RESUMO
BACKGROUND: Trop-2 and Nectin-4 are transmembrane proteins overexpressed in many tumours and targets of antibody-drug conjugates (ADC). In metastatic colorectal cancer (mCRC), the role of Trop-2 and Nectin-4 has been poorly investigated. METHODS: Tumour samples of patients randomised in the phase III TRIBE2 were assessed for Trop-2 and Nectin-4 expression. RESULTS: Three hundred eighty-six tumours were assessed for Trop-2 expression. 90 (23%), 115 (30%) and 181 (47%) were Trop-2 high, medium and low, respectively. Patients with low Trop-2 tumours achieved longer PFS (12 versus 9.9 months, p = 0.047) and OS (27.3 versus 21.3 months, p = 0.015) than those with high/medium Trop-2 tumours. These findings were confirmed in multivariate analysis (p = 0.022 and p = 0.023, respectively). A greater OS benefit from treatment intensification with FOLFOXIRI/bevacizumab was observed in patients with high/medium Trop-2 tumours (p-for-interaction = 0.041). Two hundred fifty-one tumours were assessed for Nectin-4 expression. Fourteen (5%), 67 (27%) and 170 (68%) were high, medium and low, respectively. No prognostic impact was observed based on Nectin-4 expression and no interaction effect was reported between Nectin-4 expression groups and treatment arm. CONCLUSIONS: In mCRC, expression levels of Trop-2 and Nectin-4 are heterogeneous, suggesting a target-driven development of anti-Trop2 and anti-Nectin-4 ADCs. Medium/high Trop-2 expression is associated with worse prognosis and higher benefit from chemotherapy intensification.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Bevacizumab/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Prognóstico , Neoplasias Retais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina , Fluoruracila , LeucovorinaRESUMO
Anti-EGFRs plus doublet chemotherapy is considered the optimal upfront option for RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC). Early-onset (EO) mCRC has an increasing incidence and its prognostic/predictive role and management is debatable. We performed a post hoc analysis of Valentino study, that randomized RAS wild-type mCRC patients to two panitumumab-based maintenance regimens after FOLFOX/panitumumab induction. We assessed the safety and efficacy outcomes in patients stratified for age (<50/≥50 years old). We assessed progression-free survival (PFS), overall survival (OS), response rate (ORR), rate of treatment-related and panitumumab-related adverse events (AEs) and quality of life (QoL). In 229 patients enrolled, 35 (15%) had EO mCRC, with a higher rate of female sex (P = .020) and lower rate of primary tumor resection (P = .001). Median PFS and OS were 10.9 vs 10.8 months (P = .593) and 28.1 vs 27.5 months (P = .865) in patients <50 and ≥50 years old, respectively, with no significant impact of maintenance arm. ORR and disease control rate were 74% vs 65% (P = .337) and 97% vs 81% (P = .013) in patients <50 or ≥50 years old. In younger patients, a trend for increased chemotherapy-related AEs (peculiarly anemia) was shown, while significantly decreased EGFR-related hypomagnesemia and increased skin rash were reported. No significant differences in treatment intensity or QoL were observed. In patients with EO mCRC and RAS wild-type status, we found no differences in terms of survival outcomes based on age when selecting maintenance strategies. Management of treatment-related AEs should consider the differential toxicity profile of age and sex.
