LEONARDO GOMES DA FONSECA
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/07 - Laboratório de Gastroenterologia Clínica e Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/07 - Laboratório de Gastroenterologia Clínica e Experimental, Hospital das Clínicas, Faculdade de Medicina
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- Safety and efficacy of sorafenib in patients with Child-Pugh B advanced hepatocellular carcinoma(2015) FONSECA, Leonardo Gomes Da; BARROSO-SOUSA, Romualdo; BENTO, Afonso Da Silva Alves; BLANCO, Bruna Paccola; VALENTE, Gabriel Luis; PFIFFER, Tulio Eduardo Flesch; HOFF, Paulo Marcelo; SABBAGA, JorgeSorafenib demonstrated a survival benefit in the treatment of advanced hepatocellular carcinoma (HCC) in phase III trials. However, almost all the patients included in those trials exhibited well-preserved liver function (Child-Pugh A). The aim of this study was to describe our experience with sorafenib in Child-Pugh B HCC patients. A database of patients with advanced HCC treated with sorafenib was retrospectively evaluated. The median overall survival of Child-Pugh B patients (n=20) was 2.53 months [95% confidence interval (CI): 0.33-5.92 months] and of Child-Pugh A patients (n=100) 9.71 months (95% CI: 6.22-13.04). Child-Pugh B patients had a significantly poorer survival compared to Child-Pugh A patients (P=0.002). The toxicities were similar between the two groups. Metastasis, vascular invasion and alpha-fetoprotein level >1,030 ng/ml were not associated with survival among Child-Pugh B patients (P=0.281, 0.189 and 0.996, respectively). Although the survival outcomes were worse in Child-Pugh B patients treated with sorafenib, the toxicity profile was manageable. Therefore, there remains the question of whether to treat this subgroup of patients and more data are required to define the role of sorafenib in the context of liver dysfunction.
- Metronomic oral cyclophosphamide plus prednisone in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer(2015) BARROSO-SOUSA, Romualdo; FONSECA, Leonardo Gomes da; SOUZA, Karla Teixeira; CHAVES, Ana Carolina Ribeiro; KANN, Ariel Galapo; CASTRO JR., Gilberto de; DZIK, CarlosWe evaluated the efficacy and safety of metronomic oral cyclophosphamide (CTX) and prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients. We analyzed retrospectively patients with mCRPC previously treated with docetaxel, and who received metronomic CTX (from 50 mg PO daily to 150 mg PO, 14 days/7 days off) and prednisone 10 mg PO daily between September 2009 and April 2014 were analyzed. The primary endpoint was prostate-specific antigen (PSA) decrease >= 50 %. Secondary analysis included PSA decrease >= 30 %, time-to-treatment failure (TTF) and toxicity. Demographics and baseline characteristics were summarized using descriptive statistics. PSA response and adverse events were reported as relative rates. Kaplan-Meier estimates were calculated and plotted for time-to-event endpoints. Forty patients were evaluated. The median age was 69 years old (52-86), 12 (30.0 %) patients presented a Karnofsky performance status (KPS) of <80 %, and 34 (85 %) presented with bone with or without nodal metastases. Median pretreatment PSA was 192 ng/dL (7-2696 ng/dL). All patients were previously exposed to docetaxel, including 33 (82.5 %) with docetaxel-refractory disease. PSA response rate was achieved in eight (20.0 %) out of 40 patients. Additionally, PSA declines of >= 30 % occurred in 14 (35.0 %) patients. The median TTF was 3 months (95 % confidence interval 2.5-3.5). The treatment was well tolerated. Grade 3/4 lymphopenia was reported in 11 (27.5 %) patients and was the only grade 3-4 toxicity reported. Metronomic oral CTX showed activity and safety in docetaxel-pretreated mCRPC patients. This regimen deserves further investigation in this setting.
