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BACKGROUND: Few data regarding post-induction management following first-line anti-epidermal growth factor receptor (EGFR)-based doublet regimens in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) are available. METHODS: This multicenter, retrospective study aimed at evaluating clinicians' attitude, and the safety and effectiveness of post-induction strategies in consecutive patients affected by left-sided RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR as first-line regimen, who did not experience disease progression within 6 months from induction initiation, at 21 Italian and 1 Spanish Institutions. The measured clinical outcomes were: progression-free survival (PFS), overall survival (OS), adverse events, and objective response rate (ORR). RESULTS: At the data cutoff, among 686 consecutive patients with left-sided RAS/BRAF wild-type mCRC treated with doublet plus anti-EGFR as first-line regimen from March 2012 to October 2020, 355 eligible patients have been included in the present analysis. Among these, 118 (33.2%), 66 (18.6%), and 11 (3.1%) received a maintenance with 5-fluorouracil/leucovorin (5FU/LV)+anti-EGFR, anti-EGFR, and 5FU/LV, respectively, while 160 (45.1%) patients continued induction treatment (non-maintenance) until disease progression, unacceptable toxicity, patient decision, or completion of planned treatment. The median period of follow-up for the overall population was 33.7 months (95%CI = 28.9-35.6). The median PFS values of the 5FU/LV+anti-EGFR, anti-EGFR, 5FU/LV, and non-maintenance cohorts were 16.0 (95%CI = 14.3-17.7, 86 events), 13.0 (95%CI = 11.4-14.5, 56 events), 14.0 (95%CI = 8.1-20.0, 8 events), and 10.1 months (95%CI = 9.0-11.2, 136 events), respectively (p < 0.001). The median OS values were 39.6 (95%CI = 31.5-47.7, 43 events), 36.1 (95%CI = 31.6-40.7, 36 events), 39.5 (95%CI = 28.2-50.8, 4 events), and 25.1 months (95%CI = 22.6-27.6, 99 events), respectively (p < 0.001). After adjusting for key covariates, a statistically significant improvement in PFS in favor of 5FU/LV+anti-EGFR (HR = 0.59, 95%CI = 0.44-0.77, p < 0.001) and anti-EGFR (HR = 0.71, 95%CI = 0.51-0.98, p = 0.039) compared to the non-maintenance cohort was found. Compared to the non-maintenance cohort, OS was improved by 5FU/LV+anti-EGFR (HR = 0.55, 95%CI = 0.38-0.81, p = 0.002) and, with marginal significance, by anti-EGFR (HR = 0.67, 95%CI = 0.51-0.98, p = 0.051). No difference was found in ORR. Any grade non-hematological and hematological events were generally higher in the non-maintenance compared to the maintenance cohorts. CONCLUSION: Among the treatment strategies following an anti-EGFR-based doublet first-line induction regimen in patients affected by left-sided RAS/BRAF wild-type mCRC treated in a "real-life" setting, 5FU/LV+anti-EGFR resulted the most adopted, effective, and relatively safe regimen.
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BACKGROUND: Doublets plus antiepidermal growth factor receptors monoclonal antibodies (EGFRi) are widely considered the preferable first-line regimen in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC), resulting superior in terms of activity and efficacy compared to doublets plus bevacizumab. However, data comparing doublet plus EGFRi and triplet plus bevacizumab are lacking, and the relative benefit of an intensive regimen plus an antiangiogenic backbone in this population is debated. METHODS: This multicenter, retrospective study aimed at evaluating clinicians' attitude to triplet-bevacizumab and doublet-EGFRi as first-line regimen in patients with left-sided RAS/BRAF wild-type mCRC treated in clinical practice at 22 Oncology Units from March 2012 to October 2020. A random case-control matching was performed to compare activity (ORR), and effectiveness (PFS, OS, secondary resection rate of metastases with curative intent) between triplet-bevacizumab and doublet-EGFRi, on the basis of ECOG-PS, age, gender, and burden of disease. RESULTS: A total of 718 patients were consecutively treated with doublet-EGFRi (686, 95.5%) or triplet-bevacizumab (32, 4.5%). After case-control matching, median PFS was 13.6 (95% CI, 8.9-31.7) and 16.1 (95% CI, 12.1-36.8) months (P= .621), while median OS was 30.2 (95% CI, 14.4-69.5) and 38.1 (95% CI, 33.1-101.1) months (P= .0283) in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. The ORR was 65.6% and 90.6% (P= .016), while the secondary resection rate was 18.8% and 46.9% (P= .016), in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. Triplet-bevacizumab was associated with a higher incidence of G3/G4 neutropenia (25.0% vs. 12.5%, P= .041). CONCLUSION: Although a doublet-EGFRi remains the recommended upfront regimen in patients with left-sided RAS and BRAF wild-type mCRC, our real life data suggest a triplet-bevacizumab might be at least equally active and effective in properly selected cases.
