Background: The decision to resect or not the primary tumor in asymptomatic patients with synchronous metastatic colorectal cancer (mCRC) is a complex and challenging issue for oncologists, ...especially when an antiangiogenic-based therapy is planned. Methods: Patients enrolled in the phase III TRIBE and TRIBE2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively, were included. We assessed the association of primary tumor resection (PTR) with progression-free survival (PFS), overall survival (OS), response rate (ORR), rate of grade > 2 adverse events (AEs), and serious gastrointestinal and surgical AEs in the overall population and according to the treatment arm. Results: Of the 999 patients included, 513 (51%) underwent PTR at baseline. Longer PFS and OS were observed in resected patients compared to those with unresected primary tumors: 11.2 vs. 10.0 months (p < 0.001) and 26.6 vs. 22.5 (p < 0.001), respectively. In multivariate models, PTR was confirmed as an independent prognostic factor for better PFS (p = 0.032) and OS (p = 0.018). Patients with PTR experienced a higher incidence of grade 3 or 4 diarrhea (p = 0.055) and lower incidence of anemia (p = 0.053), perforation (p = 0.015), and serious gastrointestinal and surgical AEs (p < 0.001). No statistically significant differences were noted in incidence of bleeding (p = 0.39). The benefit of FOLFOXIRI + bevacizumab in terms of PFS (p for interaction: 0.46), OS (p for interaction: 0.80), ORR (p for interaction: 0.36), and incidence of grade 3 or 4 AEs was independent of PTR. Conclusions: PTR at baseline was independently associated with good prognosis in synchronous mCRC patients and with lower incidence of serious gastrointestinal and surgical AEs during upfront chemotherapy plus bevacizumab. The benefit and toxicity profile of FOLFOXIRI plus bevacizumab was independent of PTR.
Background
Early activation of palliative care for patients with advanced cancer is central in the treatment trajectory. At the Veneto Institute of Oncology, a simultaneous-care outpatient clinic ...(SCOC) has been active since 2014, where patients are evaluated by an oncologist together with a palliative care team. Recently, we reported on consecutive patients admitted at SCOC from 2018 to 2021 in terms of appropriateness, process, and outcome indicators. Here, we report further analysis in the same group of 753 patients, evaluating other parameters and the correlation between symptom intensity, gender, age, and survival.
Methods
SCOC data were retrieved from a prospectively maintained database.
Results
Among the patients, 42.2% were women, and the median age was 68 years, with 46.7% of patients aged ≥70 years. The most prevalent disease type was gastrointestinal cancer (75.2%), and 90.9% of the patients had metastatic disease. The median score for the distress thermometer was 4; the vast majority of the patients (98.6%) reported physical problems, and 69.4% presented emotional issues. Younger women demonstrated a significantly greater median distress than other patients (p=0.0018). Almost all symptoms had a higher prevalence on the 0–3 Edmonton Symptom Assessment Scale (ESAS) score, except for fatigue. About 43.8% of the patients received systemic anticancer treatment (SAT) in the last 60 days of life, 15.0% of whom received SAT in the last month and 3.1% in the last 2 weeks. For some symptoms, women frequently had more ESAS >3. Pain and nausea were significantly less reported by older patients compared with younger adults. Men had a lower risk of having MUST score ≥ 2 (p=0.0311). Men and older patients showed a lower prognosis awareness (p=0.0011 and p=0.0049, respectively). Older patients received less SAT within the last 30 days of life (p=0.0006) and had death risk decreased by 20.0%.
Conclusion
Our study identified two subgroups of patients with advanced cancer who require special attention and support due to important symptoms’ burden detected by Patient Reported Outcome Measures tests: women and younger adults. These categories of patients require special attention and should be provided early access at SCOC. The role of an oncologist remains crucial to intercept all patients in need of early palliative care and balancing trade-offs of anticancer treatment in advanced metastatic disease.
