XELAVIRI compared sequential (Arm A) versus initial (Arm B) irinotecan in combination with fluoropyrimidine plus bevacizumab in patients with metastatic colorectal cancer, trial identification: ...NCT01249638. In the full analysis set of the study, non-inferiority of time to failure of strategy (TFS) was not shown. The present analysis was performed to evaluate the effect of gender on treatment outcome and tolerability.
The study end-points overall response rate (ORR), progression-free survival (PFS), TFS and overall survival (OS) were evaluated in female versus male patients and in molecular subgroups (i.e. RAS mutational status). Interaction of treatment and gender was tested by likelihood ratio tests.
In total, 281 male and 140 female patients (n = 421) were evaluated. Among the male patients, the ORR was 33.6% without and 58.3% with initial irinotecan (P < 0.001). PFS (hazard ratio HR 0.54; 95% confidence interval CI 0.42–0.69; P < 0.001) and OS (HR 0.63; 95% CI 0.47–0.85; P = 0.002) were also significantly better with initial irinotecan. Among the female patients, the ORR was 42.7% in Arm A and 43.1% in Arm B, PFS was similar (HR 1.09; 95% CI 0.76–1.55; P = 0.649) without and with initial irinotecan. A strong trend for inferior outcome with regard to OS with initial irinotecan was observed (HR 1.46; 95% CI 0.95–2.24; P = 0.081) and the trend reached significance in the multivariate analysis (HR 1.78; 95% CI 1.08–2.95; P = 0.02). Formal interaction of treatment and gender was observed for ORR (P = 0.018), PFS (P = 0.002) and OS (P = 0.001). Treatment-related adverse events were not significantly different between male and female patients.
The present analysis suggests that gender interacts with efficacy of initial irinotecan when used in combination with fluoropyrimidines and bevacizumab. Although male patients derived a significant and clinically meaningful benefit from initial combination chemotherapy, this was not observed in female patients.
•We evaluate the efficacy of initial irinotecan according to gender in mCRC.•Male patients seem to benefit from initial irinotecan, whereas women do not.•Baseline characteristics and toxicities were similar in male versus female patients.
The evidence on the efficacy of anticancer therapy is limited in older patients with metastatic colorectal cancer (mCRC). This retrospective analysis of phase III FIRE-3 trial assesses the efficacy ...of FOLFIRI plus either cetuximab or bevacizumab according to the patients' age and sidedness of primary tumour.
The study endpoints overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between younger (<65 years) and older (≥65 years) patients, followed by stratification according to primary tumour sidedness. ORR was compared using Fisher´s exact test, OS and PFS were estimated by the Kaplan-Meier method and compared using the log-rank test. Univariate Cox regression analyses assessed hazard ratios and 95% confidence intervals for OS and PFS.
Overall, older patients with RAS WT tumours had a significantly shorter OS when compared to younger patients (25.9 months vs 29.3 months, HR 1.29; P = 0.02). Also the proportion of right-sided tumours was significantly greater in older patients (27.1% vs 17.9%; P = 0.029). Secondary resection rates were numerically higher in younger patients (25.4% vs. 17.6%, P = 0.068) than in older patients. This was primarily seen in the Cetuximab arm, where older patients underwent less likely resection (13.1% vs. 26%; P = 0.02). Older patients with left-sided tumours showed only a trend towards greater efficacy of cetuximab (HR 0.86; P = 0.38). In patients with right-sided primary tumours, older patients did not appear to benefit from cetuximab in contrast to younger patients (≥65 years: 16.6 months vs 23.6 months, HR 1.1; P = 0.87; <65 years: 21.9 months vs 16.4 months HR 1.5; P = 0.31).
In FIRE-3, OS was generally shorter in older patients in comparison to younger patients. This could be explained by the overrepresentation of right-sided tumours and a lower secondary resection rate in older patients. The efficacy of targeted therapy was dependent on tumour sidedness in older patients with RAS WT mCRC.
FIRE-3 (NCT00433927).
