MARIA IGNEZ FREITAS MELRO BRAGHIROLI
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina
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- Young-age onset colorectal cancer in Brazil: Analysis of incidence, clinical features, and outcomes in a tertiary cancer center(2019) SILVA, Andrea C. B.; VICENTINI, Maria Fernanda B.; MENDOZA, Elizabeth Z.; FUJIKI, Fernanda K.; FONSECA, Leonardo G. da; BRAGHIROLI, Maria Ignez F. M.; HOFF, Paulo M.Background: Recent studies report increasing incidence of colorectal cancer (CRC) in the young-age population, but data concerning clinical behavior, pathologic findings, and prognosis are controversial for this group. Early recognition of CRC in young patients is a challenge and diagnosis at advanced stage is clearly associated with worse outcomes. Materials and methods: We retrospectively reviewed medical records of 5806 patients diagnosed with CRC between January/2011 and November/2016 and identified 781 patients aged less than 50-years-old. Results: We found an absolute increasing in the incidence of CRC in patients <50 years old of 1.88%-2.23% annually, with a relative increasing of 35.3% between 2011 and 2016. Median age was 42 years, 57.4% were female and 20.9% reported family history of CRC. Left-sided tumors were more frequent and the majority of patients were symptomatic. The most common stages at diagnosis were III (34.1%) and IV (37.3%). The median overall survival (OS) for stage IV was 25 months (95% Cl 20.7-29.3) and was not reached for Stages I-III (P < 0.001). Family history of CRC was independently associated with better OS in stage IV(P= 0.02). For stages I-III, wild-type KRAS, family history of CRC, and absence of angiolymphatic invasion were associated with better OS (P.0.02, P=0.01 and P < 0.001, respectively). Conclusions: In our cohort, the incidence of early-onset CRC is increasing over the past years. Young patients were more likely to be diagnosed with metastatic disease, left-sided and/or rectum site and symptoms at presentation. These findings highlight the emerging importance of young-age onset CRC and the need to discuss strategies to early diagnosis.
- Regorafenib in Patients with Antiangiogenic-Naive and Chemotherapy-Refractory Advanced Colorectal Cancer: Results from a Phase IIb Trial(2019) RIECHELMANN, Rachel P.; LEITE, Luiz S.; BARIANI, Giovanni M.; GLASBERG, Joao; RIVELLI, Thomas G.; FONSECA, Leonardo Gomes da; NEBULONI, Daniela R.; I, Maria Braghiroli; QUEIROZ, Marcelo A.; ISEJIMA, Alice M.; KAPPELER, Christian; KIKUCHI, Luciana; HOFF, Paulo M.Background Regorafenib is a multikinase inhibitor with antiangiogenic effects that improves overall survival (OS) in metastatic colorectal cancer (mCRC) after failure of standard therapies. We investigated the efficacy and safety of regorafenib in antiangiogenic therapy-naive chemotherapy-refractory advanced colorectal cancer. Patients and Methods This single-center, single-arm, phase IIb study (NCT02465502) enrolled adults with mCRC whose disease had progressed on, or who were intolerant to, standard therapy, but who were antiangiogenic therapy-naive. Patients received regorafenib 160 mg once daily for 3 weeks per 4-week cycle. The primary endpoint was progression-free survival (PFS) rate at week 8. Results Of 59 treated patients, almost half had received at least four prior lines of therapy. Patients received a median of 86% of the planned dose. The week 8 PFS rate was 53% (95% confidence interval [CI], 39.1-64.3); median PFS was 3.5 months (95% CI, 1.8-3.6). Median OS was 7.4 months (95% CI, 5.3-8.9). Tumor response (RECIST version 1.1) was 2%, and metabolic response rate (criteria from the European Organisation for Research and Treatment of Cancer) was 41%. The most frequently reported regorafenib-related grade >= 3 adverse events were hypertension (36%), hand-foot skin reaction (HFSR, 25%), and hypophosphatemia (24%). There were no regorafenib-related deaths. An exploratory analysis showed that patients with grade >= 2 HFSR had longer OS (10.2 months) with regorafenib treatment versus those with grades 0-1 (5.4 months). Conclusion These findings support the antitumor activity of regorafenib in antiangiogenic-naive patients with chemotherapy-refractory mCRC. Implications for Practice The multikinase inhibitor regorafenib improved overall survival in the phase III CORRECT and CONCUR trials in heavily pretreated patients with treatment-refractory metastatic colorectal cancer (mCRC). Exploratory subgroup analysis from CONCUR suggested that regorafenib treatment prior to targeted therapy (including bevacizumab) may improve outcomes. In this single-center, single-arm phase IIb study, regorafenib demonstrated antitumor activity in 59 antiangiogenic-naive patients with chemotherapy-refractory mCRC. Further studies should assess the efficacy of regorafenib in this patient population, as well as explore the reasons behind improved outcomes among patients who had a metabolic response and those who developed hand-foot skin reaction.
