RESUMO
BACKGROUND: It is reported that treatment with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) induces hypogonadism both in male patients with ALK-positive cancer and in murine models. METHODS: In this study, three groups, including an experimental group of male patients with ALK-positive, advanced non-small cell lung cancer (ANSCLC) who were receiving alectinib (cohort A), a control group of female patients with ALK-positive ANSCLC who were receiving alectinib (cohort B), and a control group of male patients with ALK-negative ANSCLC (cohort C), prospectively underwent a full hormone assessment for androgen deficiency at 8 weeks after the start of treatment and in case of reported suspected symptoms. Patients with major sexual dysfunctions were referred to an endocrinologist. RESULTS: Ninety-five patients were consecutively enrolled onto the study. Among sixty-eight male patients, both median total testosterone levels (2.93 vs. 4.92 ng/ml; p = .0001) and free testosterone levels (0.11 vs. 0.17 pg/ml; p = .0002) were significantly lower in ALK-positive ANSCLC patients in cohort A compared with ALK-negative patients in cohort C; conversely, median FSH (10.32 vs. 17.52 mUI/ml; p = .0059) and LH levels (4.72 vs. 7.49 mUI/ml; p = .0131) were significantly higher in cohort C compared to cohort A. Median inhibin B levels were higher in ALK-positive male patients (74.3 vs. 44.24 pg/ml; p = .0038), but all patients had inhibin B values within the normal range. The percentage of male patients who had positive scores on the Androgen Deficiency in Aging Males (ADAM) questionnaire was 62% in cohort A and 26.8% in cohort C, including eight patients who reported at least one major symptom and were referred to Andrology Unit. No significant differences in the endocrine assessment were reported between cohorts A and B. CONCLUSIONS: Symptoms of androgen deficiency should be tracked in male patients with ALK-positive ANSCLC who are receiving alectinib, and testosterone replacement should be considered, as appropriate.
Assuntos
Quinase do Linfoma Anaplásico , Carbazóis , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Piperidinas , Testosterona , Humanos , Masculino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias Pulmonares/tratamento farmacológico , Carbazóis/uso terapêutico , Carbazóis/efeitos adversos , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Idoso , Adulto , Testosterona/sangue , Testosterona/deficiência , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Disfunções Sexuais Fisiológicas/induzido quimicamente , Feminino , Androgênios/deficiência , Estudos Prospectivos , Hipogonadismo/induzido quimicamente , Hipogonadismo/tratamento farmacológico , Receptores Proteína Tirosina QuinasesRESUMO
BACKGROUND: Only few ES-SCLC patients experience long-term survival benefit by maintenance IT. Adipokines-induced metabolic meta-inflammation has been related to enhanced responsiveness to IT in obese patients; however, their prognostic role in SCLC is currently controversial. METHODS: Pre-treatment CT scan was used for determining distribution of abdominal adiposity, and blood samples were collected at fasting for measuring glycemia, insulin, ghrelin, leptin and adipokines (TNF-α, IFN-γ, IL-6 and MCP-1). Patients with known history of DM type II or metabolic syndrome with HOMA index > 2.5 were considered insulin resistant (IR). RESULTS: In ES-SCLC pts receiving maintenance IT, increased leptin concentration and higher leptin/visceral adipose tissue (VAT) ratio were significantly associated with prolonged PFS. By applying a hierarchical clustering algorithm, we identified a cluster of patients characterized by higher leptin values and lower pro-inflammatory cytokines (TNF-α, IFN-γ and IL-6) who experienced longer PFS (13.2 vs 8.05 months; HR: 0.42 [0.18-0.93] p = 0.02) and OS (18.04 vs 12.09 mo; HR: 0.53 [0.25-1.29] p = 0.07). CONCLUSIONS: Adipokines can play a crucial role to determining effectiveness of anti-cancer immunotherapy. The role of metabolic immune dysfunctions needs further pre-clinical validation and is currently investigated in the larger prospective cohort.