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Neoplasias Colorretais , Proteínas Proto-Oncogênicas B-raf , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Estudos de Casos e Controles , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Fluoruracila/uso terapêutico , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Estudos RetrospectivosRESUMO
Chemotherapy is associated with different patterns of histopathological changes of the non-tumor-bearing liver. Hepatic infarction represents a relatively rare condition; the prevalence in several series of consecutive autopsies is 1.1%. To the best of our knowledge, no cases of liver infarction secondary to chemotherapy have been reported to date. We report a case of segmental hepatic infarction following the adjuvant chemotherapy with Oxaliplatin and Capecitabine in a patient who had undergone total gastrectomy and distal esophagectomy for gastric cancer. Liver infarction is usually managed by conservative therapy; interventional procedures such as percutaneous imaging-guided drainage or surgical evacuation should be reserved in cases where septic complications occur, with development of a hepatic abscess from the necrotic area. It is important to avoid misdiagnoses with liver metastases in order to define the most appropriate clinical management strategy. KEY WORDS: Adjuvant chemotherapy, Gastric cancer, Liver infarction, Hepatic necrosis.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/efeitos adversos , Carcinoma de Células em Anel de Sinete , Infarto Hepático/induzido quimicamente , Oxaliplatina/efeitos adversos , Neoplasias Gástricas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/administração & dosagem , Carcinoma de Células em Anel de Sinete/tratamento farmacológico , Carcinoma de Células em Anel de Sinete/cirurgia , Quimioterapia Adjuvante/efeitos adversos , Esofagectomia , Gastrectomia , Infarto Hepático/terapia , Humanos , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Fígado/patologia , Masculino , Necrose , Oxaliplatina/administração & dosagem , Neoplasias Gástricas/cirurgiaRESUMO
BACKGROUND: Recently, the GRANT (GRade, Age, Nodes, and Tumor) score was validated through an adjuvant trial population. METHODS: This retrospective study evaluated the performance of the GRANT score as a prognostic model for disease-free survival (DFS), compared to the University of California Los Angeles Integrated Staging System (UISS) score, in a "real-life" population of early renal cell carcinoma patients. A uni-/multivariate analysis of DFS was also performed, to weigh the roles of baseline clinical factors. RESULTS: From February 1998 to January 2018, 134 consecutive patients were enrolled, of which 85 patients (63.4%) had a favorable GRANT score, 49 (36.6%) an unfavorable GRANT score, and 21 (15.7%), 84 (62.6%), and 29 (21.6%) patients had a low, intermediate, or high risk of recurrence according to the UISS score, respectively. The median follow-up was 96 months. The median DFS of the overall study population was 53.7 months (95% CI: 38.4-87.8). Only bilateral renal cell carcinoma (p = 0.0041), Fuhrman grade 3/4 (p = 0.0008), pT3b- 4 (p = 0.0324), and pN1-2 (p = 0.0303) pathological status were confirmed as independent predictors of a shorter DFS by the multivariate analysis. The median DFS of patients with favorable and unfavorable GRANT scores were 84.9 (95% CI: 49.8-129) and 38.4 months (95% CI: 24.4-87.8), respectively, with a statistically significant difference (p = 0.0147). The median DFS of patients with low, intermediate, and high risk of recurrence according to the UISS score were 92.3 (95% CI: 18.1-153.9), 51.7 (95% CI: 36.2-87.8), and 49.8 months (95% CI: 31.3-129), respectively, without statistically significant differences (p = 0.4728). DFS c-statistic values were 0.59 (95% CI: 0.51-0.67) and 0.51 (95% CI: 0.42-0.60) for the GRANT and the UISS scores, respectively. CONCLUSION: The GRANT score might be a useful tool that is user-friendly and easy to perform in clinical practice.