Background: First-line decision making is the key to the successful care of mCRC patients and RAS/BRAF status is crucial to select the best targeted agent. In hub centers, a relevant proportion of ...patients referred from small volume centers may not have standard tissue-based (STB) molecular results available at the time of the first visit (T0). Liquid biopsy (LB) may help circumvent these hurdles. Methods: A monoinstitutional prospective head-to-head comparison of LB versus (vs.) STB testing was performed in a real-world setting. Selection criteria included: mCRC diagnosis with unknown RAS/BRAF status at T0, tumoral tissue archived in external centers, no previous treatment with anti-EGFR. At T0, patients underwent plasma sampling for LB testing and procedure for tissue recovery. RAS/BRAF genotyping was carried out by droplet digital PCR on circulating-tumoral (ct) DNA. The primary endpoint was the comparison of time to LB (T1) vs. STB (T2) results using the Mann–Whitney U test. Secondary endpoints were the concordance between LB and STB defined as overall percent agreement and the accuracy of LB in terms of specificity, sensitivity, positive and negative predictive value. We also performed an exploratory analysis on urinary (u) ctDNA. Results: A total of 33 mCRC patients were included. Mean T1 and T2 was 7 and 22 days (d), respectively (p < 0.00001). T2 included a mean time for archival tissue recovery of 17 d. The overall percent agreement between LB and STB analysis was 83%. Compared to STB testing, LB specificity and sensitivity were 90% and 80%, respectively, with a positive predictive value of 94% and negative one of 69%. In detail, at STB and LB testing, RAS mutation was found in 45% and 42% of patients, respectively; BRAF mutation in 15%. LB results included one false positive and four false negative. False negative cases showed a significantly lower tumor burden at basal CT scan. Concordance between STB and uctDNA testing was 89%. Conclusions: Faster turnaround time, high concordance and accuracy are three key points supporting the adoption of LB in routinary mCRC care, in particular when decision on first-line therapy is urgent and tissue recovery from external centers may require a long time. Results should be interpreted with caution in LB wild-type cases with low tumor burden.
BackgroundImmune checkpoint inhibitors (ICIs) are the new standard of care in microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC). Since tumor ...response dynamic parameters already shown a strong association with survival outcomes in patients with mCRC treated with first-line therapy, we investigated the association of early tumor shrinkage (ETS) and depth of response (DoR) in patients with MSI-H/dMMR mCRC treated with ICIs.MethodsThis is a retrospective, multicenter, cohort study in patients with dMMR and/or MSI-high mCRC treated with ICIs (anti-PD-1/PD-L1 with or without anti-CTLA-4 agents) with measurable disease and at least one post-baseline radiological disease reassessment. The Kaplan-Meier method and Cox proportional-hazards regression models were used for survival analyses. A maximally selected statistics method in a Cox regression model for progression-free survival (PFS) was used to determine the optimal cut-offs for ETS and DoR.ResultsWe included a total of 169 patients: 116 (68.6%) were treated with anti-PD-1 monotherapy, whereas 53 (31.4%) with anti-PD-1 plus anti-CTLA-4 agents. Patients with primary progressive disease (N=37, 21.9%), experienced an extremely poor overall survival (OS) and were evaluated separately. In patients with clinical benefit, we observed a significant association between ETS and DoR with both OS and PFS, and we identified a relative reduction of at least 1% as the optimal cut-off for ETS and a relative reduction of at least 50% as the optimal cut-off for DoR.ConclusionsETS and DoR are important prognostic factors in patients with MSI-high mCRC treated with ICIs that might be useful to design treatment intensification/deintensification strategies. A prospective validation of both is warranted.
Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations ...restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926 ; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting.