Assuntos
Neoplasias Colorretais , Qualidade de Vida , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Panitumumabe/uso terapêutico , Prognóstico , Proteínas Proto-Oncogênicas B-rafRESUMO
INTRODUCTION: In patients with metastatic colorectal cancer (mCRC), baseline circulating tumour DNA (ctDNA) variant allele fraction (VAF) might serve as a surrogate of disease burden and should be evaluated in comparison with CEA and RECIST-defined sum of target lesions. METHODS: In this pre-planned analysis of the VALENTINO trial, we included patients with RAS wild-type mCRC receiving upfront FOLFOX/panitumumab with available baseline liquid biopsy. CtDNA was analysed by means of a 14-gene NGS panel. For each patient, the gene with the highest VAF in ctDNA was selected. RESULTS: The final cohort included 135 patients. The median VAF was 12.6% (IQR: 2.0-45.2%). Higher VAF was observed in patients with liver metastases and with synchronous metastases presentation. Patients with high VAF had poorer median OS compared to those with low VAF (21.8 vs 36.5 months; HR: 1.82, 95%CI: 1.20-2.76; p = 0.005). VAF outperformed baseline CEA and target lesion diameter in the prognostic stratification and remained significantly correlated with OS (p = 0.003) in a multivariate model. VAF was not significantly correlated with dimensional response and PFS. CONCLUSION: CtDNA measured by VAF is prognostic in patients with RAS wild-type mCRC. Response and PFS after an anti-EGFR-based first-line strategy are independent from initial tumour burden.
Assuntos
DNA Tumoral Circulante/sangue , Neoplasias do Colo/patologia , Frequência do Gene , Mutação , Carga Tumoral/genética , Proteínas ras/genética , Idoso , DNA Tumoral Circulante/genética , Neoplasias do Colo/sangue , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Feminino , Humanos , Itália , Masculino , Metástase Neoplásica , Prognóstico , Resultado do TratamentoRESUMO
BACKGROUND: In patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC), growing evidence supports anti-epidermal growth factor receptor (EGFR) retreatment, whereas little is known on the outcomes of anti-EGFR-based reinduction therapy during the upfront strategy. METHODS: We included patients enrolled in the Valentino study who had disease progression and received at least one dose of post-progression therapy. The Kaplan-Meier method and Cox proportional hazards regression were used for the survival analysis. When comparing the outcomes of anti-EGFR-based reinduction versus any second line, a propensity score-based matching was used. RESULTS: Liver-limited/single site of disease (P < .001 and P = .002), left-sidedness (P = .029), surgery of metastases (P = .003), early tumor shrinkage, and deeper responses (P = .018 and P = .036) were associated with the use of anti-EGFR-based reinduction versus any other second line. All patients treated with reinduction had an anti-EGFR-free interval of at least 3 months. In the propensity score-matched population, progression-free survival (PFS) was similar in the 2 treatment groups, the overall survival (OS) was significantly longer for patients treated with reinduction (P = .029), and the response rate was higher in patients treated with reinduction (P = .033). An oxaliplatin-free interval ≥12 months, left-sidedness, and molecular hyperselection beyond RAS/BRAF were associated with significantly better outcomes after anti-EGFR-based reinduction. CONCLUSIONS: Reinduction strategies with anti-EGFR-based regimens are commonly used in clinical practice. Our data highlight the importance of clinical-molecular selection for re-treatments and the need for prospective strategy trials in selected populations.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Panitumumabe/farmacologia , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Retais/tratamento farmacológicoRESUMO
BACKGROUND: EOX (epirubicin, oxaliplatin, and capecitabine) is one of the standard regimens for metastatic or locally advanced gastric cancer (GC). A new combination based on fractional docetaxel (low-TOX) has been developed in an attempt to increase the efficacy of EOX and reduce the heavy toxicity of classical docetaxel regimens. METHODS: Overall, 169 previously untreated GC patients were randomized between EOX (arm A) and low-TOX (arm B). The primary endpoint was progression-free survival (PFS), while secondary ones were overall survival (OS), overall response rate (ORR), disease control rate (DCR), and tolerability. The study was designed to detect a 35% (80% power at a two-sided 5% significance level) PFS increase with low-TOX and an interim analysis for futility was planned after the first 127 events. RESULTS: At the cut-off date of interim analysis, median PFS was 6.3 months [95% confidence interval (CI) 5.0-8.1] in arm A vs 6.3 months (95% CI 5.0-7.8) in arm B, without statistical difference. OS was comparable in the two arms: 12.4 in arm A (95% CI 9.1-19.2) vs 11.5 months in arm B (95% CI 8.6-15.0). ORR was 33% and 24%, while DCR was 68% and 67%, respectively. Treatment modification (91% vs 78%, P = 0.017) and number of patients with CTC grade ≥ 3 adverse events (42 vs 35) were higher in arm B. CONCLUSIONS: A triplet regimen based on the fractional dose of docetaxel achieves no improvement over EOX which remains a potential standard treatment in many patients with inoperable, locally advanced or metastatic GC.
