was not found to be predictive of survival; instead, patients with "favorable subtypes" of CUP had significantly longer OS.

Conclusions: Survival in patients with CUP in Canada has been increasing over the last decade. Identifying the primary site does not influence survival, and efforts should be focused on discovering novel "favorable subtypes" which have superior outcomes.