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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conferenceObject A phase II trial of metformin and fluorouracil (MetFU) for patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard treatment(2014) MIRANDA, Vanessa Costa; FARIA, Luiza Dib; BRAGHIROLI, Maria Ignez Freitas Melro; JACOBS, Monica; SABBAGA, Jorge; HOFF, Paulo Marcelo; RIECHELMANN, Rachel Pimenta- 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.
- Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas(2015) BRAGHIROLI, Maria Ignez; FERRARI, Anezka C. R. de Celis; PFIFFER, Tulio Eduardo; ALEX, Alexandra Kichfy; NEBULONI, Daniela; CARNEIRO, Allyne S.; CAPARELLI, Fernanda; SENNA, Luiz; LOBO, Juliana; HOFF, Paulo Marcelo; RIECHELMANN, Rachel P.Background: In patients with adenocarcinoma of the pancreas, there are no standard second-line regimens. Many pre-clinical studies have shown that metformin alone or when combined with paclitaxel has antitumour effects on this tumour. We have tested here the combination of paclitaxel and metformin for patients with gemcitabine-refractory pancreatic cancer. Methods: An uncontrolled phase II trial was carried out based on a two-stage Simon's design, with metformin and paclitaxel for patients with locally advanced or metastatic pancreatic cancer whose disease had progressed during first line treatment with a gemcitabine-based regimen. The primary endpoint was the disease control rate at eight weeks as per response evaluation criteria in solid tumours (RECIST) 1.1. Patients received paclitaxel 80 mg/m(2) weekly for three weeks every 28 days and metformin 850 mg p.o. t.i.d. continuously until progression or intolerance state was reached. Results: Twenty patients were enrolled from July 2011 to January 2014: N = 6 (31.6%) achieved the primary endpoint, with all presenting stable disease. Median overall survival (OS) was 128 days (range 17-697) and the median progression free survival (PFS) was 44 days (range 14-210). Eight patients (40%) presented treatment-related G3-4 toxicities with the most common one being diarrhoea. Conclusions: Despite the encouraging pre-clinical evidence of the antitumour activity of metformin in adenocarcinoma of the pancreas, the primary endpoint of the disease control rate was not met. Besides, the treatment combination was poorly tolerated and could not be studied further. This study highlights the importance of performing clinical trials to reassure preclinical or observational data.
conferenceObject Prospective study of biomarkers in squamous cell carcinoma of the anal canal (SCCAC) and their influence on treatment outcomes: Five-year long-term results.(2020) MONIZ, Camila Motta Venchiarutti; RIECHELMANN, Rachel Pimenta; BRAGHIROLI, Maria Ignez; RIBEIRO, Suilane Coelho; RIVELLI, Thomas Giollo; BARIANI, Giovanni M.; CHEN, Andre Tsin Chih; NAHAS, Caio; BONADIO, Renata Colombo; ORTEGA, Cinthia; FRANCO, Rejane; MEIRELES, Sibele; PEREIRA, Allan Andresson Lima; SABBAGA, Jorge; COUDRY, Renata A.; HOFF, Paulo Marcelo- A Prospective Cohort Study of Biomarkers in Squamous Cell Carcinoma of the Anal Canal (SCCAC) and their Influence on Treatment Outcomes(2021) MONIZ, C. M. V.; RIECHELMANN, R. P.; OLIVEIRA, S. C. R.; BARIANI, G. M.; RIVELLI, T. G.; ORTEGA, C.; PEREIRA, A. A. L.; MEIRELES, S. I.; FRANCO, R.; CHEN, A.; BONADIO, R. C.; NAHAS, C.; SABBAGA, J.; COUDRY, R. A.; BRAGHIROLI, M. I.; HOFF, P. M.Background: Although Chemoradiation (CRT) is the curative treatment for SCCAC, many patients present primary resistance. Since it is a rare tumor, response predictors remain unknown. Methods: We performed a prospective cohort study to evaluate biomarkers associated with CRT response, progression-free survival (PFS), and overall survival (OS). The primary endpoint was response at 6 months (m). Tumor DNA and HPV were analyzed by next-generation sequencing, while KI-67 and PD-L1 by immunohistochemistry in tumor tissue. Results: Seventy-eight patients were recruited between October/2011 and December/2015, and 75 were response evaluable. The median age was 57 years, 65% (n=49) were stage III and 12% (n=9) were HIV positive (HIV+). At 6m, 62.7% (n=47) presented CR. On multivariate analyses, stage II patients were 4.7 more likely to achieve response than stage III (OR, 4.70; 95%CI, 1.36-16.30; p=0.015). HIV+ was associated with a worse response (OR, 5.72; 95%CI, 2.5-13.0; p<0.001). 5-year PFS and OS rates were 63.3% and 76.4%, respectively, with a median follow up of 66m. On multivariate analyses, older age (HR 1.06, p=0.022, 95%IC 1.01-1.11) and absence of CR at 6m (HR 3.36, p=0.007, 95%IC 1.39-8.09) were associated with inferior OS. The 5-year OS rate was 62.5% in HIV+ group compared to 78% among HIVpts, although this difference was not statistically significant (p=0.4). PIK3CA, MET and TP53 mutations, HPV, Ki-67 expression, and PD-L1 expression, were not associated with PFS and OS. Conclusions: Clinical stage III and HIV+ were associated with worse response to CRT at 6m. The absence of CR was the main factor associated with poor 5-year OS. © The author(s).
- Proton pump inhibitors and antibiotics impact on toxicities and clinical outcomes in cancer patients treated with immunotherapy.(2021) ARAUJO, Haniel Alves; MONIZ, Camila Motta Venchiarutti; BRAGHIROLI, Oddone Freitas Melro; MAK, Milena Perez; URATANI, Lucas Fernando; TIECHER, Ricardo Dahmer; MORAES, Priscila Muniz; BARBOSA, Ingrid; CAMARGO, Veridiana Pires De; BRAGHIROLI, Maria Ignez Freitas Melro; CASTRO, Gilberto; HOFF, Paulo Marcelo; DIZ, Maria Del Pilar
- 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.
bookPart Terapia molecular em tumores gastrintestinais(2017) SCARANTI, Mariana; BRAGHIROLI, Maria Ignez; HOFF, Paulo Marcelo Gehm