Assuntos
Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/efeitos adversos , Docetaxel , Epirubicina , Fluoruracila/efeitos adversos , Humanos , Oxaliplatina , Neoplasias Gástricas/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Perioperative FLOT (5-fluorouracil, oxaliplatin and docetaxel) has recently become the gold standard treatment for fit patients with operable gastric (GC) or gastroesophageal (GEJ) adenocarcinoma, getting a 5-year overall survival (OS) of 45%, over 23% with surgery alone. METHODS: RealFLOT is an Italian, multicentric, observational trial, collecting data from patients with resectable GC or GEJ adenocarcinoma treated with perioperative FLOT. Aim of the study was to describe feasibility and safety of FLOT, pathological complete response rate (pCR), surgical outcomes and overall response rate (ORR) in an unselected real-world population. Additional analyses evaluated the correlation between pCR and survival and the prognostic role of microsatellite instability (MSI) status. RESULTS: Of 206 patients enrolled that received perioperative FLOT at 15 Italian centers, 124 (60.2%) received at least 4 full-dose cycles, 190 (92.2%) underwent surgery, and 142 (68.9%) started the postoperative phase. Among patients who started the postoperative phase, 105 (51.0%) received FLOT, while 37 (18%) received de-intensified regimens, depending on clinical condition or previous toxicities. pCR was achieved in 7.3% of cases. Safety profile was consistent with literature. Neutropenia was the most common G 3-4 adverse event (AE): 19.9% in the preoperative phase and 16.9% in the postoperative phase. No toxic death was observed and 30-day postoperative mortality rate was 1.0%. ORR was 45.6% and disease control rate (DCR) was 94.2%. Disease-free survival (DFS) and OS were significantly longer in case of pCR (p = 0.009 and p = 0.023, respectively). A trend towards better DFS was observed among MSI-H patients. CONCLUSIONS: These real-world data confirm the feasibility of FLOT in an unselected population, representative of the clinical practice. pCR rate was lower than expected, nevertheless we confirm pCR as a predictive parameter of survival. In addition, MSI-H status seems to be a positive prognostic marker also in patients treated with taxane-containing triplets.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Junção Esofagogástrica , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Itália , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Prognóstico , Estudos Prospectivos , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgiaRESUMO
BACKGROUND: Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them achieves long-term benefit from trastuzumab-based upfront strategy. To advance precision oncology, we investigated the therapeutic efficacy of different HER2-targeted strategies, in HER2 "hyper"-amplified (≥ 8 copies) tumors. METHODS: We undertook a prospective evaluation of HER2 targeting with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates, in a selected subgroup of HER2 "hyper"-amplified gastric patient-derived xenografts (PDXs), through the design of ad hoc preclinical trials. RESULTS: Despite the high level of HER2 amplification, trastuzumab elicited a partial response only in 2 out of 8 PDX models. The dual-HER2 blockade with trastuzumab plus either pertuzumab or lapatinib led to complete and durable responses in 5 (62.5%) out of 8 models, including one tumor bearing a concomitant HER2 mutation. In a resistant PDX harboring KRAS amplification, the novel antibody-drug conjugate trastuzumab deruxtecan (but not trastuzumab emtansine) overcame KRAS-mediated resistance. We also identified a HGF-mediated non-cell-autonomous mechanism of secondary resistance to anti-HER2 drugs, responsive to MET co-targeting. CONCLUSION: These preclinical randomized trials clearly indicate that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results suggest that a selected subpopulation of HER2-"hyper"-amplified GC patients could strongly benefit from this strategy. Despite the negative results of clinical trials, the dual blockade should be reconsidered for patients with clearly HER2-addicted cancers.