3576
Background: Primary tumor location (PTL: left vs. right) is an established prognostic marker in metastatic colorectal cancer (mCRC) and has predictive impact for anti-EGFR antibody (mAb) ...efficacy in patients with RAS ( KRAS and NRAS) wild-type (WT) mCRC. This analysis of five pooled studies evaluates PTL as a prognostic and - concerning anti-EGFR mAb efficacy - predictive marker in BRAF V600E-mutant/ RAS WT and mCRC. Methods: The analysis is based on individual patient data of five pooled 1
st
-line studies with varying treatment strategies: the pooled population comprises of BRAF V600E-mutant/ RAS WT ( BRAFmt) mCRC with known PTL. For analysis, treatment was stratified into two groups: treated with or without anti-EGFR mAb. Dichotomous variables (overall response rate, ORR; characteristics) were compared by Chi-Square or Fisher’s exact test and time-to event endpoints (progressive-free survival, PFS; overall survival, OS) by Kaplan-Meier method, log rank test and Cox regression. Results: Of 102 patients (pts) with BRAFmt mCRC, 55 pts (54%) presented with right-sided primary tumors (RPT), 47 (46%) presented with left-sided primary tumors (LPT). Pts with RPT were more likely to be female ( p= 0.04). ORR was inferior in RPT compared to LPT (35% vs. 55%; p= 0.04). No difference was seen in PFS (HR 0.8 (95% CI 0.6-1.3; p= 0.32) or OS (HR 0.8; 95% CI 0.8-1.3; p= 0.46). In male pts PTL trended to be associated with longer OS (HR 0.6; 95% CI 0.3-1.0; p= 0.06). 25 pts with RPT (45%) and 21 with LPT (45%) received anti-EGFR mAb. In pts with LPT anti-EGFR mAb based treatment was associated with higher ORR (81% vs. 35%; p< 0.01). No effect was seen in RPT (ORR 35% vs. 36%; p= 0.82). Anti-EGFR mAb treatment resulted in inferior PFS in RPT (HR 2.0; 95% CI 1.1-3.5; p= 0.02) and showed a trend towards improved PFS in LPT (HR 0.6; 95% CI 0.3-1.1; p= 0.11). Pts with RPT had a worse OS when treated with anti-EGFR mAb (HR 1.8; 95% CI 1.0-3.1; p= 0.05), whereas pts with LPT appeared to have a favorable outcome when treated with an anti-EGFR mAb containing regimen (HR 0.4; 95% CI 0.2-0.7; p< 0.01). Conclusions: This exploratory analysis of five studies suggests that PTL has limited prognostic impact in BRAFmt mCRC but might carry predictive information regarding anti-EGFR mAb efficacy in a 1
st
-line treatment setting. Further prospective studies are needed to validate these results and to grasp the differences in the heterogeneous group of BRAFmt pts. Clinical trial information: FIRE-1 was before mandatory registration, NCT00254137, NCT00433927, NCT01249638, NCT01328171.
Purpose
To investigate the expression of the receptor protein ACE-2 alongside the urinary tract, urinary shedding and urinary stability of SARS-CoV-2 RNA.
Methods
Immunohistochemical staining was ...performed on tissue from urological surgery of 10 patients. Further, patients treated for coronavirus disease (COVID-19) at specialized care-units of a university hospital were assessed for detection of SARS-CoV-2 RNA in urinary samples via PCR, disease severity (WHO score), inflammatory response of patients. Finally, the stability of SARS-CoV-2 RNA in urine was analyzed.
Results
High ACE-2 expression (3/3) was observed in the tubules of the kidney and prostate glands, moderate expression in urothelial cells of the bladder (0–2/3) and no expression in kidney glomeruli, muscularis of the bladder and stroma of the prostate (0/3). SARS-CoV-2 RNA was detected in 5/199 urine samples from 64 patients. Viral RNA was detected in the first urinary sample of sequential samples. Viral RNA load from other specimen as nasopharyngeal swabs (NPS) or endotracheal aspirates revealed higher levels than from urine. Detection of SARS-CoV-2 RNA in urine was not associated with impaired WHO score (median 5, range 3–8 vs median 4, range 1–8, p = 0.314), peak white blood cell count (median 24.1 × 1000/ml, range 5.19–48.1 versus median 11.9 × 1000/ml, range 2.9–60.3,
p
= 0.307), peak CRP (median 20.7 mg/dl, 4.2–40.2 versus median 11.9 mg/dl, range 0.1–51.9,
p
= 0.316) or peak IL-6 levels (median: 1442 ng/ml, range 26.7–3918 versus median 140 ng/ml, range 3.0–11,041,
p
= 0.099). SARS-CoV-2 RNA was stable under different storage conditions and after freeze–thaw cycles.