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BACKGROUND AND AIMS: The prognostic role of family history of cancer (FHC) in resected colorectal cancer (CRC) is controversial. The aim of the current study was to evaluate its impact in a monoinstitutional series of stage III CRC patients. METHODS: This single institution retrospective analysis is aimed at evaluating whether FHC affects overall survival (OS) and disease-free survival (DFS) in stage III CRC patients. Moreover, the role of both colorectal FHC (FHCRC, in patients with at least one relative with CRC) and FHC "burden" have been investigated; patients were classified according to FHC in FHC negative, FHC-low (one "familial cluster" among parents/children/grandparents, brothers/sisters, uncles/cousins), and FHC-high (at least two clusters of those above mentioned). RESULTS: From October 2000 to March 2019, 112 consecutive stage III CRC patients have been evaluated. Median age was 67 years (range 24-89); male/female ratio was 64/48. Fifty-three (47.3%) patients were FHC-negative while 59 (52.7%) patients were FHC-positive, 18 (16.1%) of whom were FHCRC-positive. Thirty-three (29.5%) patients were FHC-low, and 10 (8.9%) were FHC-high. At a median follow-up of 41.9 months, no statistically significant differences in DFS were found. FHC-positive patients had a significantly longer OS than FHC-negative (HR = 0.32 [95% CI 0.12-0.84], p = 0.0210), and a significant trend towards improved OS according to the FHC burden was found (p = 0.0255). No statistically significant differences were found in DFS and OS according to FHCRC. CONCLUSION: In this retrospective analysis, FHC-positive stage III CRC patients had a significantly longer OS compared to FHC-negative. Moreover, this survival benefit seems to increase according to the FHC burden. Further prospective studies, with longer follow-up and larger sample size, are necessary to confirm FHC as prognostic factor in this setting.
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Neoplasias Colorretais/patologia , Predisposição Genética para Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Feminino , Seguimentos , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
: Background: The optimal anti-angiogenic strategy as second-line treatment in RAS wild-type metastatic colorectal cancer (mCRC) treated with anti-EGFR (Epidermal Growth Factor Receptor) based first-line treatment is still debated. METHODS: This multicenter, real-world, retrospective study is aimed at evaluating the effectiveness of second-line Bevacizumab- and Aflibercept-based treatments after an anti-EGFR based first-line regimen. Clinical outcomes measured were: objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AEs) profiles. RESULTS: From February 2011 to October 2019, 277 consecutive mCRC patients received Bevacizumab-based (228, 82.3%) or Aflibercept-based (49, 17.7%) regimen. No significant difference was found regarding ORR. The median follow-up was 27.7 months (95%CI: 24.7-34.4). Aflibercept-treated group had a significantly shorter PFS compared to Bevacizumab-treated group (5.6 vs. 7.1 months, respectively) (HR = 1.34 (95%CI: 0.95-1.89); p = 0.0932). The median OS of the Bevacizumab-treated group and Aflibercept-treated group was 16.2 (95%CI: 15.3-18.1) and 12.7 (95%CI: 8.8-17.5) months, respectively (HR= 1.31 (95%CI: 0.89-1.93) p = 0.16). After adjusting for the key covariates (age, gender, performance status, number of metastatic sites and primary tumor side) Bevacizumab-based regimens revealed to be significantly related with a prolonged PFS (HR = 1.44 (95%CI: 1.02-2.03); p = 0.0399) compared to Aflibercept-based regimens, but not with a prolonged OS (HR = 1.47 (95%CI: 0.99-2.17); p = 0.0503). The incidence of G3/G4 VEGF inhibitors class-specific AEs was 7.5% and 26.5% in the Bevacizumab-treated group and the Aflibercept-treated group, respectively (p = 0.0001). CONCLUSION: Our analysis seems to reveal that Bevacizumab-based regimens have a slightly better PFS and class-specific AEs profile compared to Aflibercept-based regimen as second-line treatment of RAS wild-type mCRC patients previously treated with anti-EGFR based treatments. These results have to be taken with caution and no conclusive considerations are allowed.