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medicina de Precisão/métodos , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Humanos , Imunoconjugados/uso terapêutico , Estudos Prospectivos , Proteínas Tirosina Quinases/antagonistas & inibidores , Neoplasias Gástricas/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: The combination of anti-EGFRs and doublet chemotherapy is considered the optimal upfront option for patients with RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC). The prophylactic or reactive treatment with tetracyclines for EGFR inhibitor-induced skin toxicity is currently clinical practice, though non-conclusive results are available. METHODS: We performed a post hoc analysis of the Valentino study that randomized RAS wild-type mCRC patients to two panitumumab-based maintenance regimens after the first-line induction, aimed at assessing the safety and efficacy of the administration of a pre-emptive doxycycline prophylaxis for anti-EGFR-related skin toxicity. We assessed the rate of treatment-related and panitumumab-related adverse events (AEs), treatment intensity, progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 226 patients, out of the 229 enrolled in the Valentino study, were eligible for the analysis. Overall, 143 (63%) and 83 (37%) patients received or not the antibiotic prophylaxis for skin toxicity. Any grade and G3/4 panitumumab-related AEs were reported in 89% versus 92% (p = 0.650) and 27% versus 27% (p = 1.000) patients who received or not the pre-emptive prophylaxis, respectively. Any grade and G3/4 skin rash occurred in 81% versus 90% (p = 0.085) and 27% versus 25% (p = 0.876) patients receiving or not the prophylaxis, respectively. No significant differences in terms of treatment duration, treatment delays or dose reductions, PFS, and OS were observed in the two sub-populations. CONCLUSION: The adequate management of anti-EGFR-related skin toxicity is fundamental to optimize the outcome of mCRC patients, balancing the survival benefit with patients' quality of life, especially in the first-line setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Doxiciclina/uso terapêutico , Panitumumabe/uso terapêutico , Dermatopatias/induzido quimicamente , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Doxiciclina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Panitumumabe/farmacologiaRESUMO
BACKGROUND: Few real-world series on the efficacy and safety of anti-programmed cell death protein-1(PD-1)/programmed death ligand-1(PD-L1)-based therapy are available in molecularly unselected patients with poor performance status (PS) and specific types of advanced cancers, because such populations are typically excluded from clinical trials due to poor life expectancy and risk of toxicity. MATERIALS AND METHODS: This multicenter retrospective case series included patients with microsatellite instability (MSI)-high metastatic cancers with Eastern Cooperative Oncology Group (ECOG) PS of 2 or 3 not related to comorbidities receiving anti-PD-1 with or without anti-CTLA-4 therapy after failure of at least one prior treatment line. RESULTS: We included 27 patients with six diverse tumor types: colorectal (n = 18), gastric (n = 5), biliary tract, pancreatic, small bowel, and endometrial cancers (n = 1 each). Baseline ECOG PS was 2 (74%) or 3 (26%). Overall response rate was 33%, with six partial and three complete responses. Median time to response was 3.1, months and median duration of response was 16.9 months. Median progression-free survival was 3.4 months (95% CI: 2.3 to not evaluable), and 18-month overall survival was 50.8% (95% confidence interval, 32.7-78.8). Baseline variables were not associated with survival outcomes. ECOG PS 1 was reached by 52% of patients in a median time of 6 weeks, and ECOG PS 0 was reached by 30% of patients in a median time of 10 weeks. CONCLUSION: In a high proportion of patients with MSI-high cancers and poor performance status related to end-stage disease, salvage immunotherapy can induce potentially long-lasting "Lazarus responses". Immunotherapy decisions near the end-of-life should be carefully integrated with predictive biomarkers and with palliative care measures in the real-world setting. IMPLICATIONS FOR PRACTICE: In this retrospective cohort study of 27 pretreated patients with microsatellite instability (MSI)-high cancers and Eastern Cooperative Oncology Group performance status of 2 or 3 not related to comorbidities, PD-1/PD-L1-based therapy induced a RECIST response in 33% of patients, with a median duration of 16.9 months, and an improvement of performance status in 52% of patients. MSI-high status can be used in clinical practice as a tumor-agnostic predictive biomarker to select critically ill patients with end-stage cancers for salvage immunotherapy.