- Phase 2 Trial of Metformin Combined With 5-Fluorouracil in Patients With Refractory Metastatic Colorectal Cancer(2016) MIRANDA, Vanessa C.; BRAGHIROLI, Maria Ignez; FARIA, Luiza Dib; BARIANI, Giovanni; ALEX, Alexandra; BEZERRA NETO, Joao Evangelista; CAPARELI, Fernanda C.; SABBAGA, Jorge; SANTOS, Juliana Ferreira Lobo dos; HOFF, Paulo M.; RIECHELMANN, Rachel P.Effects of metformin in colorectal cancer have not been tested in clinical trials. In this phase 2 trial with 50 patients, metformin and 5-fluorouracil (5-FU) showed median progression-free survival of 2 months and overall survival of 7.9 months. However, among patients who experienced stable disease at 8 weeks, disease stabilization lasted for 5.6 months and patients survived for 16 months. Obese patients and those with longer periods off 5-FU seemed to derive more benefit. Background: Observational and preclinical studies have suggested that metformin has antitumor effects in solid tumors, including colorectal cancer (CRC). However, the effects of metformin in CRC have not been tested in clinical trials. Patients and Methods: This was a single-center, single-arm phase 2 clinical trial where histologically confirmed CRC patients with measurable and progressing metastatic disease previously treated with 5-fluorouracil (5-FU), irinotecan, oxaliplatin, and an antieepidermal growth factor receptor (if the tumor was RAS wild type) were enrolled to receive metformin 850 mg orally continuously 2 times a day plus 5-FU 425 mg/m(2) and leucovorin 50 mg intravenously weekly until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was disease control rate at 8 weeks. Results: Among 50 patients included, 11 (22%) met the primary end point. The median progression-free survival was 1.8 months and the median overall survival 7.9 months. Analyzing only the 11 patients who experienced disease control at 8 weeks, their median progression-free survival was 5.6 months and their median overall survival was 16.2 months. There was a trend for prolonged median survival for obese patients (12.4 vs. 5.8 months) and those longer off 5-FU. The treatment was well tolerated; the main adverse effects were diarrhea, nausea, vomiting, and myelotoxicity. Conclusion: Metformin and 5-FU showed an overall modest but intriguing activity in patients with refractory CRC in this phase 2 study. Some patients experienced long-term disease control. Further trials are needed to confirm these results, particularly in obese patients with CRC.
- Are There Strategies to Integrate the Continuum of Care for Metastatic Colorectal Cancer When Resources Are Limited?(2015) SANTINI, Fernando Costa; BRAGHIROLI, Maria Ignez; HOFF, Paulo M.Colorectal cancer is one of the most frequent neoplasias worldwide, affecting both men and women. Patients with inoperable or metastatic colorectal cancer (CRC) are candidates for palliative treatment with chemotherapy, which can significantly prolong survival. The number of active drugs has progressively increased over the past years, as well as available techniques directed towards resection or ablation of metastasis. Consequently, patients are able to live longer, with better quality of life. As new technologies become available, the treatments are becoming increasingly complicated, and the cost has increased in a proportion that most health systems can hardly afford. While the price of new therapies poses a challenge in more economically developed countries, it has a much greater impact in emerging and underdeveloped economies. In this article, we will discuss some strategies that could help dealing with this major problem, while reasonably maintaining the benefits of newer drugs and technologies to patient treatment.