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Background: Immune-checkpoint inhibitors have radically changed the treatment landscape of Non-Small-Cell Lung Cancer (NSCLC). It is still unclear whether specific clinical characteristics might identify those patients benefiting from immunotherapy more than others. The aim of this study was to identify clinical characteristics associated with disease-specific survival (DSS), time-to-treatment failure (TTF), objective responses (OR) and progressive disease (PD) in NSCLC patients treated with Nivolumab.Methods: This was a multicenter retrospective study conducted on 294 patients treated with Nivolumab for advanced NSCLC.Results: Of the more than 50 variables analyzed, five showed a significant correlation with DSS: ECOG PS, size of the biggest brain metastasis, number of metastatic sites, toxicity, and malignant pleural effusion. Three variables significantly correlated with TTF: malignant pleural effusion, number of metastatic sites, number of liver metastases. Malignant pleural effusion was the only variable showing a significant correlation with OR, as well as the only one correlating with all the endpoints of the study.Conclusions: This study identified clinical characteristics associated with survival and response during treatment with Nivolumab in NSCLC patients. The unfavorable association between malignant pleural effusion and objective response is a novel finding with important translational implications.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Derrame Pleural Maligno/complicações , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Sarcopenia represents one of the hallmarks of all chronic diseases, including cancer, and was already investigated as a prognostic marker in the pre-immunotherapy era. Sarcopenia can be evaluated using cross-sectional image analysis of CT-scans, at the level of the third lumbar vertebra (L3), to estimate the skeletal muscle index (SMI), a surrogate of skeletal muscle mass, and to evaluate the skeletal muscle density (SMD). We performed a retrospective analysis of consecutive advanced cancer patient treated with PD-1/PD-L1 checkpoint inhibitors. Baseline SMI and SMD were evaluated and optimal cut-offs for survival, according to sex and BMI (+/-25) were computed. The evaluated clinical outcomes were: objective response rate (ORR), immune-related adverse events (irAEs), progression free survival (PFS) and overall survival (OS). From April 2015 to April 2019, 100 consecutive advanced cancer patients were evaluated. 50 (50%) patients had a baseline low SMI, while 51 (51%) had a baseline low SMD according to the established cut offs. We found a significant association between SMI and ECOG-PS (p = 0.0324), while no correlations were found regarding SMD and baseline clinical factors. The median follow-up was 20.3 months. Patients with low SMI had a significantly shorter PFS (HR = 1.66 [95% CI: 1.05-2.61]; p = 0.0291) at univariate analysis, but not at the multivariate analysis. They also had a significantly shorter OS (HR = 2.19 [95% CI: 1.31-3.64]; p = 0.0026). The multivariate analysis confirmed baseline SMI as an independent predictor for OS (HR = 2.19 [1.31-3.67]; p = 0.0027). We did not find significant relationships between baseline SMD and clinical outcomes, nor between ORR, irAEs and baseline SMI (data not shown). Low SMI is associated with shortened survival in advanced cancer patients treated with PD1/PDL1 checkpoint inhibitors. However, the lack of an association between SMI and clinical response suggests that sarcopenia may be generally prognostic in this setting rather than specifically predictive of response to immunotherapy.
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Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoterapia/métodos , Vértebras Lombares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Músculo Esquelético/patologia , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Contagem de Células , Feminino , Seguimentos , Humanos , Vértebras Lombares/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Melanoma/diagnóstico , Melanoma/mortalidade , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Tamanho do Órgão , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Retrospectivos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida , Tomografia Computadorizada por Raios XRESUMO
AIMS AND METHODS: This multicenter retrospective study aims to evaluate the correlations between Body Weight Loss (BWL), Body Mass Index (BMI) and clinical outcomes (ORR, PFS, and OS) of advanced gastric cancer (aGC) patients treated with second-line ramucirumab-based therapy in a "real-life" setting. RESULTS: From December 2014 to October 2018, 101 consecutive aGC patients progressed to a first-line chemotherapy were treated with ramucirumab alone (10.9%) or in combination with paclitaxel (89.1%). Median BMI was 21.2 kg/m2 and mBWL since first-line treatment commencement was 4.5%. Among 53 patients who underwent primary tumor resection (PTR), 73.6% experienced BWL, while 26.4% did not experience BWL (p = 0.0429). Patients who underwent PTR had a significantly higher probability of experiencing BWL (yes vs no) [OR = 2.35 (95% CI 1.02-5.42), p = 0.0439]. Among the 89 evaluable patients, ORR was 26.9% (95% CI 17.2-40.1). At a median follow-up of 17.3 months, mPFS was 5.4 months (95% CI 3.6-6.8) and mOS was 8.7 months (95% CI 7.3-11.9). In the multivariate analysis, only ECOG-PS and BMI were confirmed independent predictors for shorter PFS [HR = 1.69 (95% CI 1.01-2.82), p = 0.04] [HR = 1.97 (95% CI 1.12-3.46), p = 0.01] and OS [HR = 1.69 (95% CI 1.01-2.83), p = 0.04] [HR = 2.08 (95% CI 1.17-3.70), p = 0.01]. CONCLUSION: Efficacy of ramucirumab is confirmed in this "real-life" analysis. BWL seems not to have correlations with clinical outcomes in these patients, while BMI and ECOG-PS remain major prognostic factors. A possible explanation for the lack of prognostic effect of BWL might be the proportion of patients subjected to PTR in this series (52.5%).