218
Background: Immune checkpoint inhibitors (ICI) showed high efficacy in both first and subsequent lines in metastatic colorectal cancer with mismatch repair deficiency (dMMR-mCRC); however, they ...still fail in a minority of patients (pts). In non-preplanned analyses from previous studies, RAS mutations ( RASm) have been related to limited activity of ICI monotherapy (ICIm) as compared to ICI doublets (ICId) in dMMR-mCRC. Emerging data suggest different immunological features in presence of RASm, resulting in lower immunogenicity. Methods: NERDY is a retrospective, monocentric study designed to investigate the effect of ICIm and ICId on dMMR-mCRC basing on RASm. Pts with dMMR-mCRC treated with ICIm/ICId at our Institute were included. Clinical-pathological features for each patient were collected. On primary tumor specimens, proinflammatory pathways and CMS subgroup will be assessed by Nanostring and RNA-Seq respectively. The study is exploratory and no formal hypothesis has been postulated. Both PFS and OS were calculated with Kaplan-Meier. Cox proportional hazard model was adopted in the interaction tests. Primary objective was to assess OS and PFS according to RAS in dMMR-mCRC pts treated with ICIm or ICId. Secondary objectives were to describe the inflammatory infiltrate and TMB in dMMR-mCRC according to RAS status. Results: From June 2015 to January 2022, a total of 126 consecutive dMMR-mCRC pts treated with ICI were included, 33 RASm/93 RASwt. RASm pts were more frequently males (p=0.015) and younger (median age 47 vs 65). An imbalance was observed in sidedness (more right-CRC in RASwt than in RASm as BRAF effect, p=0.001) and timing of ICI (administered in later lines in RASm, p=0.013). No differences in ECOG-PS, histotype, disease burden, stage at diagnosis, treatment with ICIm vs ICId and best response. At a median follow up of 53.5 months (95%CI 34.7-56.9), a trend toward longer PFS in pts treated with ICId over ICIm was found in the overall population (HR 0.62; 95%CI 0.36-1.05; p=0.055), being significantly longer in RASm-only pts (HR 0.41; 95%CI 0.13-1.28; p=0.047) but not in RASwt-only pts (HR 0.64; 95%CI 0.34-1.20; p=0.139). No difference was observed in OS between ICId and ICIm in the overall population (HR 0.64; 95%CI 0.36-1.16; p=0.121), in RASwt (HR 0.59; 95%CI 0.29-1.20; p=0.132) nor in RASm pts (HR 0.59; 95%CI 0.19-1.78; p=0.275). Interaction test for RAS and ICI treatment type was not significant for PFS (HR 0.63; 95%CI 0.21-1.94; p=0.423) nor for OS (HR=1.00; 95%CI 0.29-3.41; p=0.999). Conclusions: Preliminary clinical results of the NERDY study suggest enhanced activity of ICId compared to ICIm in pts with RASm dMMR-mCRC. Further data are expected from pending translational analyses and a pre-planned adjunctive cohort from two other Italian centers will be used for external validation.
e15571
Background: Currently, no validated biomarkers are available for second-line anti-angiogenic treatment in RAS wild type (wt) metastatic colorectal cancer (mCRC) patients (pts) progressing ...after first-line anti-EGFR. Here, we present the results of a pre-planned interim analysis of the DISTINCTIVE trial (NCT04252456) on prognostic groups identified with the combination of hematologic parameters and based on the association of clinical and translational biomarkers. Methods: RAS wt mCRC pts progressing after first line oxaliplatin-based + anti-EGFR therapy receive FOLFIRI-aflibercept and are prospectively stratified in 2 groups according to Elisa-assessed baseline VEGFR2 plasma levels. Other circulating angiogenic factors are evaluated at specific timepoints. Clinical and laboratory data are collected to assess their correlation with outcome. Primary endpoint is overall survival (OS) according to VEGFR2 levels. Secondary endpoints are OS, progression free survival (PFS), response rate, safety and angiogenic factors levels. Statistical analysis is performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; multivariate analysis: logistic regression; cut-off: ROC curves). Results: Of 73 pts enrolled (04/2018-06/2020), 44 were eligible for interim analysis. Median OS was 11.9 months (m) (95% CI 10-14.2). We identified at first 2 prognostic groups: favorable prognosis (baseline monocytes ≤0.7x10
3
/μL + RBC > 3.81x10
6
/μL + MRR≤1528) and unfavorable prognosis (monocytes > 0.7x10
3
/μL and/or RBC ≤3.81x10
6
/μL and/or MRR > 1528). OS was 14.2 months (m) (95% CI 10.467-14.2) in the favorable prognosis group vs 6.9 m (95% CI 4.867-9.133) in the unfavorable prognosis group (HR 0.008, p < 0,0001). Then, we performed multivariate analysis on circulating angiogenic factors and on laboratory values; VEGFR2 levels at disease progression (PD) and baseline RBC maintained an independent role (Exp(b) 0.0891, p = 0.0464 and Exp(b) 0.1170, p = 0.0148, respectively). By combining these findings we separated pts in a favorable prognosis group (VEGFR2≤4ng/ml + RBC > 3.81x10
6
/μL) and unfavorable prognosis group (VEGFR2 > 4ng/ml and/or RBC ≤ cut off). OS was significantly improved in the favorable prognostic group (14.2 m 95% CI 11.167-14.2 vs 9.1 m 95% CI 6. 367-10.067, HR 0.03, p = 0.0001). Conclusions: Our results showed the prognostic role of the combination of hematologic parameters and VEGFR2 levels + RBC count in RAS WT anti-EGFR resistant mCRC pts treated with FOLFIRI-Aflibercept. These findings represent a promising association of translational and clinical factors in predicting survival in the specific study population. Clinical trial information: NCT04252456.