Assuntos
Insulinas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Adipocinas , Imunoterapia , Inflamação , Interleucina-6 , Leptina , Neoplasias Pulmonares/terapia , Estudos Prospectivos , Carcinoma de Pequenas Células do Pulmão/terapia , Fator de Necrose Tumoral alfaRESUMO
INTRODUCTION: Myocardial bridge is a morphological anomaly of the heart characterised by the presence of a myocardial segment above a coronary artery, which results in a higher risk of cardiovascular events. In patients with prostate cancer treated with androgen receptor-targeted agents, a higher risk of cardiotoxicity was observed. CASE REPORT: An 88 years old man with metastatic castration-resistant prostate cancer in treatment with enzalutamide, denosumab, and triptorelin presented to our attention complaining dyspnoea and angina pectoris. MANAGEMENT AND OUTCOME: Blood examinations revealed normal Troponin I levels. Transthoracic echocardiography revealed no signs of acute myocardial ischaemia. The treadmill stress test revealed S-T tract under levelling in V4-V6 with a very slow resolution. Coronary angiography identified a myocardial bridge in the medium tract of the interventricular anterior artery. Due to these findings, ranolazine and simvastatin were started and, after multidisciplinary assessment, we decided to continue the treatment with enzalutamide. At the first follow-up visit echocardiography found out the cardiological reports stability and no therapy changes were performed. During follow-up visit cardiological revaluation showed reports stability and no therapy changes were performed. DISCUSSION: Due to the high prevalence of prostate cancer in elderly patients at high cardiovascular risk and the increasing use of androgen receptor-targeted agent, a multidisciplinary approach is highly recommended to weigh survival benefits on toxicities. This case report may support the use of androgen receptor-targeted agent in elderly patients with controlled cardiovascular diseases, a population that is often excluded from randomised trials.
Assuntos
Antineoplásicos , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Idoso , Idoso de 80 Anos ou mais , Receptores Androgênicos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Antineoplásicos/efeitos adversos , Nitrilas/uso terapêutico , Castração , Resultado do Tratamento , Antagonistas de Androgênios/uso terapêuticoRESUMO
BACKGROUND: In untreated ALK-positive non-small cell lung cancer no randomized controlled trials (RCTs) are available directly comparing next-generation ALK-inhibitors. We conducted a sensitivity analysis using the likelihood of being helped or harmed (LHH). METHODS: Phase III trials comparing ALK-inhibitors to crizotinib were included. Efficacy outcomes were progression-free survival (PFS), objective response rate (ORR), PFS in patients with brain metastases and intracranial ORR. Safety outcomes were grade 3-4 adverse events (AEs), dose reductions and discontinuations. RESULTS: Six RCTs (1524 patients) were included. Lorlatinib and brigatinib had the lowest NNT for intracranial outcomes. Alectinib demonstrated favourable LHHs for grade 3-4 AEs, dose reductions and discontinuations. Brigatinib LHHs were low for common AEs, mainly laboratory anomalies and hypertension. Ensartinib showed mainly skin toxicity. Lorlatinib LHHs were low for specific grade 3-4 AEs, mainly metabolic alterations. CONCLUSIONS: The four ALK-inhibitors exhibited favourable risk-benefit ratios. Lorlatinib showed the lowest NNT for systemic efficacy and, alongside with Brigatinib, lower NNTs for intracranial efficacy. Alectinib exhibited higher LHHs for AEs. REGISTRATION: PROSPERO registration number: CRD42023389101.
RESUMO
PURPOSE: The clinical and research FPG500 program (ClinicalTrials.gov identifier: NCT06020625) is currently ongoing at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS to tailor matched targeted therapies (MTTs) according to biomarkers predictive of response identified by comprehensive genome profiling (CGP). MATERIALS AND METHODS: The non-small cell lung cancer (NSCLC) cohort results from the FPG500 program are outlined. CGP was performed by TruSight Oncology 500 High Throughput (TSO500HT) assay or Oncomine Focus Assay plus Archer's FusionPlex Lung Panel according to tumor cell content and DNA/RNA quantity. Relevant issues for Molecular Tumor Board (MTB) evaluation included uncommon genomic findings, evaluation for off-label therapies, uncertain result confirmation, and variants of suspect germline origin requiring genetic counseling. Progression-free survival (PFS) and overall survival (OS) for the enrolled patients were assessed using Kaplan-Meier