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Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Índice de Massa Corporal , Neoplasias Gástricas/tratamento farmacológico , Redução de Peso/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Quimioterapia Adjuvante , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Resultado do Tratamento , Redução de Peso/fisiologia , RamucirumabRESUMO
BACKGROUND: Several trials evaluated the role of intensive regimens, made of triplet chemotherapies plus bevacizumab, as first-line treatment for patients with metastatic colorectal cancer (mCRC). We previously reported, in a Phase II prospective study, the efficacy and the tolerability of FIrB/FOx regimen, reporting interesting results in terms of received dose intensities (rDIs) and safety. METHODS: We reported a retrospective update of 85 patients treated with FIrB/FOx, an intensive regimen of 5-fluorouracil, bevacizumab, and weekly alternate irinotecan and oxaliplatin, to confirm its feasibility in "real life". Subgroup analyses were performed, particularly among patients treated with standard and modified FIrB/FOx (based on age, performance status, and/or comorbidities). RESULTS: Overall, 3-month objective response rate (ORR) and 6-month ORR were 75.9% and 55.3%, respectively. Median progression-free survival (PFS) and median overall survival (OS) were 14.4 and 34.9 months, respectively. Among the patients treated with standard and modified regimens, 3-month ORR, PFS, and OS were 75.8% and 76% (P=1.0000), 14.4 and 14.4 months (P=0.8589), and 37.8 and 26.6 months (P=0.7746), respectively. Among the K/NRAS wild-type and K/NRAS mutant patients, 3-month ORR, PFS, and OS were 95.2% and 74.5% (P=0.0526), 15.3 and 14.4 months (P=0.8753), and 37.8 and 51.4 months (P=0.8527), respectively. The rDIs were ≥80% of full doses both in the standard and in the modified regimens subgroups. Cumulative G3/4 toxicities were neutropenia (14.1%), diarrhea (17.6%), asthenia (9.4%), vomiting (5.6%), and hypertension (16.5%). CONCLUSION: This update shows that intensive regimens such as FIrB/FOx are also feasible options for first-line treatment of mCRC patients in the "real-life" setting.
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Prolonged exposure to temozolomide (TMZ) could improve clinical outcomes in recurrent glioblastoma multiforme (GBM) patients. We previously developed a dose-dense regimen of TMZ in a phase II study (180 mg/m2 from days 1 to 5 every two weeks). A retrospective analysis of patients with macroscopic residual GBM treated with "post-induction" dose-dense TMZ was conducted, adding an explorative subgroup analyses among patients with different O6-methylguanine DNA methyltransferase (MGMT) expressions (negative vs positive, < vs ≥ of 50 % of cells stained, < vs ≥ 70% of cells stained). Thirty-six patients were evaluated; after a median follow-up of 36 weeks, median Progression Free Survival (PFS) and median Overall Survival (OS) were 19 and 34 weeks, respectively. MGMT expression (70% cut-off) and sex were confirmed as independent predictors for disease control rate (DCR) at multivariate analysis. At univariate analysis ECOG-PS, Sex (female), extensive tumor resection was shown to be related to a longer PFS, while MGMT expression (cutoff 70%) to a shorter PFS. Multivariate analysis with Cox hazard regression confirmed only ECOGPS as an independent predictor for PFS. ECOG-PS showed to be significant related to a longer OS. Our analysis showed that dose-dense TMZ regimens are still an option for patients with recurrent GBM, but should be used for re-challenge treatments. MGMT immunohistochemistry high expression might be used as a "surrogate" negative predictor for DCR for dd-TMZ treatments.