conferenceObject CARDIAC SAFETY OF (NEO) ADJUVANT TRASTUZUMAB IN THE BRAZILIAN COMMUNITY SETTING: A SINGLE CENTER EXPERIENCE(2012) FONSECA, L. G.; TAKAHASHI, T. K.; MAK, M. P.; BARROSO-SOUSA, R.; TESTA, L.; HELENA, V. Petry; COSTA, R. De Paula; HOFF, P. M.; MANO, M. S.Background Trastuzumab-associated cardiotoxicity (TAC) has been established in the context of clinical trials. However, when newly registered agents are used in a broader patient population, their safety profile does not always mirror that of the pivotal trials. Trastuzumab (T) only became available in the Brazilian public sector in 2008 and herein we report our off-trial experience so far. Methods Retrospective, single center cohort of HER-2 positive breast cancer patients (pts) treated with (neo)adjuvant chemotherapy and T from July 2008 to March 2012. 95.3% were treated according to local protocol (11.4% TCH; 83.9% AC-TH). Major cardiac event (MCE) was defined as a left ventricular ejection fraction (LVEF) drop of 10% and absolute drop to < 50 % by echocardiogram (ECHO) or as symptomatic heart failure (HF) regardless of the LVEF value or any cardiac event considered clinically meaningful. A multivariable Cox proportional hazards model was used to control for other cardiac risk factors. Results 237 women were identified: median age 53 y (27-83), 99.6% ECOG-PS 0-1, median body mass index 27.4 kg/m2 (17 – 46), 30.4% had hypertension (HTN), 8.8% had diabetes mellitus (DM), 5.9% had previous cardiopathy. 54.8% had ER-positive tumors; 40.7% received neoadjuvant T; most were stage II or III (22.3% and 37.1%). Median number of ECHO assessments was 2.7 (0-6); 136 pts (57.2%) completed T as planned. 20.2% had MCE (13.9% discontinued T). 3.8% discontinued T due to symptomatic HF and 5% for non-cardiac reasons. 41.6% of MCE pts recovered cardiac function. Median initial LVEF was 64.83 ± 1.5 % (no event) vs 64.81 ± 1.5 % (MCE) p = 0.26; median 3-month LFVE was 64.67 ± 4 % (no event) vs 56.12 ± 3 % (MCE) p = 0.0036. HTN, DM, obesity, age, radiotherapy, use of anthracycline and previous cardiopathy were not significantly associated with TAC. Conclusions Our results suggest that TAC in our routine practice is slightly higher than reported in literature (6 to 17%), possibly reflecting selection bias in clinical trials. Symptomatic TAC was as expected for AC-TH (4%). We failed to identify risk factors for TAC, possibly due to the low number of events. Cardiac function must be closely monitored during T treatment and careful pt selection is crucial.conferenceObject Pretreatment neutrophil to lymphocyte ratio and prognosis of patients with advanced hepatocelullar carcinoma treated with sorafenib.(2014) FONSECA, Leonardo Gomes; BARROSO-SOUSA, Romualdo; BLANCO, Bruna Paccola; VALENTE, Gabriel Luls; BRAGHLROLL, Maria Ignez Freltas Melro; PFIFFER, Tullo Eduardo Flesch; SABBAGA, Jorge; HOFF, Paulo MarceloconferenceObject ORAL METRONOMIC CYCLOPHOSPHAMIDE IN PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER STRATIFIED BY PRIOR DOCETAXEL THERAPY(2012) BARROSO-SOUSA, R.; CHAVES, A. C. R.; FONSECA, L. G.; CASTRO JR., G. De; DZIK, C.; HOFF, P. M.Background: Treatment options remain limited for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Here we aimed to investigate the efficacy and safety of low-dose oral cyclophosphamide (CTX), an intermittent metronomic chemotherapy regimen, in pts with mCRPC, previously treated or not with docetaxel. Methods: All pts previously diagnosed with mCRPC and treated with CTX 100mg/ day (3 weeks on and 1 week off, every 28 days) plus prednisone 10mg/day between Oct/2006 and Feb/2012 