analysis. RESULTS: In 2022, 283 patients with NSCLC were considered for sequencing, with 93% meeting eligibility criteria. TSO500HT sequencing was conducted in 76% of patients. Follow-up data were obtained for 187 patients, among whom 81% received treatment. Potential driver alterations were identified in 59% of patients, with 41% receiving MTT: 25% were prescribed approved MTTs, whereas 16% gained access to experimental drugs post-MTB evaluation; of note, 18% did not receive any MTT because the regimen was not yet reimbursed in our country. Median PFS and OS varied among treatment groups, with standard chemotherapy/immunotherapy at 7.7 and 10.7 months, approved tyrosine kinase inhibitors at 18.8 and 23.9 months, and MTT post-MTB discussion at 14 and 23.4 months, respectively. CONCLUSION: The early data of the FPG program (NSCLC cohort) support the implementation of CGP and MTB in clinical practice to grant access to patients harboring actionable molecular alterations to the most effective and individualized available treatment options, thus improving their survival outcomes.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos de Coortes , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
BACKGROUND: In RAS wild type (wt) metastatic colorectal cancer (mCRC) maintenance therapy after induction with fluoropyrimidine (FP)-based cytotoxic therapy (CT) plus anti-EGFR agents is controversial. METHODS: Phase II-III randomized trials were included. Maintenance strategies considered were: observation, anti-EGFR or FP monotherapy, FP + anti-EGFR, doublet CT + anti-EGFR. RESULTS: Maintenance with FP + anti-EGFR (HR 0.56, 95% CrI 0.36-0.89) showed the greatest PFS benefit compared to observation, ranking first on SUCRA analysis (96.4%). Considering OS, doublet CT+ anti-EGFR, FP + anti-EGFR and anti-EGFR monotherapy yielded similar results. For PFS, FP + anti-EGFR confirmed to be valuable in BRAF wt patients and left sided tumors. In left sided tumors, the OS benefit of adding CT was limited. FP plus anti-EGFR showed a favourable safety profile compared to doublet CT + anti-EGFR. CONCLUSIONS: FP + anti-EGFR can be considered a valuable maintenance option in RAS wt mCRC. EGFR monotherapy can be considered, especially in left-sided tumors.
RESUMO
Background: In hormone-receptor positive/HER2-negative metastatic breast cancer (mBC) no randomized comparisons are available between CDK4/6 inhibitors. We undertook this systematic review and meta-analysis to assess the reliability of the likelihood of being helped or harmed (LHH). Methods: PubMed, CENTRAL, Embase and oncological meetings websites were searched to September 13th, 2022. We included phase III randomized controlled trials (RCTs) investigating palbociclib, ribociclib and abemaciclib in addition to endocrine therapy (ET) compared to placebo in hormone-receptor positive/HER2-negative advanced or mBC. Outcomes were progression-free survival (PFS), overall survival (OS), adverse events (AEs), dose reductions and discontinuations. Hazard ratios (HRs) and risk differences were computed with a random effect model to estimate the number needed to treat/harm (NNT/NNH). LHH was computed as (1/NNT)/(1/NNH). PROSPERO registration number: CRD42022362417. Findings: 2204 records were screened and seven RCTs (4415 patients) were included. A significant PFS benefit was observed in patients treated with a CDK4/6 inhibitor compared to placebo (HR 0.549; 0.508-0.594, I 2 = 0). Palbociclib, ribociclib and abemaciclib had similar NNTs (4.4, 5.0 and 4.4). Palbociclib and ribociclib showed lower LHHs for grade 3-4 neutropenia (0.33 and 0.35) and febrile neutropenia ([FN], 14.27 and 15.52), while abemaciclib the lowest LHH for any grade diarrhea (0.42). Abemaciclib had a lower LHH for grade 3-4 fatigue (9.92) and the highest LHH for all grade 3-4 AEs (0.62), while ribociclib the lowest LHH (1.75) for grade 3-4 hepatotoxicity. Palbociclib had the highest LHH for dose reductions and discontinuations (0.65 and 6.17). Considering OS, an overall benefit was observed (HR 0.788, 0.727-0.856, I 2 = 0%); ribociclib and abemaciclib had lower NNTs (9.7 and 10.0). Ribociclib showed the highest LHH for diarrhea (1.29), fatigue (7.37), dose reductions (0.28) and discontinuations (2.40), while abemaciclib the highest LHHs for neutropenia (0.40), FN (12.53) and hepatotoxicity (2.23). Interpretation: Palbociclib and ribociclib showed lower LHHs for haematological toxicities and abemaciclib for diarrhea. Palbociclib confirmed to be a manageable drug. The LHH appears to be a reliable synthesis tool for balancing risks and benefits of experimental drugs when head-to-head comparisons are missing. Funding: None.