article 6 Citação(ões) na Scopus Is Surgery Always Necessary in Rectal Cancer?(2014) SABBAGA, Jorge; BRAGHIROLI, Maria Ignez; HOFF, Paulo M.Rectal cancer is a major health problem around the world, representing about one-third of the total colorectal cancer cases. Because of its anatomical location, there is a higher risk of local recurrence, and treatment often requires a complex multidisciplinary approach which includes neoadjuvant radiotherapy, chemotherapy, and a radical surgical procedure that commonly leads to a permanent colostomy. The cure rate with this strategy is good, with some patients having no residual disease in the surgical specimen. While the prognosis for those Patients is excellent, their quality of life is permanently compromised. In this article, we review risks and benefits of the standard treatment approach and compare standard treatment with alternative methods aimed at rectal preservation.- Real-world Data for High-risk Stage II Colorectal Cancer - The Role of Tumor Side in the Adjuvant Setting(2021) ARAUJO, Camila S.; MONIZ, Camila M. Venchiarutti; BONADIO, Renata C.; WATARAI, Gabriel Y.; ROJAS, Jessica; NOGUEIRA, Pedro V. S.; MARTINEZ, Jessica K.; MORAES, Priscila M. G.; I, Maria Braghiroli; SABBAGA, Jorge; HOFF, Paulo M.The impact of sidedness in the high-risk stage II colorectal cancer setting is uncertain. Although controversial, data suggest a modest benefit of adjuvant chemotherapy in this scenario. This study analyzes the overall survival and recurrence-free survival according to the tumor side and considers adjuvant chemotherapy exposure and clinical and molecular features. In this retrospective cohort, the tumor side did not influence overall survival. Background: The impact of sidedness in the high-risk stage II colorectal cancer (CRC) setting is uncertain. Although controversial, available data suggest a possible modest benefit of adjuvant chemotherapy (CT) in the adjuvant scenario. The aim of this study is to analyze the overall survival (OS) and recurrence-free survival (RFS) according to the tumor side. Patients and Methods: In this single-center retrospective cohort, we analyzed patients treated between January 2011 and December 2018. We evaluated OS and RFS of high-risk patients according to the tumor side and considering adjuvant CT exposure and clinical and molecular features. Results: A total of 1047 patients with stage II CRC were evaluated. Of these, 540 had high-risk criteria and microsatellite stability (MSS) or unknown status. One hundred fifty-seven (29%) patients had right-sided tumors, and 352 (65.2%) had left-sided tumors. Most patients received adjuvant CT, and the majority of them had T3 stage tumors, >= 12 lymph node resection, left tumor, MSS, and moderate differentiation. OS did not differ according to tumor side (5-year OS rates: 81.9% for right-sided tumors vs. 83% for left-sided tumors; hazard ratio, 0.91; 95% confidence interval, 0.55-1.53; P = .744). Adjuvant CT was associated with a superior RFS and OS, with 5-year OS rates of 87.7% versus 76.1% in the no-adjuvant group (hazard ratio, 0.46; 95% CI, 0.28-0.73; P = .001). Conclusion: The tumor side did not influence the outcomes in this study. Adjuvant CT was associated with improved RFS and OS in patients with high-risk stage II CRC, with a total gain of 11.6% in 5-year OS.
- Evaluation of F-18-FDG PET-CT as a prognostic marker in advanced biliary tract cancer(2018) BRAGHIROLI, Maria I.; MOTA, Jose M.; DUARTE, Paulo S.; MORITA, Tiago O.; BARIANI, Giovanni M.; NEBULONI, Daniela; BUCHPIGUEL, Carlos A.; HOFF, Paulo M.; RIECHELMANN, Rachel P.BackgroundAdvanced biliary tract cancers have a dismal prognosis. Treatment with gemcitabine plus cisplatin has resulted in a significant improvement in survival; however, early assessment of outcomes poses a challenge.ObjectiveWe carried out a prospective study to evaluate the prognostic role of fluorine-18 fluorodeoxyglucose (F-18-FDG) PET-CT scans in patients with advanced biliary tract cancer.Patients and methodsPatients with advanced unresectable or metastatic biliary tract cancer starting first-line chemotherapy with gemcitabine plus cisplatin underwent F-18-FDG PET-CT studies at baseline and after two cycles of therapy. The total lesion glycolysis (TLG) measured at baseline as well as the variation in TLG between the two studies were analyzed as prognostic indicators of overall survival. The survival analyses were carried out using Kaplan-Meier curves and the comparison of survival curves was performed using the Breslow test.ResultsOf the 42 patients included, 37 had the first F-18-FDG PET-CT and 27 had the second F-18-FDG PET-CT. Patients with lower TLG values at baseline or after two cycles of therapy presented a higher median survival than patients with higher baseline TLG values. Patients with a higher decrease in the TLG values between the two studies also had a higher median survival time. However, these results only trended for statistical significance (P values ranging between 0.05 and 0.16).ConclusionLower baseline TLG measured by F-18-FDG PET-CT as well as a decrease in metabolic uptake after chemotherapy were associated with a trend toward longer median survival among patients with advanced biliary cancers.