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The most frequent site of recurrence in breast cancer (BC) is the bone, particularly in patients with 'luminal-like' disease. Denosumab has been shown to prevent aromatase inhibitors (AIs) induced bone resorption in postmenopausal early BC patients and reduce skeletal-related events (SREs) in bone metastatic breast cancer (BMBC). A 'real life' analysis of 90 BMBC patients treated with denosumab was performed. Eighty-six patients (95.6%) had 'luminal-like' disease, 72 (80%) had bone metastases at the time of first recurrence of disease. Among 50 patients with metachronous 'luminal-like' disease, 40 (80%) had first recurrence to the bone. Among these patients median time to skeletal recurrence (TSkR) was shorter for patients who were previously exposed to AIs compared to those who were not (53.0 vs. 102.0 months, respectively; P=0.0300) and longer for patients previously treated with tamoxifen compared to those who were not (102.0 vs. 59.0 months, respectively; P=0.0466). Both of them were not confirmed at multivariate analysis. In the overall population, 17 first SREs were observed (16 radiation therapy) and median time to first SRE was not reached. A statistically significant difference in the incidence of SREs was detected only between patients with exclusively osteolytic bone metastases vs. those without (P=0.013). The presence of exclusively-osteolytic bone metastases was the only factor significantly associated with a shorter time to first SRE (P=0.011). The only G3 toxicity reported was hypocalcemia in one patient. No osteonecrosis of the jaw events (ONJ) occurred. This study demonstrated that a pro-active attitude enables the treatment of the majority of patients with denosumab without significant class-related toxicities. The majority of SREs were from radiation therapy, so pain still remains the clinical hallmark of bone metastases, particularly for osteolytic ones. The suggestion that estrogen deprivation with AIs can favor a 'bone-related' risk conditions for developing bone metastases must be considered with caution and surely needs further validations.
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To date, there is no consensus regarding firstline chemotherapy for patients with HER2negative, locally advanced/metastatic gastric cancer (a/m GC). In the present study we reported a retrospective caseseries of patients treated with a weekly regimen containing timedflat infusion of 5fluorouracil (TFI/5FU), docetaxel and oxaliplatin. From June 2007 to July 2017, 32 consecutive a/m GC patients were treated with firstline standard (st) or modulated (mod) 'FD/FOx' regimen: Weekly 12 h (from 10.00 p.m. to 10.00 a.m.) TFI/5FU for two consecutive nights at 900 mg/m2/day, associated to weekly alternating docetaxel, 50 mg/m2 and oxaliplatin, 80 mg/m2. The median age of the patients was 60 years and their Eastern Cooperative Oncology Groupperformance status (ECOGPS) was as follows: i) ECOGPS 0/1, (n=28, 87.5%); and ii) ECOGPS 2 (n=4, 12.5%). Patient activity, efficacy and safety data were collected and subgroup analyses were conducted among patients treated with st and mod FD/FOx. In the intentiontotreat (ITT) analysis, the objective response rate (ORR) was 75% (95% CI, 5390) and the disease control rate (DCR) was 87.5% (95% CI, 67.697.3). After a median followup of 16 months, median progressionfree survival (PFS) and median overall survival (OS) were 14.0 and 19.0 months, respectively. The received doseintensities were ~80% of the standard doses for each agent. The most relevant treatmentrelated grade 3 adverse events were: Neutropenia (40.6%), asthenia (18.7%) and diarrhea (18.7%). The only treatmentrelated grade 4 adverse event was neutropenia (9.3%). No febrile neutropenia was observed and none of the patients died as a result of adverse events. FD/FOx regimen appeared to be a feasible option as a firstline treatment of a/m GC patients, especially in case of hightumor burden, with the need of rapid tumor shrinkage and diseaserelated symptoms palliation.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Fluoruracila/administração & dosagem , Compostos Organoplatínicos/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Taxoides/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Docetaxel , Esquema de Medicação , Junção Esofagogástrica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina , Estudos RetrospectivosRESUMO
BACKGROUND: Pazopanib is an oral multitargeted tyrosine-kinase inhibitor, used as a single agent to treat advanced renal cell carcinoma. Treatment with other tyrosine-kinase inhibitors is known to be associated with asymptomatic elevations of serum amylase and lipase levels. As regards the pazopanib, data are lacking in literature. CASE PRESENTATION: We report one case of pancreatic toxicity associated with pazopanib administration. Before starting treatment, patient had no risk factors for pancreatitis. The patient, an Italian 68 years old woman, started pazopanib at doses of 800 mg daily as first-line therapy for metastatic renal cell carcinoma. Six months after the start of treatment, blood tests showed for the first time a significant increase in serum lipase and amylase in the absence of symptoms and radiological findings of pancreatitis. The patient continued treatment without interruptions or dose reductions. However, the continuation of the treatment led to a further increase of pancreatic enzymes. We tried to continue the treatment by reducing the dose but only the discontinuation was associated with normalization of amylase and lipase's levels. On the other hand the treatment with pazopanib got prolonged response of the disease in the absence of signs of pancreatitis. We therefore decided to continue treatment with pazopanib 400 mg daily with close monitoring of blood levels of pancreatic enzymes. CONCLUSIONS: We hypothesize that the increase of pancreatic enzymes is not a dose-dependent event. The mechanism for pancreatic toxicity induced by tyrosine-kinase inhibitors is unknown and no predictive factors have been identified. There are no clear guidelines on the management of the drug in the presence of pancreatic enzyme increase. In any case, we believe that a careful monitoring of pancreatic enzymes during treatment with pazopanib is advisable.