Assuntos
Instabilidade de Microssatélites , Neoplasias , Efeitos Psicossociais da Doença , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Estudos RetrospectivosRESUMO
BACKGROUND: Epstein-Barr virus (EBV)-positive gastric cancers (GCs) have been recently identified as a molecular subgroup showing excellent outcomes after surgery for early-stage disease and responsiveness to immune checkpoint inhibitors (ICIs) for metastatic stage. No data are available on the prevalence, clinical characteristics, and prognosis of this subgroup of GCs in the metastatic setting. MATERIALS AND METHODS: In this cohort study, we assessed the impact of EBV status in patients with metastatic GC treated with chemotherapy at two Italian institutions. RESULTS: Among the 175 cases analyzed, only 7 (4%) were EBV positive and all showed long-lasting and even complete responses to first-line chemotherapy with fluorouracil and platinum and a significantly better survival compared with EBV-negative patients (3-year overall survival: 80% vs. 20.1%; hazard ratio: 0.12). CONCLUSION: If confirmed in larger data sets, our results may give a strong rationale for investigating the addition of ICIs to chemotherapy, in order to maximize the chance of achieving durable and complete responses in this uncommon subtype of GC. IMPLICATIONS FOR PRACTICE: To date, no data are available on the prevalence and clinical characteristics of patients with Epstein-Barr virus (EBV)-positive metastatic gastric cancer (GC), a specific subtype of GC showing excellent outcomes after radical surgery in early-stage disease and responsiveness to immune checkpoint inhibitors (ICIs). This cohort study showed that patients with EBV-positive GC who did not receive ICIs had exceptional, long-lasting, and even complete responses to first-line chemotherapy with fluorouracil and platinum and a significantly better survival compared with EBV-negative patients. If confirmed in larger series, these results may give a strong rationale for investigating the combination of chemotherapy and ICIs to achieve durable and potentially complete response in this uncommon subtype of GC.
Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Estudos de Coortes , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Humanos , Prognóstico , Neoplasias Gástricas/tratamento farmacológicoRESUMO
INTRODUCTION: For energy production, cancer cells maintain a high rate of glycolysis instead of oxidative phosphorylation converting glucose into lactic acid. This metabolic shift is useful to survive in unfavorable microenvironments. We investigated whether a positive glycolytic profile (PGP) in gastric adenocarcinomas may be associated with unfavorable outcomes under an anticancer systemic therapy, including the anti-angiogenic ramucirumab. MATERIALS AND METHODS: Normal mucosa (NM) and primary tumor (PT) of 40 metastatic gastric adenocarcinomas patients who received second-line paclitaxel-ramucirumab (PR) were analyzed for mRNA expression of the following genes: HK-1, HK-2, PKM-2, LDH-A, and GLUT-1. Patients were categorized with PGP when at least a doubling of mRNA expression (PT vs. NM) in all glycolytic core enzymes (HK-1 or HK-2, PKM-2, LDH-A) was observed. PGP was also related to TP53 mutational status. RESULTS: Mean LDH-A, HK-2, PKM-2 mRNA expression levels were significantly higher in PT compared with NM. 18 patients were classified as PGP, which was associated with significantly worse progression-free and overall survival times. No significant association was observed between PGP and clinical-pathologic features, including TP53 positive mutational status, in 28 samples. CONCLUSIONS: Glycolytic proficiency may negatively affect survival outcomes of metastatic gastric cancer patients treated with PR systemic therapy. TP53 mutational status alone does not seem to explain such a metabolic shift.