at our institution were included in this retrospective analysis. The primary efficacy endpoint was prostate-specific antigen (PSA) decrease ≥ 50%. Secondary endpoints were PSA decrease ≥ 30% and toxicity. Kaplan-Meier estimates were calculated and plotted for time to treatment failure (TTF). Single and multivariate Cox proportional hazards modeling was used to estimate hazard ratios with 95% confidence intervals (95% CI). Results: 51 pts with mCRPC were identified, of which 30 (59%) had been already treated with docetaxel. The median age was 72 y.o. (56-86) and 27 pts (53%) were ECOG PS0-1 and 24 pts (47%) PS2-3. Five pts presented with visceral metastasis (10%) and median PSA 525 ng/dL (12-4099) before treatment. Median number of previous cytotoxic lines was 1 (0-2). After a median number of cycles CTX of 3, PSA decrease of ≥ 50% was achieved in 28.6% and 16.7% of docetaxel-naive and docetaxel-pretreated pts, respectively (p= 0.30). Besides, PSA declines of ≥ 30% occurred in 38.1% and 30.0% of docetaxel-naive and docetaxel-pretreated patients, respectively (p= 0.54). Overall, the median TTF was estimated to be 2.4 mo. (95% CI 1.87 – 3.73). Previously treatment with docetaxel was not statistically significant to TTF, and the median TTF was 2.1 mo. (95% CI 1.6 – 3.2) for docetaxel-pretreated and 3.4 mo. (95% CI 1.7 – 5.4) for docetaxel-naïve patients (HR 1.47; 95% CI 0.78 – 2.74; p = 0.22). In general, oral CTX was safe and well tolerated and the most commonly observed G3-4 AE was lymphopenia (29%). Conclusions: Oral metronomic CTX plus prednisone seems to be active and safe in mCRPC, even in pts previously treated with docetaxel. Its convenient oral administration, low cost, and acceptable toxicity profile may justify future investigations of this classic alkylating agent in mCRPC. Disclosure: All authors have declared no conflicts of interest.- Cardiac Safety of (Neo)Adjuvant Trastuzumab in the Community Setting: A Single-Center Experience(2014) FONSECA, Leonardo Gomes da; GAGLIATO, Debora de Melo; TAKAHASHI, Tiago K.; MAK, Milena Perez; BARROSO-SOUSA, Romualdo; TESTA, Laura; HELENA, Vanessa Petry; COSTA, Romulo de Paula; HOFF, Paulo M.; MANO, Max S.Background: Trastuzunnab improves the survival of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). The incidence and long-term impact of trastuzumab-related cardiotoxicity in the community setting is of great clinical importance. Material and Methods: Patients with HER2-positive BC treated with (neo)adjuvant trastuzumab were retrospectively evaluated. Cardiotoxicity was defined as cardiac death or absolute decrease in left ventricular ejection fraction of at least 10% to a value less than 50%, or symptomatic heart failure. Results: We evaluated 237 patients: median age 53 years (range 27-83 years). 40.5% of these patients had received neoadjuvant and 59.5% adjuvant chemotherapy. The majority (83.9%) were treated with an anthracycline-based regimen. Median exposure to trastuzumab was 8 months (range 2-12 months). Cardiotoxicity was diagnosed in 20.2%, but symptoms only occurred in 3.8%. 41.6% recovered cardiac function. None of the risk factors were associated with cardiotoxicity. Conclusion: The incidence of trastuzumab-related cardiotoxicity found in this study was slightly higher than those reported in randomized clinical trials. Nevertheless, most patients were asymptomatic. We describe the cardiac outcomes of a non-selected population, which possibly reflects those found in the 'real world'. The risks versus benefits of trastuzumab use remain in favor of treatment, but cardiotoxicity should be monitored.