Assuntos
Pâncreas/patologia , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Idoso , Amilases/sangue , Feminino , Humanos , Indazóis , Lipase/sangue , Pâncreas/efeitos dos fármacos , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagemRESUMO
BACKGROUND: Ipilimumab is a fully human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 , a key negative regulator of T-cell activation approved by the Food and Drug Administration as of March 2011 for the treatment of metastatic melanoma. As a result of the up-regulation of the immune system, several immune-mediated adverse effects have been reported including colitis, dermatitis, hepatitis and rarely hypophysitis. The most frequent immune-mediated adverse effects described in literature include gastrointestinal toxicity such as diarrhea, colitis and case of colitis and ileitis. CASE PRESENTATION: In this paper we report an interesting case of immune-mediate ileitis without colitis in a 54 years old woman with metastatic melanoma treated with ipilimumab. We also discuss about case management and the possible pathological mechanisms considering also previous reports. CONCLUSIONS: The aim of this article is to support further investigations concerning epigenetic and genetic analysis in order to personalize biological therapy and to reduce immune related adverse events observed after ipilimumab administration.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Ileíte/induzido quimicamente , Ileíte/patologia , Anticorpos Monoclonais/uso terapêutico , Feminino , Humanos , Ipilimumab , Melanoma/tratamento farmacológico , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Medicina de Precisão , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologiaRESUMO
Sunitinib has previously been reported to be potentially effective in the treatment of malignant melanomas expressing c-KIT. Here we report on the case of a 77-year-old gentleman affected by a metastatic clear cell carcinoma of the kidney and a metastatic malignant melanoma with liver and lung metastases. Despite the negativity for CD117 and the absence of KIT amplification or mutations in the melanoma specimen, he achieved a partial response both in the lungs and in the liver while on sunitinib (50 mg once/day, 4 weeks on/2 weeks off) for the treatment of kidney cancer. To our knowledge, this represents the first evidence of sunitinib activity in KIT wild-type melanoma. Further studies should be performed to confirm these preliminary data.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Indóis/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Pirróis/administração & dosagem , Idoso , Biomarcadores Farmacológicos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/secundário , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Melanoma/genética , Melanoma/patologia , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , SunitinibeRESUMO
INTRODUCTION: More than 20 years ago the World Health Organization (WHO) published the booklet 'Cancer Pain Relief', including the fundamentals and clear principles, which was summarized in five simple sentences: 'by mouth', 'by the clock', 'by the ladder', 'for the individual' and 'attention to detail'. Over the years, several modifications to the analgesic ladder have been proposed, as the addition of two further steps, related to the switch of opioid and/or non-invasive route of administration, and to the use of invasive approaches, or again the skip of the second step; nevertheless the educational value and benefits related to the worldwide dissemination are of paramount importance. AREAS COVERED: To date, all the guidelines are inspired by the strategy of WHO; below some of the most important international guidelines published in the last two years are compared, particularly as regards the criteria of choice of opioids for moderate/severe pain. EXPERT OPINION: The discussion on the role of the second step of the WHO analgesic ladder is still open. The challenge for new formulations of 'old' opioids will be to better manage cancer pain, with more tailored efficacy and possibly less side effects.
Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Dor Irruptiva/tratamento farmacológico , Neoplasias , Manejo da Dor , Analgésicos Opioides/efeitos adversos , Dor Irruptiva/complicações , Humanos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Medição da Dor , Guias de Prática Clínica como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: Itch is a common side-effect of treatment with anti-EGFR antibodies and tyrosine-kinase inhibitors. We designed a pilot single-centre study to assess the effects of aprepitant-a neurokinin receptor inhibitor-for management of severe pruritus induced by biological drugs. METHODS: In this single-group, prospective study, we consecutively enrolled 45 outpatients with metastatic solid tumours treated with biological drugs at the Campus Bio-Medico Hospital of Rome, Rome, Italy, between September, 2010, and November, 2011. We classified patients into two groups: a refactory group, for patients with pruritis refractory to standard treatment, or a naive group, for patients who had not been previously treated for pruritis. Aprepitant (125 mg on day 1; 80 mg on day 3; 80 mg on day 5) was given to patients in the refractory group after at least 1 week of standard systemic treatment. In the naive group, aprepitant was given in the same schedule as the refractory group, after first onset of severe pruritus. Intensity of itch was evaluated by Visual Analogue Scale (VAS) score. The primary endpoint was change in median VAS score. This trial is registered with ClinicalTrials.gov, number NCT01683552. FINDINGS: Median VAS in the refractory group was 8·00 (95% CI 7·93-8·57) at baseline and 1·00 (0·00-2·00) after 1 week of treatment with aprepitant (p<0·0001). In the naive group, VAS score was 8·00 (7·43-8·37) at baseline and 0·00 (0·06-1·08) after 1 week of treatment (p<0·0001). 41 (91%) patients responded to aprepitant (ie, had a >50% reduction in intensity of pruritis) and pruritus recurred in only six (13%) patients. No adverse events related to aprepitant occurred. INTERPRETATION: Aprepitant decreases severe pruritus induced by biological treatments; it is an old drug, widely available, and therefore easy to add to the armamentarium of supportive treatment. Although to our knowledge no other studies of the anti-itch activity of aprepitant are planned, the results of our trial warrant confirmation in phase 2 and 3 trials. FUNDING: None.
Assuntos
Antineoplásicos/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Morfolinas/uso terapêutico , Neoplasias/tratamento farmacológico , Antagonistas dos Receptores de Neurocinina-1 , Prurido/tratamento farmacológico , Adulto , Idoso , Aprepitanto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Medição da Dor , Projetos Piloto , Estudos ProspectivosRESUMO
INTRODUCTION: Sarcomas are rare heterogeneous malignancies of mesenchymal origin relatively common during childhood. Disruption of the mammalian target of rapamycin (mTOR) pathway is a very common event during the tumorigenesis of several types of cancer. In particular, strong preclinical evidences suggest pivotal roles of this pathway during the sarcomagenesis. Therefore, the inhibition of mTOR via rapamycin, rapamycin analogs (rapalogs) and ATP-competitive inhibitors seems to be a promising path to follow for a fully tailored therapy. AREAS COVERED: The aim of the present review is to summarize the available data about the mechanisms of mTOR pathway, its biological implications and its possible role in the pathogenesis of soft tissue sarcoma. Moreover, preclinical and clinical evidences of different mTOR inhibitors in the treatment of sarcomas are reported. EXPERT OPINION: Early studies with mTOR inhibitors have demonstrated promising antitumor activity in patients with metastatic sarcoma who have failed standard treatments: that is why mTOR inhibitors represents today a promising chance to improve the prognosis of those patients affected by these rare disease, which is today still extremely poor.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia , Sarcoma/tratamento farmacológico , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Antibióticos Antineoplásicos/uso terapêutico , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Sarcoma/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Sirolimo/uso terapêutico , Pesquisa Translacional BiomédicaRESUMO
Cetuximab (IMC-C225, Erbitux ImClone Systems Inc, New York, NY) is a recombinant, human/mouse chimeric monoclonal antibody (MAb) that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) as well as other ligands. Cetuximab binding to the EGFR blocks phosphorylation and activation of receptor-associated kinases and their associated downstream signalling (MAPK, PI3K/Akt, Jak/Stat pathways) resulting in inhibition of many cellular processes such as induction of apoptosis, cell growth, decreased Matrix Metallo-Proteinase (MMPs) and vascular endothelial growth factor (VEGF) production. Cetuximab is also able to display cytotoxic effect through antibody-dependent cellular cytotoxicity (ADCC). In vitro and in vivo experiments elucidated a wide range of biological properties attributed to cetuximab, these include: direct inhibition of EGFR tyrosine kinase activity, inhibition of cell cycle progression, inhibition of angiogenesis, invasion and metastatization processes, activation of pro-apoptotic molecules and synergic cytotoxicity effect with chemotherapy and radiotherapy. Several studies have shown cetuximab is able to inhibit growth of EGFR-expressing tumor cells in vitro as well as in nude mice bearing xenografts of human cancer cell lines. Moreover, numerous clinical trials demonstrated cetuximab efficacy in different tumor types and it is approved by Food and Drugs Administration (FDA) for use in the treatment of metastatic colorectal cancer (mCRC) as single agent or in combination with chemotherapy, for locally/regionally advanced head and neck squamous cell carcinoma (HNSCC) in combination with radiotherapy, and as monotherapy for recurrent/metastatic HNSCC after failing platinum-based chemotherapy. This review will illustrate pre-clinical and clinical data on biological properties of cetuximab focusing on the predictive markers of clinical response to this drug.