Assuntos
Adenocarcinoma/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glicólise/genética , Paclitaxel/uso terapêutico , Terapia de Salvação/mortalidade , Neoplasias Gástricas/metabolismo , Adenocarcinoma/mortalidade , Idoso , Feminino , Mucosa Gástrica/metabolismo , Humanos , Masculino , Mutação , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , RamucirumabRESUMO
The treatment scenario of metastatic colorectal cancer (mCRC) has been rapidly enriched with new chemotherapy combinations and biological agents that lead to a remarkable improvement in patients' outcome. Kinase gene fusions account for less than 1% of mCRC overall but are enriched in patients with high microsatellite instability, RAS/BRAF wild-type colorectal cancer. mCRC patients harboring such alterations show a poor prognosis with standard treatments that could be reversed by adopting novel therapeutic strategies. Moving forward to a positive selection of mCRC patients suitable for targeted therapy in the era of personalized medicine, actionable gene fusions, although rare, represent a peculiar opportunity to disrupt a tumor alteration to achieve therapeutic goal. Here we summarize the current knowledge on potentially actionable gene fusions in colorectal cancer available from retrospective experiences and promising preliminary results of new basket trials.
Assuntos
Neoplasias Colorretais , Fusão Gênica , Instabilidade de Microssatélites , Proteínas de Fusão Oncogênica , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Metástase Neoplásica , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismoRESUMO
BACKGROUND: Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs. METHODS: We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials. RESULTS: Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615). CONCLUSIONS: The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Leucovorina/administração & dosagem , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina/administração & dosagem , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: We built and externally validated a nomogram for predicting the overall survival (OS) probability of advanced gastric cancer patients receiving second-line treatment. METHODS: The nomogram was developed on a set of 320 Italian patients and validated on two independent sets (295 Italian and 172 Korean patients). Putative prognostic variables were selected using a random forest model and included in the multivariable Cox model. The nomogram's performance was evaluated by calibration plot and C index. RESULTS: ECOG performance status, neutrophils to lymphocytes ratio, and peritoneal involvement were selected and included into the multivariable model. The C index was 0.72 (95% CI 0.68-0.75) in the development set, 0.69 (95% CI 0.65-0.73) in the Italian validation set, but only 0.57 (95% CI 0.52-0.62) in the Korean set. While Italian calibrations were quite good, the Korean one was poor. Regarding 6-month OS predictions, calibration was best in both Caucasian cohorts and worst the in Asian one. CONCLUSIONS: Our nomogram may be a useful tool to predict 3- or 6-month OS in Caucasian gastric cancer patients eligible for second-line therapy. Based on three easy-to-collect variables, the Gastric Life nomogram may help clinicians improve patient selection for second-line treatments and assist in clinical trial enrollment.
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Nomogramas , Neoplasias Gástricas/mortalidade , Idoso , Estudos de Coortes , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , República da Coreia/epidemiologia , Neoplasias Gástricas/patologiaRESUMO
Locally recurrent rectal cancer is resected with clear margins in only 50% of cases, and these patients achieve a three-year survival rate of 50%. Outcomes and therapeutic strategies for nonresectable locally recurrent rectal cancer have been much less explored. The aim of the study was to assess the three-year progression-free survival and the three-year overall survival in locally recurrent rectal cancer patients treated by chemotherapy/chemoradiation only vs. chemotherapy/chemoradiation and R2 surgical debulking vs. palliative care. A total of 86 patients affected by nonresectable locally recurrent rectal cancer were included: three-year progression-free survival was 15.8% with chemotherapy/chemoradiation vs. 20.3% with R2 surgical debulking (Log-rank p=0.567), but both rates were higher than best palliative care (0.0%, Log-rank p=0.0004). Three-year overall survival rates were respectively 62.0%, 70.8% and 0.0% (Log-rank p<0.0001). Chemotherapy/chemoradiation (HR 0.33, p=0.028) and R2 surgical debulking with or without chemotherapy/chemoradiation (HR 0.23, p=0.005) were independent predictors of improved progression-free survival on multivariate analysis. In conclusion, both chemotherapy/chemoradiation alone and R2 surgery with or without chemotherapy/chemoradiation provide a survival benefit over palliative care in nonresectable locally recurrent rectal cancer. However, considering that pelvic debulking is burdened by a high rate of complications, and considering its negligible impact on progression-free survival and overall survival when associated to medical therapy, surgery should be avoided in this setting.