Approximately 50% of colorectal cancers occur in older patients. International societies recommend geriatric tools to optimise treatment of older patients. Comprehensive Geriatric Assessment (CGA) is ...a multidimensional assessment used to classify patients as fit, vulnerable, or frail. The CGA-based oncological multidimensional prognostic index (onco-MPI) also classifies patients as high-, intermediate-, or low-risk based on tumour characteristics. We investigated the role of CGA and onco-MPI in older patients with metastatic colorectal cancer (mCRC) in a real-world setting.
Data for consecutive mCRC patients aged ≥70 years were retrieved from a prospectively maintained database from 2010 to 2020. We analyzed patients' and tumours' characteristics, and the CGA domains. Onco-MPI was calculated by a validated algorithm derived from CGA domains. Pearson's test was used to verify whether onco-MPI scores and chemotherapy administration were correlated.
The study included 488 mCRC patients with a mean age of 76.1 years. According to CGA, 52% of patients were fit, 28% vulnerable, and 20% frail. According to onco-MPI, 9% were low, 54% intermediate, and 37% high-risk. The median OS was 22.7 months. The following factors improved OS: 0–1 ECOG PS, low onco-MPI, fit based on CGA, chemotherapy administration, and doublet regimen. Chemotherapy administration significantly correlated with onco-MPI scores, leading to a survival gain regardless of the risk subgroups. First-line regimen had no impact on survival across the CGA and onco-MPI categories.
CGA and onco-MPI scores confirmed their prognostic impact in older mCRC patients and may aid in decision-making and subgroup stratification in dedicated trials.
•Geriatric assessment in older cancer patients is recommended by current guidelines.•We analysed onco-MPI and comprehensive geriatric assessment in older mCRC patients.•The study demonstrated the prognostic role of onco-MPI and geriatric assessment.•Onco-MPI adds valuable information for proper management of older cancer patients.•Therapy was modulated by onco-MPI leading to survival benefit in all subgroups.
In clinical trials, the assessment of safety is traditionally focused on the overall rate of high-grade and serious adverse events (AEs). A new approach to AEs evaluation, taking into account chronic ...low-grade AEs, single patient’s perspective, and time-related information, such as ToxT analysis, should be considered especially for less intense but potentially long-lasting treatments, such as maintenance strategies in metastatic colorectal cancer (mCRC).
We applied ToxT (Toxicity over Time) evaluation to a large cohort of mCRC patients enroled in randomised TRIBE, TRIBE2, and VALENTINO studies, in order to longitudinally describe AEs throughout the whole treatment duration and to compare AEs evolution over cycles between induction and maintenance strategies, providing numerical and graphical results overall and per single patient. After 4–6 months of combination therapy, 5-fluorouracil/leucovorin (5-FU/LV) + bevacizumab or panitumumab was recommended in all studies except for the 50% of patients in the VALENTINO trial who received panitumumab alone.
Out of 1400 patients included, 42% received FOLFOXIRI (5-FU/LV, oxaliplatin, and irinotecan)/bevacizumab, 18% FOLFIRI/bevacizumab, 24% FOLFOX/bevacizumab, 16% FOLFOX/panitumumab. Mean grade of general and haematological AEs was higher in the first cycles, then progressively decreasing after the end of induction (p < 0.001), and always remaining at the highest levels with FOLFOXIRI/bevacizumab (p < 0.001). Neurotoxicity became more frequent over the cycles with late high-grade episodes (p < 0.001), while the incidence but not the grade of hand-and-foot syndrome gradually increased (p = 0.91). Anti-VEGF-related AEs were more severe in the first cycles, then setting over at low levels (p = 0.03), while anti-EGFR-related AEs still affected patients during maintenance.
