Summary Background FIRE-3 compared first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic ...colorectal cancer. The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes ( KRAS and NRAS exons 2–4). We report here efficacy results for the FIRE-3 final RAS ( KRAS/NRAS , exons 2–4) wild-type subgroup. Moreover, new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assessed objective responses and progression-free survival. Methods FIRE-3 was a randomised phase 3 trial comparing FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint of the FIRE-3 study was the proportion of patients achieving an objective response according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 in the intention-to-treat population. A centralised radiological review of CT scans was done in a post-hoc analysis to assess objective response according to RECIST 1.1, early tumour shrinkage, depth of response, duration of response, and time to response in the final RAS wild-type subgroup. Comparisons between treatment groups with respect to objective response rate and early tumour shrinkage were made using Fisher's exact test (two-sided), while differences in depth of response were investigated with a two-sided Wilcoxon test. This trial is registered at ClinicalTrials.gov , number NCT00433927. Findings In the final RAS wild-type population (n=400), median overall survival was better in the FOLFIRI plus cetuximab group than the FOLFIRI plus bevacizumab group (33·1 months 95% CI 24·5–39·4 vs 25·0 months 23·0–28·1; hazard ratio 0·70 0·54–0·90; p=0·0059), although investigator-assessed objective response and progression-free survival were comparable between treatment groups. Centralised radiological review of CT-assessable patients (n=330) showed that the proportion of patients achieving an objective response (113 of 157, 72·0% 95% CI 64·3–78·8 vs 97 of 173, 56·1% 48·3–63·6; p=0·0029), frequency of early tumour shrinkage (107 of 157, 68·2% 60·3–75·4 vs 85 of 173, 49·1% 41·5–56·8; p=0·0005), and median depth of response (–48·9% –54·3 to −42·0 vs −32·3% –38·2 to −29·2; p<0·0001) were significantly better in extended RAS wild-type patients receiving FOLFIRI plus cetuximab versus those receiving FOLFIRI plus bevacizumab. No differences in duration of response and time to response were observed between treatment groups. Interpretation This analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup. Funding Merck KGaA and Pfizer.
The current coronavirus disease 2019 (COVID-19) pandemic is a challenge for physicians in triaging patients in emergency rooms. We found a potentially dangerous overlap of classical urinary symptoms ...and the as yet not fully described symptoms of COVID-19. After a patient was primarily triaged as a urosepsis case and then subsequently diagnosed with COVID-19, we focused on an increase in urinary frequency as a symptom of COVID-19 and identified this in seven males out of 57 patients currently being treated in our COVID-19 wards. In the absence of any other causes, urinary frequency may be secondary to viral cystitis due to underlying COVID-19 disease. We propose consideration of urinary frequency as an anamnestic tool in patients with infective symptoms to increase awareness among urologists during the current COVID-19 pandemic to prevent fatal implications of misinterpreting urological symptoms.
The XELAVIRI trial compared sequential (fluoropyrimidine and bevacizumab; irinotecan (Iri) at progression) versus initial combination therapy (fluoropyrimidine, bevacizumab, Iri) of treatment-naïve ...metastatic colorectal cancer (mCRC). In the confirmatory analysis, the primary end-point (non-inferiority of sequential therapy regarding time to failure of strategy, TFS) was not met. Nevertheless, significant differences regarding treatment efficacy were observed according to RAS status. Here, we evaluate the consensus molecular subtypes (CMS) as additional biomarkers for sequential versus combination therapy.
Gene expression was measured using NanoString after mRNA extraction from formalin-fixed paraffin-embedded tumour specimens. CMS were predicted using multinomial regression and correlated with updated data for TFS, overall (OS) and progression-free survival.
CMS were predicted in 337 of 421 (80.0%) patients (CMS1: 18.4%; CMS2: 51.6%; CMS3: 2.7%; CMS4: 27.3%). CMS2 together with RAS/BRAF wild-type status was identified as potential predictive marker of benefit from initial combination therapy for OS (HR 0.56, 95% CI 0.33–0.96, p = 0.036) and progression-free survival (HR 0.28, 95% CI 0.29–0.79, p = 0.004) and also trending in TFS (HR 0.63, 90% CI 0.41–0.95, p = 0.066). In patients with RAS-mutated mCRC, CMS1 was associated with longer OS after initial combination therapy (HR 0.43, 95% CI 0.20–0.95, p = 0.038). Interaction testing (two-sided) of CMS and RAS/BRAF status in favour of the combination treatment strategy was significant for OS (p = 0.012)
In patients with RAS/BRAF wild-type mCRC, CMS2 may serve as an additional biomarker of benefit from the initial combination therapy, including Iri.
Trial registration ID (clinicaltrials.gov) NCT01249638.
•Consensus molecular subtypes (CMS) are novel biomarkers in colorectal cancer (CRC).•CMS were predicted in the randomised phase III XELAVIRI trial using gene expression.•No prognostic benefit of CMS in a collective with elderly patients with colorectal cancer.•CMS and RAS status might act as biomarkers of treatment intensification in XELAVIRI.•RAS WT CMS2 tumours most likely to benefit from initial combination treatment.