RESUMO
Achieving successful hematopoietic stem cell transplantation (HSCT) relies on two fundamental pillars: effective mobilization and efficient collection through apheresis to attain the optimal graft dose. These cornerstones pave the way for enhanced patient outcomes. The primary challenges encountered by the clinical unit and collection facility within a transplant program encompass augmenting mobilization efficiency to optimize the harvest of target cell populations, implementing robust monitoring and predictive strategies for mobilization, streamlining the apheresis procedure to minimize collection duration while ensuring adequate yield, prioritizing patient comfort by reducing the overall collection time, guaranteeing the quality and purity of stem cell products to optimize graft function and transplant success, and facilitating seamless coordination between diverse entities involved in the HSCT process. In this review, we aim to address key questions and provide insights into the critical aspects of mobilizing and collecting hematopoietic stem cells for transplantation purposes.
Assuntos
Remoção de Componentes Sanguíneos , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante Homólogo , Remoção de Componentes Sanguíneos/métodos , Células-Tronco HematopoéticasRESUMO
PURPOSE: To demonstrate the negative prognostic impact of a panel of genomic alterations (PRESSING-HER2 panel) and lack of HER2 amplification by next-generation sequencing (NGS) in patients with HER2+, RAS wild-type metastatic colorectal cancer receiving dual HER2 blockade. EXPERIMENTAL DESIGN: The PRESSING-HER2 panel of HER2 mutations/rearrangements and RTK/MAPK mutations/amplifications was assessed by NGS. HER2 amplification was confirmed by NGS if copy-number variation (CNV) was ≥ 6. With a case-control design, hypothesizing 30% and 5% PRESSING-HER2 positivity in resistant [progression-free survival (PFS) <4 months and no RECIST response] versus sensitive cohorts, respectively, 35 patients were needed per group. RESULTS: PRESSING-HER2 alterations included HER2 mutations/rearrangements, EGFR amplification, and BRAF mutations and had a prevalence of 27% (9/33) and 3% (1/35) in resistant versus sensitive patients (P = 0.005) and 63% predictive accuracy. Overall, HER2 nonamplified status by NGS had 10% prevalence. Median PFS and overall survival (OS) were worse in PRESSING-HER2+ versus negative (2.2 vs. 5.3 months, P < 0.001; 5.4 vs. 14.9 months, P = 0.001) and in HER2 nonamplified versus amplified (1.6 vs. 5.2 months, P < 0.001; 7.4 vs. 12.4 months, P = 0.157). These results were confirmed in multivariable analyses [PRESSING-HER2 positivity: PFS HR = 3.06, 95% confidence interval (CI), 1.40-6.69, P = 0.005; OS HR = 2.93, 95% CI, 1.32-6.48, P = 0.007]. Combining PRESSING-HER2 and HER2 CNV increased the predictive accuracy to 75%. CONCLUSIONS: PRESSING-HER2 panel and HER2 nonamplified status by NGS warrant validation as potential predictive markers in this setting. See related commentary by Raghav et al., p. 260.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Progressão , Prognóstico , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Metastatic Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors characterized by high morbidity and limited systemic treatment options, mainly based on radiometabolic treatments or chemotherapy. Based on the preclinical rationale that PGGLs carcinogenesis relies on angiogenesis, treatment with tyrosine kinase inhibitors (TKI) may represent another viable therapeutic option. METHODS: We conducted a prospective phase II study in patients with metastatic or unresectable PGGLs. Patients received sunitinib (50 mg daily for 4 weeks, followed by a 2-week rest period) until progressive disease (PD), unacceptable toxicity or consent withdrawal. The primary endpoint was 12-month progression-free survival (PFS) rate; secondary endpoints were safety overall response rate (ORR) according to RECIST 1.1 criteria and overall survival (OS). EudraCT Number: 2011-002632-99. RESULTS: Fifty patients were included. At a median follow-up of 71.7 months (IQR 35.4-100.1), the 1 year-PFS rate was 53.4 % (95 %CI 41.1-69.3) and median PFS was 14.1 months (95 % CI 8.9-25.7). ORR was 15.6 %, the median OS was 49.4 months (95 %CI 21.2-NA), and grade 3 or higher treatment-related adverse events were reported in 34 % patients. No significant correlation was found between specific genetic alterations or genomic clusters and sunitinib efficacy. CONCLUSION: Sunitinib is an active drug in patients with advanced PGGLs, capable of inducing prolonged disease control with a manageable toxicity profile.
RESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report 4-year results of the phase II randomized AtezoTRIBE study. Eligible patients with metastatic colorectal cancer (mCRC) received first-line fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/bevacizumab (control group, n = 73) or FOLFOXIRI/bevacizumab plus atezolizumab (experimental group, n = 145). We present overall survival (OS) and updated outcomes according to tumor immune-related biomarkers, both in the intention-to-treat (ITT) population and the cohort of patients with proficient mismatch repair (pMMR) tumors. Median follow-up was 45.2 months (IQR, 42.6-49.2). In the ITT population, median OS was 33.0 and 27.2 months for experimental and control groups, respectively (hazard ratio [HR], 0.78 [80% CI, 0.61 to 0.98]; P = .084). An interaction effect between Immunoscore Immune-Checkpoint (IC) and treatment arm was observed (Pint, .089), with higher benefit from atezolizumab in the Immunoscore IC-high group. In the pMMR cohort (N = 202), median OS was 30.8 and 29.2 months for experimental and control groups, respectively (HR, 0.80 [80% CI, 0.63 to 1.02]; P = .117). Interactions between treatment group and tumor mutational burden (TMB) and Immunoscore IC were reported (Pint, .043 and .092, respectively), with patients bearing TMB-high and Immunoscore IC-high tumors deriving higher benefit from the addition of atezolizumab. First-line FOLFOXIRI/bevacizumab plus atezolizumab improves OS in patients with mCRC. In the pMMR group, patients with Immunoscore IC-high and/or TMB-high tumors are identified as a subgroup of interest to further develop this treatment.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorretais , Fluoruracila , Irinotecano , Leucovorina , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Leucovorina/uso terapêutico , Leucovorina/administração & dosagem , Bevacizumab/administração & dosagem , Bevacizumab/uso terapêutico , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Irinotecano/uso terapêutico , Irinotecano/administração & dosagem , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Adulto , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/administração & dosagem , Camptotecina/análogos & derivadosRESUMO
BACKGROUND: Surgery plus peri-operative/adjuvant chemotherapy is the standard of care for locally advanced GC/GEJC, though with unsatisfactory results. dMMR/MSI-high tumors have better prognosis and scant benefit from chemotherapy as compared to pMMR/MSS ones. The differential outcome of therapies in terms of safety and efficacy according to sex is still debated in GC/GEJC patients. METHODS: We previously performed an individual patient data pooled analysis of MAGIC, CLASSIC, ITACA-S, and ARTIST trials including GC/GEJC patients treated with surgery alone or surgery plus peri-operative/adjuvant chemotherapy to assess the value of MSI status. We performed a secondary analysis investigating the prognostic and predictive role of sex (female versus male) in the pooled analysis dataset in the overall population and patients stratified for MSI status (MSI-high versus MSS/MSI-low). Disease-free (DFS) and overall survival (OS) were calculated. RESULTS: Patients with MSI-high tumors had improved survival as compared to MSS/MSI-low ones irrespective of sex, whereas in those with MSS/MSI-low tumors, females had numerically longer OS and DFS (5-year OS was 63.2% versus 57.6%, HR 0.842; p = 0.058, and 5-year DFS was 55.8% versus 50.8%, HR 0.850; p = 0.0504 in female versus male patients). The numerical difference for the detrimental effect of chemotherapy in MSI-high GC was higher in females than males, while the significant benefit of chemotherapy over surgery alone was confirmed in MSS/MSI-low GC irrespective of sex. CONCLUSIONS: This pooled analysis including four randomized trials highlights a relevant impact of sex in the prognosis and treatment efficacy of MSI-high and MSS/MSI-low non-metastatic GC/GEJC.