Most of chemotherapy-related AEs (except for HFS and neuropathy) reach the highest level in the first cycles, then decrease, probably due to their active clinical management. Transition to maintenance allows relief from most AEs, especially with bevacizumab-based regimens, while anti-EGFR-related AEs may persist.
•ToxT analysis longitudinally evaluates AEs, overall and per single patient.•ToxT was applied for the first time to different upfront treatments of mCRC.•Most AEs are worse during the first cycles, then progressively ameliorate.•Transition to maintenance allows a considerable relief.•Some AEs draw peculiar trajectories, not perceived in traditional safety reports.
2025
Background: Brain metastases (BM) from primary colorectal cancer (prCRC) are rare (1-3%); few is known about CRC BM predictive factors, prognosticators and molecular pathways. High rate of HER2 ...amplification ( HER2+) in CRC with BM was previously described, being HER2+ overall rare in CRC (<5%); however, HER2+ impact on prognosis of CRC with BM is uncertain. Enrichment in high microsatellite instability (MSI-H) and BRAFV600E mutations (mut) was also documented in BM tissue compared to matched prCRC. We designed this study to describe molecular landscape and clinical characteristics of CRC with BM, with special focus on HER2. Methods: HEROES was a retrospective-prospective, observational study in which patients (pts) with resected BM from CRC and treated at our institution from 1 January 2010 until 31 December 2021 were enrolled to perform extensive molecular analysis of matched prCRC and BM tissue. Molecular characterization and TMB were obtained with Next Generation Sequencing (NGS, FoundationOne CDx). RAS/BRAF and MSI were respectively assessed with MassArray (Myriapod Colon Status kit) and immunohistochemistry (IHC) to validate NGS results. HER2 status was assessed with IHC/in situ hybridization (ISH). Tumor-infiltrating lymphocytes (TILs) were counted on hematoxylin-eosin-stained tissue. TMB was defined high if ≥ 5.02 mut/mB; TILs if ≥ 1.6 (cutoff set with ROC curve using R software v 4.1.2). Primary objective was to describe molecular landscape of paired BM and prCRC, with special focus on HER2. Secondary objectives were to search for new prognosticators of PFS after BM resection (BM-PFS), intracranial-only PFS (BM-iPFS) after BM resection, and OS in pts with resected BM from CRC. Results: Out of 100 pts with BM from CRC, 22 underwent BM resection and were included in the analysis. 18 out of 22 pts were aged ≥ 70 (82%); 19 (86%) had left colon or rectal origin. 17 (70%) had concomitant lung metastases. HER2+ was found on 4 (18%) BM, 3 (14%) of which had also HER2+ in matched prCRC; 3 (14%) BM carried BRAFV600Emut; 2 (9%) BM had MSI-H. Acquired HER2+ and BRAFV600Emut on BM were reported in two different pts. KRASmut were consistent between BM and prCRC. Factors positively influencing BM-iPFS were low TMB (HR 0.36; 95%CI 0.12-1.10; p = 0.0275) and absence of HER2 ( HER2neg) on BM (HR 0.20; 95%CI 0.03-1,52; p = 0.0013). HER2neg BM were also related to longer BM-PFS (HR 0.35; 95%CI 0.07-1.76; p=0.0402), as well as KRASmut BM (HR 0.35; 95%CI 0.11-1.06; p=0.0096). Longer OS was found in pts with ECOG PS 0-1 (p<0.0001), with ≤ 1 metastatic site (HR 0.30; 95%CI 0.09-0.94; p = 0.0076) or with high TILs in prCRC (HR 0.32; 95%CI 0.10-1.03; p = 0.0368). Conclusions: Even with the limitation of small sample size, this study supports HER2+ enrichment in both prCRC and BM from CRC. HER2neg, low TMB or KRASmut BM conferred better prognosis. ECOG PS 0-1, ≤ 1 metastatic site and TILs-enriched prCRC were related to better OS.
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