The case describes the coincidental mRNA vaccination and SARS-CoV-2 infection of a 31-year-old physician addressing the theoretical considerations and recommendations for further actions in such a ...particular constellation that we will expect more often in the near future.
The randomised open-label phase III XELAVIRI trial failed to demonstrate non-inferiority of the sequential application of fluoropyrimidine plus bevacizumab followed by additional irinotecan at first ...progression (Arm A) versus initial combination of all agents (Arm B) for untreated metastatic colorectal cancer in the initial analysis of time-to-failure-of-strategy (TFS, 90% confidence boundary of 0.8). Here, we evaluate efficacy in the full analysis set (FAS), the per-protocol set, in addition to age-related and molecular subgroups.
Median TFS, overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan–Meier method and log-rank test. Cox regression models assessed hazard ratios (HRs) and confidence intervals (CIs) (TFS: 90%; OS, PFS: 95%).
Of 421 patients, 390 (92.6%), 391 (92.9%) and 357 (84.8%) events for TFS, OS and PFS were observed in the FAS with a median follow-up of 54.2 months (Arm A) versus 52.9 months (Arm B). Non-inferiority of sequential treatment for TFS was missed in the FAS (HR 0.93; 90% CI, 0.79–1.10; P = 0.482) and not shown in the per-protocol set (HR 0.93; 90% CI, 0.75–1.13, P = 0.433). Formal non-inferiority for TFS was observed for patients older than 70 years (HR 1.06; 90% CI, 0.80–1.41; P = 0.670) and patients with RAS mutant tumours (HR 1.12; 90% CI, 0.87–1.43; P = 0.465). In RAS/BRAF wild-type tumours, combination treatment was significantly superior to sequential therapy in all end-points.
In the overall population, XELAVIRI just missed to demonstrate the non-inferiority of sequential compared to combination therapy for TFS. However, the non-inferiority of sequential treatment was observed in elderly patients and RAS mutant tumours.
Trial registration ID (clinicaltrials.gov) NCT01249638.
•Sequential vs. combination of fluoropyrimidine (FP), bevacizumab (Bev), irinotecan.•Sequential arm: start with FP + Bev, escalation with irinotecan at progression.•Sequential arm was inferior for primary end-point time-to-failure-of-strategy.•Patients >70 years and with RAS mutant mCRC benefit from sequential therapy.•Combination chemotherapy is advised in younger patients with RAS wild-type mCRC.
The development and progression of colorectal cancer (CRC) are known to be affected by the interplay between tumor and immune cells. However, the impact of CRC cells on the systemic immunity has yet ...to be elucidated. We aimed to comprehensively evaluate the circulating immune subsets and transcriptional profiles of CRC patients. In contrast to healthy controls (HCs), CRC patients had a lower percentage of B and T lymphocytes, T helper (Th) cells, non-classical monocytes, dendritic cells, and a higher proportion of polymorphonuclear myeloid-derived suppressor cells, as well as a reduced expression of CD69 on NK cells. Therefore, CRC patients exhibit a more evident systemic immune suppression than HCs. A diagnostic model integrating seven immune subsets was constructed to distinguish CRC patients from HCs with an AUC of 1.000. Moreover, NR3C2, CAMK4, and TRAT1 were identified as candidate genes regulating the number of Th cells in CRC patients. The altered composition of circulating immune cells in CRC could complement the regional immune status of the tumor microenvironment and contribute to the discovery of immune-related biomarkers for the diagnosis of CRC.
A fraction of COVID-19 patients progress to a severe disease manifestation with respiratory failure and the necessity of mechanical ventilation. Identifying patients at risk is critical for optimized ...care and early therapeutic interventions. We investigated the dynamics of SARS-CoV-2 shedding relative to disease severity.We analyzed nasopharyngeal and tracheal shedding of SARS-CoV-2 in 92 patients with diagnosed COVID-19. Upon admission, standardized nasopharyngeal swabs or sputum were collected. If patients were mechanically ventilated, tracheal aspirates were additionally obtained. Viral shedding was quantified by real-time PCR detection of SARS-CoV-2 RNA.45% (41 of 92) of COVID-19 had a severe disease course with the need for mechanical ventilation (severe group). At week 1, the initial viral shedding determined from nasopharyngeal swabs showed no significant difference between non-severe and severe cases. At week 2, a difference could be observed as the viral shedding remained elevated in severely ill patients. A time course of C-reactive-Protein (CRP), Interleukin-6 (Il-6), and Procalcitonin (PCT) revealed an even more protracted inflammatory response following the delayed drop of virus shedding load in severely ill patients. A significant proportion (47.8%) of patients showed evidence of prolonged viral shedding (>17 days), which was associated with severe disease courses (73.2%).We report that viral shedding does not differ significantly between severe and non-severe cases upon admission to the hospital. Elevated SARS-CoV-2 shedding in the second week of hospitalisation, a systemic inflammatory reaction peaking between second and third week and prolonged viral shedding are associated with a more severe disease course.