Conclusions
SARS-CoV-2 RNA in the urine of COVID-19 patients occurs infrequently. The viral RNA load and dynamics of SARS-CoV-2 RNA shedding suggest no relevant route of transmission through the urinary tract.
Purpose
Following the emergency use authorization of BNT162b2 by the Food and Drug administration (FDA) in early December 2020, mRNA- and vector-based vaccines became an important means of reducing ...the spread and mortality of the COVID-19 pandemic. The European Medicines Agency labelled immune thrombocytopenia (ITP) as a rare adverse reaction of unknown frequency after vector-, but not mRNA-vaccination. Here, we report on the long-term outcome of 6 patients who were diagnosed with de-novo, vaccine-associated ITP (VA-ITP), and on the outcome of subsequent SARS-CoV-2 re-vaccinations.
Methods
Patients were included after presenting to our emergency department. Therapy was applied according to ITP guidelines. Follow-up data were obtained from outpatient departments. Both mRNA- or vector-based vaccines were each used in 3 cases, respectively.
Results
In all patients, the onset of symptoms occurred after the 1st dose of vaccine was applied. 5 patients required treatment, 3 of them 2nd line therapy. All patients showed a complete response eventually. After up to 359 days of follow-up, 2 patients were still under 2nd line therapy with thrombopoietin receptor agonists. 5 patients have been re-vaccinated with up to 3 consecutive doses of SARS-CoV-2 vaccines, 4 of them showing stable platelet counts hereafter.
Conclusion
Thrombocytopenia after COVID-19 vaccination should trigger a diagnostic workup to exclude vaccine-induced immune thrombotic thrombocytopenia (VITT) and, if confirmed, VA-ITP should be treated according to current ITP guidelines. Re-vaccination of patients seems feasible under close monitoring of blood counts and using a vaccine that differs from the one triggering the initial episode of VA-ITP.
Zusammenfassung
Onkologische Notfälle sind in der Ätiologie und Symptomatik vielfältig und treten häufig mit der Einleitung einer Chemotherapie auf, können sich aber auch während oder mit zeitlicher ...Verzögerung manifestieren. Die Kenntnis onkologischer Notfälle unter medikamentöser Tumortherapie ist daher nicht nur für die behandelnden Fachdisziplinen wichtig, sondern auch für mit- oder weiterbetreuende Kollegen. Jeder dieser Krankheitszustände erfordert eine sorgfältige Beurteilung der Symptome, klinische, laborchemische und apparative diagnostische Schritte sowie akute Interventionen und unterstützende Pflegemaßnahmen. Im Folgenden werden sechs häufige, akut verlaufende und/oder schwerwiegende Nebenwirkungen vorgestellt und auf das spezifische Management eingegangen.
The XELAVIRI study compared application of fluoropyrimidine (FP) and bevacizumab (Bev) followed by sequential escalation to irinotecan (Iri), FP and Bev (arm A) to upfront combination therapy with ...FP, Iri and Bev (arm B) in patients with metastatic colorectal cancer (mCRC). To elucidate the impact of age on survival, we evaluated efficacy and early mortality in the underlying trial.
Patients were stratified for age in three cohorts (<65 years, 65–74 years and ≥75 years). Survival end-points were expressed by the Kaplan-Meier method and compared by log-rank testing and Cox regression. Objective response and 60-day mortality were evaluated by chi-square testing.
The efficacy analyses suggest more substantial benefit from upfront combination chemotherapy in younger patients with mCRC. Elderly patients (≥75 years) derived limited benefit from upfront combination chemotherapy, particularly in terms of overall survival. Of 421 randomised patients, 13 patients (3.1%) died within 60 days after treatment initiation with the highest prevalence in elderly patients (1.6% < 65 years, 2.8% 65–74 years and 5.2% ≥ 75 years, p = 0.26). The frequency of 60-day mortality was significantly associated with age (with a maximum of 8.7% in patients aged ≥75 years) in patients undergoing upfront combination therapy (p = 0.027) but not in patients receiving sequential treatment (p = 0.63).
Combination therapy with FP, Iri and Bev does not substantially improve the outcome of patients aged ≥75 years as compared with sequential treatment algorithm. These patients appear to be at a relevant risk for 60-day mortality under Iri-based combination chemotherapy plus Bev.