RESUMO
Background: Adults and children can develop post-Covid-19 condition (PCC) (also referred to as Long Covid). However, existing evidence is scarce, partly due to a lack of a standardised case definition, short follow up duration, and heterogenous study designs, resulting in wide variation of reported outcomes. The primary aim of this study was to characterise risk factors for PCC and longitudinal rates of recovery in a cohort of children and young people using a standardised protocol. Methods: We performed a prospective "disease-based" cohort study between 01/02/2020 to 31/10/2022 including children aged 0-18 years old, with a previous diagnosis of Covid-19. Children with microbiologically confirmed SARS-CoV-2 infection, were invited for an in-clinic follow-up assessment at a paediatric post-covid clinic in Rome, Italy, at serial intervals (3-, 6-, 12- and 18-months post-onset). PCC was defined as persistence of otherwise unexplained symptoms for at least three months after initial infection. The statistical association between categorical variables was obtained by Chi-squared tests or Fisher's exact tests. Multivariable logistic regressions are presented using odds ratios (OR) and 95% confidence interval (CI). Survival analysis was conducted using the Kaplan-Meier method. Findings: 1243 children were included, median age: 7.5 (4-10.3) years old; 575 (46.3%) were females. Of these, 23% (294/1243) were diagnosed with PCC at three months post-onset. Among the study population, 143 patients remained symptomatic at six months, 38 at 12 months, and 15 at 18 months follow up evaluation. The following risk factors were associated with PCC: >10 years of age (OR 1.23; 95% CI 1.18-1.28), comorbidities (OR 1.68; 95% CI 1.14-2.50), and hospitalisation during the acute phase (OR 4.80; 95%CI 1.91-12.1). Using multivariable logistic regression, compared to the Omicron variant, all other variants were significantly associated with PCC at 3 and 6 months. At least one dose of vaccine was associated with a reduced, but not statistically significant risk of developing PCC. Interpretation: In our study, acute-phase hospitalisation, pre-existing comorbidity, being infected with pre-Omicron variants and older age were associated with a higher risk of developing PCC. Most children recovered over time, but one-in-twenty of those with PCC at three months reported persistent symptoms 18 months post-Sars-CoV-2 infection. Omicron infection was associated with shorter recovery times. We did not find a strong protective effect of vaccination on PCC development. Although our cohort cannot be translated to all Italian children with PCC as more nationwide studies are needed, our findings highlight the need of new strategies to prevent and treat pediatric PCC are needed. Funding: This study has been funded by Pfizer non-competitive grant, granted to DB (# 65925795).
RESUMO
Background: In early breast cancer (BC) the impact of denosumab on survival outcomes is still unclear. We undertook a systematic review and meta-analysis to assess efficacy and safety of adjuvant denosumab in addition to standard anticancer therapy. Methods: PubMed, CENTRAL, Scopus, Embase, and oncological meetings websites were screened to identify potentially eligible randomized controlled trials (RCTs). Survival outcomes were disease-free survival (DFS), bone-metastasis-free survival (BMFS), and overall survival (OS). Fracture incidence and time to first fracture were bone-health outcomes. Osteonecrosis of the jaw (ONJ), atypical femur fractures (AFF), and other adverse events were also evaluated. Pooled hazard ratios (HRs) and risk ratios (RR) with respective 95% confidence interval (95% CI) were computed using a random-effects model. Exploratory subgroup analyses were performed. Results: Two phase III RCTs were included, the Austrian Breast & Colorectal Cancer Study Group-18 (ABCSG-18) and the D-CARE trials, for a total of 7929 patients. In the ABCSG-18 trial, denosumab was administered every 6 months during endocrine therapy (for a median of seven cycles) while the D-CARE trial used an intensive schedule for a total treatment duration of 5 years. Adjuvant denosumab showed no difference in DFS (HR: 0.932; 95% CI: 0.748-1.162), BMFS (HR: 0.9896; 95% CI: 0.751-1.070), and OS (HR: 0.917; 95% CI: 0.718-1.171) compared to placebo in the overall population. In hormone receptor positive/human epidermal growth factor receptor 2 (HER2) negative BC patients, a DFS (HR: 0.883; 95% CI: 0.782-0.996) and BMFS (HR: 0.832; 95% CI: 0.714-0.970) benefit was observed and BMFS was prolonged in all hormone receptor positive patients (HR: 0.850; 95% CI: 0.735-0.983). Fracture incidence (RR: 0.787; 95% CI: 0.696-0.890) and time to first fracture (HR: 0.760; 95% CI: 0.665-0.869) were also improved. No increase in overall toxicity was seen with denosumab and no differences were observed for ONJ and AFF between the 60-mg every 6-month schedule and placebo. Conclusion: Denosumab addition to anticancer treatment does not improve DFS, BMFS, or OS in the overall population, although a DFS improvement was observed in hormone receptor positive/HER2 negative BC patients and a BMFS improvement in all hormone receptor positive patients. Bone-health outcomes were improved with no added toxicity with the 60-mg schedule. Registration: PROSPERO identifier: CRD42022332787.