The XELAVIRI trial investigated the optimal treatment strategy for patients with untreated metastatic colorectal cancer. We tested the noninferiority of initial treatment with a fluoropyrimidine plus ...bevacizumab, followed by the addition of irinotecan at first progression (arm A) versus upfront use of fluoropyrimidine plus irinotecan plus bevacizumab (arm B) in a 1:1 randomized, controlled phase III trial.
The primary efficacy end point was time to failure of the strategy (TFS). Given a 90% CI, a power of 70%, and a one-sided α of .05, the margin for noninferiority was set at 0.8. In the case of demonstrated noninferiority of TFS, an analysis of symptomatic toxicities during TFS would define the superior strategy. Secondary end points included the effect of molecular subgroups on efficacy parameters.
A total of 421 randomly assigned patients (arm A: n = 212; arm B: n = 209) formed the full analysis set. Median age was 71 and 69 years, respectively. Noninferiority of TFS was not shown (hazard ratio HR, 0.86; 90% CI, 0.73 to 1.02). In detail, patients with RAS/BRAF wild-type tumors benefitted from combination chemotherapy (HR, 0.61; 90% CI, 0.46 to 0.82; P = .005), whereas patients with RAS mutant tumors (HR, 1.09; 90% CI, 0.81 to 1.46; P = .58) did not (Cox model for interaction of study arm and RAS status: P = .03). Comparable results were obtained for overall survival.
Noninferiority of sequential escalation therapy compared with initial combination chemotherapy could not be demonstrated for TFS. RAS status may be important to guide therapy as treatment of patients with upfront combination therapy was clearly superior in RAS/BRAF wild-type tumors, whereas sequential escalation chemotherapy seems to provide comparable results in patients with RAS mutant tumors.
The evidence concerning the cost-effectiveness of UGT1A1*28 genotyping is ambiguous and does not allow drawing valid conclusions for Germany. This study evaluates the cost-effectiveness of UGT1A1 ...genotyping in patients with metastatic colorectal cancer undergoing irinotecan-based chemotherapy compared to no testing from the perspective of the German statutory health insurance.
A decision-analytic Markov model with a life time horizon was developed. No testing was compared to two genotype-dependent therapy strategies: 1) dose reduction by 25%; and 2) administration of a prophylactic G-CSF growth factor analog for homozygous and heterozygous patients. Probability, quality of life and cost parameters used in this study were based on published literature. Deterministic and probabilistic sensitivity analyses were performed to account for parameter uncertainties.
Strategy 1 dominated all remaining strategies. Compared to no testing, it resulted in only marginal QALY increases (0.0002) but a cost reduction of €580 per patient. Strategy 2 resulted in the same health gains but increased costs by €10 773. In the probabilistic analysis, genotyping and dose reduction was the optimal strategy in approximately 100% of simulations at a threshold of €50 000 per QALY. Deterministic sensitivity analysis shows that uncertainty for this strategy originated primarily from costs for irinotecan-based chemotherapy, from the prevalence of neutropenia among heterozygous patients, and from whether dose reduction is applied to both homozygotes and heterozygotes or only to the former.
This model-based synthesis of the most recent evidence suggests that pharmacogenetic UGT1A1 testing prior to irinotecan-based chemotherapy dominates non-personalized colon cancer care in Germany. However, as structural uncertainty remains high, these results require validation in clinical practice, e.g. based on a managed-entry agreement.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy parameters and predictors of long-term outcome in metastatic ...colorectal cancer (mCRC). We analyzed these endpoints in mCRC patients treated with first-line bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within the phase 3 XELAVIRI trial.
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. We evaluated progression-free survival and overall survival with ETS as stratification parameter according to treatment arm, molecular subgroup, and sex.
In 370 patients analyzed, a higher rate of ETS (60.9% vs. 43.5%;
= 0.001) and significantly greater DpR (-40.0% vs. -24.7%;
< 0.001) were observed in the initial combination therapy arm. The improvement was pronounced in
/
wild-type tumors. ETS correlated with improved survival irrespective of treatment arm (PFS:
< 0.001; OS:
= 0.012) and molecular subgroup (PFS:
< 0.001; OS:
< 0.001). Male patients in contrast to female patients with ETS had survival benefit (PFS:
< 0.001, HR 0.532; OS:
< 0.001, HR 0.574 vs. PFS:
= 0.107; OS:
= 0.965).
Initial irinotecan-based combination therapy with bevacizumab improved ETS and DpR in mCRC patients with a particularly high irinotecan sensitivity of RAS/BRAF wild-type tumors. ETS seems to be a suitable prognostic marker for fluoropyrimidine- and bevacizumab-based combinations in mCRC. This finding was rather driven by male patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.
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