•Benefit from upfront combination chemotherapy might depend on age and RAS status.•Elderly patients do not derive survival benefit from initial combination therapy.•Patients aged ≥75yrs show relevant 60-day mortality with initial combination therapy.•Elderly patients can be considered for sequential/less intensive therapy approaches.
Abstract only
3552
Background: Prognostic biomarkers beside RAS/BRAF status are necessary to identify metastatic colorectal cancer (mCRC) patients who benefit from combined (COMB) versus sequential ...(SEQ) treatment with fluoropyrimidine, bevacizumab and irinotecan (randomized phase III XELAVIRI trial). Methods: mRNA was extracted from formalin-fixed paraffin embedded (FFPE) tumor tissue of 337 patients, gene expression was measured by the Nanostring PanCancer Progression Panel. Consensus molecular subtypes (CMS) classification was re-derived using a multinomial regression model. Data of Guinney et al. (Nat. Med. 2015. 21:1350-6) and FIRE-3 served as training and validation set. RAS/BRAF MUT were assessed by pyrosequencing. Median overall (OS) and progression free survival (PFS), hazard ratios (HR) and 95% confidence interval (CI) were estimated by Kaplan-Meier method and univariate Cox regression. Results: The multinomial regression model employed in the present analysis correctly predicted CMS labels in 98.3 % of the original Guinney- and 100.0 % of FIRE-3 population. In XELAVIRI, CMS subgroups were predicted as follows: CMS1: n = 62 (18.4 %); CMS2: n = 174 (51.6 %); CMS3: n = 9 (2.7 %); CMS4: n = 92 (27.3 %). A general prognostic impact of CMS was not observed when all patients were analysed. In RAS/BRAF WT mCRC patients, substantial benefit of COMB versus SEQ treatment was shown for OS and PFS in CMS2 and CMS4, but not in CMS1. Conversely, OS was significantly longer for COMB treatment in patients with RAS MUT and CMS1 mCRC, while SEQ treatment was not inferior in RAS MUT and CMS2 or CMS4 subgroups (see TABLE). Additional data for overall response rates, early tumor shrinkage and sidedness might be presented at the meeting. Conclusions: This retrospective analysis of XELAVIRI suggests that CMS may serve as biomarker that predicts response to initially combined versus less intensive sequential chemotherapy in patients with RAS/BRAF WT mCRC.Table: see text
Abstract only
3571
Background: Early response parameters such as early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy ...endpoints and potential predictors of long-term outcome. We analyzed the association of these endpoints with bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within a randomized phase III trial. Methods: DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR-image) were analyzed in the XELAVIRI-trial. Moreover, progression-free survival (PFS) and overall survival (OS) were evaluated with ETS as stratification parameter (ETS vs. no ETS) according to treatment arm, molecular subgroup, and sex. Results: 370 patients were available for analysis of early treatment response parameters. A higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p < 0.001) were observed in the initial combination compared to the sequential therapy arm, respectively. The improvement of ETS and DpR was pronounced in the subpopulation of RAS/ BRAF wildtype patients. Male in contrast to female patients significantly benefitted from initial combination treatment in terms of median DpR (male: -40.0% vs. -22.2%; p < 0.001; female: -34.0% vs. -24.4%; p = 0.13) and rate of ETS (male: 64.8% vs. 40.2%; p < 0.001; female: 52.5% vs. 49.3%; p = 0.73). Achievement of ETS correlated with improved survival irrespective of treatment arm (PFS: p < 0.001; OS: p = 0.012) and molecular subgroup (PFS: p < 0.001; OS: p < 0.001). Whereas the survival benefit in male patients achieving ETS was statistically significant (PFS: p < 0.001, HR 0.532 (0.409-0.692); OS: p < 0.001, HR 0.574 (0.437-0.756)), there were no significant differences in PFS (p = 0.107) and OS (p = 0.965) of female patients depending on ETS. Conclusions: In the XELAVIRI trial, initial irinotecan-based combination therapy with bevacizumab improves ETS and DpR in mCRC patients. Improvement in early response parameters appears pronounced in patients with RAS/ BRAF wildtype tumors suggesting a high sensitivity to irinotecan-based treatment. ETS was predictive of PFS and OS regardless of treatment arm. This finding was rather driven by male than female patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.
PDF