conferenceObject Outcomes of sunitinib therapy in patients (pts) with metastatic renal cell carcinoma (mRCC) with poor risk features(2013) BARROSO-SOUSA, Romualdo; MUNHOZ, Rodrigo Ramella; FONSECA, Leonardo Gomes; FEDE, Angelo Bezerra de Sousa; LINCK, Rudinei Diogo Marques; MONIZ, Camila Motta Venchiarutti; MAK, Milena Perez; SOUZA, Ciro Eduardo; HOFF, Paulo M.; DZIK, Carlos- Activity and safety of sunitinib in poor risk metastatic renal cell carcinoma patients(2014) BARROSO-SOUSA, Romualdo; MUNHOZ, Rodrigo R.; MAK, Milena P.; FONSECA, Leonardo G.; FEDE, Angelo B. S.; LINCK, Rudinei Diogo Marques; COELHO, Clovis R.; MONIZ, Camila M. V.; SOUZA, Ciro E.; DZIK, CarlosPurpose: To assess the activity, safety and treatment patterns of sunitinib in patients with poor-risk metastatic renal cell carcinoma (mRCC). Materials and Methods: We retrospectively reviewed the charts of poor risk patients treated with sunitinib from October 2006 to July 2013 who met the eligibility criteria. The primary endpoint was overall survival (OS). Tumor radiological response was measured according to RECIST 1.1 and adverse events (AEs) were assessed through standard criteria. Results: Median OS was 8.16 months (95% CI, 5.73-10.59). Of the 53 patients included in this analysis, 9 (17.0%) achieved partial response, 12 (22.6%) had stable disease. Median treatment duration was 3.30 months (95% CI: 1.96-4.63) and 26.4% of patients discontinued treatment due to toxicity. Grade 3 or higher AEs occurred in 39.6% of patients, the most common being fatigue (15.1%), neutropenia (9.5%), nausea, vomiting and diarrhea (7.5% each). Discussion: Sunitinib may benefit some unselected poor-risk patients, although the rates of AEs and drug discontinuation suggest a need for careful patient monitoring.
- Pre-treatment neutrophil-to-lymphocyte ratio affects survival in patients with advanced hepatocellular carcinoma treated with sorafenib(2014) FONSECA, Leonardo Gomes da; BARROSO-SOUSA, Romulado; BENTO, Afonso da Silva Alves; BLANCO, Bruna Paccola; VALENTE, Gabriel Luis; PFIFFER, Tulio Eduardo Flesch; HOFF, Paulo Marcelo; SABBAGA, JorgeSorafenib is the first systemic therapy to demonstrate survival benefit in advanced hepatocellular carcinoma (HCC) in randomized controlled trials with rigorous patient selection. Neutrophil-to-lymphocyte ratio (NLR) has been shown to be associated with poor survival in various solid tumors. Our aim is to evaluate the prognostic role of NLR in HCC patients treated with sorafenib. A total of 105 advanced HCC patients treated with sorafenib were retrospectively reviewed, and relevant data from the clinical records were collected. Univariate and multivariate analysis were carried out to identify factors associated with survival. The median age of the cohort was 59.7 years, and 84.8 % were Child-Pugh class A, and 86.7 % had ECOG performance status 0 or 1. Median duration of sorafenib treatment was 100 days. Median overall survival (OS) of the entire cohort was 8.03 months. Median OSwas 5.23 months (95 % CI 2.96-7.50 months) and 10.05 months (95 % IC 2.52-18.47 months) for patients with NLR>3.5 and NLR <= 3.5, respectively (p = 0.002). Alpha-fetoprotein [1,030 ng/mL and serum albumin B3.8 g/dL were also associated with worse prognosis (p = 0.006 and p = 0.042, respectively). The subgroup of patients with high alpha-fetoprotein, low albumin and NLR>3.5 had median OS of 1.7 months, whereas the subgroup with none of these parameters had median OS of 16.5 months (p< 0.001). NLR affects survival in advanced HCC patients treated with sorafenib. Selecting HCC patients based on the laboratorial features may improve the therapeutic effectiveness of sorafenib.