conferenceObject Should all patients (pts) with advanced biliary cancers receive first-line treatment with cisplatin and gemcitabine (GC)?(2013) MIRANDA, Vanessa Costa; DIB-FARIA, Luiza; BRAGHIROLI, Maria Ignez Freitas Melro; SABBAGA, Jorge; SARAGIOTTO, Daniel Fernandes; CASTRO, Gilberto; HOFF, Paulo M.; RIECHELMANN, Rachel- Primary prevention of colorectal cancer: Myth or reality?(2014) TEIXEIRA, Marcela Crosara; BRAGHIROLI, Maria Ignez; SABBAGA, Jorge; HOFF, Paulo M.Colorectal cancer incidence has been rising strongly in parallel with economic development. In the past few decades, much has been learned about the lifestyle, dietary and medication risk factors for this malignancy. With respect to lifestyle, compelling evidence indicates that prevention of weight gain and maintenance of a reasonable level of physical activity can positively influence in lowering the risk. Although there is controversy about the role of specific nutritional factors, consideration of dietary pattern as a whole appears useful for formulating recommendations. Though quite often recommended, the role for many supplements, including omega-3, vitamin D, folate, and vitamin B6, remains unsettled. Only calcium and vitamin D supplementation appear to add a modest benefit, particularly in those with a low daily intake. With regard to chemoprevention, medications such as aspirin and nonsteroidal anti-inflammatory drugs, and postmenopausal hormonal replacement for women might be associated with substantial reductions in colorectal cancer risk, though their utility is affected by their side effect profile. However, the role of agents such as statins, bisphosphonates and antioxidants have yet to be determined. Ultimately, primary prevention strategies focusing on modifying envi-ronmental, lifestyle risk factors, and chemopreventive drugs are options that have already been tested, and may impact on colon cancer incidence.
- Combination of Irinotecan, Oxaliplatin and 5-Fluorouracil as a Rechallenge Regimen for Heavily Pretreated Metastatic Colorectal Cancer Patients(2018) FERNANDES, Gustavo Dos Santos; BRAGHIROLI, Maria Ignez; ARTIOLI, Michelle; PATERLINI, Ana Carolina Carvalho Rocha; TEIXEIRA, Marcela Crosara; GUMZ, Brenda Pires; GIRARDI, Daniel da Motta; BRAGHIROLI, Oddone F. M.; COSTA, Frederico Perego; HOFF, Paulo M.PurposeOur objective was to evaluate the benefit of re-exposing patients with refractory metastatic colorectal cancer (mCRC) to a combination of oxaliplatin, irinotecan and 5-fluorouracil treatment.MethodsWe retrospectively analysed patients with mCRC who received a combination of oxaliplatin, irinotecan and fluorouracil as a rechallenge regimen after progressing on the same drugs. Both FOLFOXIRI and FOLFIRINOX were used. Toxicity was evaluated for each treatment cycle, and survival analysis was performed using the Kaplan-Meier method.ResultsA total of 21 patients who were treated between January 2011 and December 2013 were selected for this study. Most of the patients (95.2%) had an ECOG status of 0-1. The median age at diagnosis was 52.1years (range 36-77years), and 14 (66.6%) patients had wild-type KRAS. Thirteen patients received FOLFIRINOX, and eight received FOLFOXIRI. Most patients had previously received at least three regimens, with 80% receiving anti-VEGF and 66% anti-EGFR antibodies. The response rate was 38%, and 24% patients had stable disease. The median time to disease progression was 4.0months (range 1.0-9.1months), and the median overall survival duration was 8.6months (range 6.3-11.5months). Most patients required dose adjustment and treatment delays. One patient experienced grade 5 neutropenic sepsis.ConclusionsBoth FOLFIRINOX and FOLFOXIRI are active and potentially feasible rechallenge treatment options for heavily pretreated patients with good performance status. With dose reduction and close monitoring for toxicity, the risk of serious adverse events can be minimised.