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1.
Cytokine ; 128: 154984, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31972343

RESUMO

BACKGROUND: Interleukin-2 (IL-2) was the cornerstone treatment for metastatic renal cell carcinoma (RCC) until the advent of tyrosine kinase inhibitors, but it still has therapeutic value. As a single bolus of IL-2 causes toxicity, there is interest in administration regimens with better tolerability and efficacy. Chronotherapy is the administration of therapy according to the circadian rhythm's influence on the immune and hormonal systems. This phase I-II trial evaluated the safety of IL-2 chronotherapy in metastatic RCC patients and determined the maximum tolerated dose. The secondary objective was to identify prognostic factors for survival. METHODS: Three chronomodulation schedules (5:00-13:00, 13:00-21:00, and 21:00-5:00) were tested. Each schedule was an 8-h IL-2 infusion, with a Gaussian distribution of drug concentration peaking at 4 h. To identify the maximum tolerated dose, the dose for different patients was escalated from 2 MIU/m2 (level I) to 18.6 MIU/m2 (level VI). RESULTS: Thirty patients were enrolled and completed treatment. Two patients were treated at 5:00-13:00, 15 at 13:00-21:00, and 13 at 21:00-5:00. Nine cases of grade 3 toxicity occurred in 7 patients at the highest dose (18.6 MIU/m2); no grade 4 toxicity occurred. The maximum tolerated dose was 14.0 MUI/m2. Patients were followed for a median of 16 months (range, 2-107). One patient was lost to follow-up, 3 patients were alive at last contact, and 26 patients died. Six patients achieved long-term survival (≥48 months). There was one complete response, four partial responses, 11 cases of stable disease and 14 of progressive disease. The response rate was 16% (5/30) and disease-control rate was 53% (16/30). Median progression-free survival was 4.5 months, and median overall survival was 14.5 months. Kaplan-Meier analyses revealed significant associations between overall survival and ECOG performance score (0 vs. 1-2), MSKCC score (0-2 vs. ≥ 3), IMDC risk score (0-2 vs. ≥ 3), IL-2 dose level (IV-VI vs. I-III), and prolactin (increase vs. no increase), and but not for chronotherapy schedule. CONCLUSION: IL-2 chronotherapy appears to be safe, moderately toxic and active in metastatic RCC. It may represent a new modality of IL-2 administration for these patients.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Renais/mortalidade , Cronoterapia/métodos , Esquema de Medicação , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão
2.
Oncologist ; 24(3): 385-393, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30606884

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with increased risk of colon cancer (CC), whereas metformin use seems to be protective. However, the impact of metformin use on the risk of death or disease recurrence after radical surgery for CC remains uncertain. MATERIALS AND METHODS: This is a substudy conducted in patients with high-risk stage II or stage III CC randomized in the TOSCA trial, which compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy. Objective of the study was to investigate the impact of metformin exposure during adjuvant chemotherapy on overall survival (OS) and relapse-free survival (RFS). We also evaluated the impact of T2DM or metformin dosage on clinical outcomes. RESULTS: Out of 3,759 patients enrolled in the TOSCA trial, 133 patients with diabetes (9.2%) and 1,319 without diabetes (90.8%) were recruited in this study. After excluding 13 patients with diabetes without information on metformin exposure, 76 patients with T2DM (63.3%) were defined as metformin users and 44 (36.7%) as metformin nonusers. After a median follow-up of 60.4 months, 26 (21.7%) patients relapsed and 16 (13.3%) died. Metformin use was neither associated with OS (adjusted hazard ratio [HR], 1.51; 95% confidence interval [CI], 0.48-4.77; p = .4781) nor with RFS (HR, 1.56; 95% CI, 0.69-3.54; p = .2881). Similarly, we found no association between T2DM or metformin dosage and OS or RFS. CONCLUSIONS: Metformin use and T2DM did not impact on OS or RFS in patients with resected CC treated with adjuvant fluoropyrimidine-oxaliplatin chemotherapy. Larger studies and longer follow-up are required to clarify the potential efficacy of metformin in improving the prognosis of patients with CC. IMPLICATIONS FOR PRACTICE: The role of the antidiabetic drug metformin in colon cancer prevention and treatment is highly debated. While low-dose metformin reduced the incidence of colorectal adenomas in two prospective studies, its effect in patients with already established colon cancer remains unclear. In this study, the potential impact of metformin on the survival of resected colon cancer patients who received adjuvant chemotherapy was investigated in the context of the TOSCA study. We did not find any association between metformin use or dosages and patient survival. Prospective studies are required to draw definitive conclusions about metformin impact on colon cancer recurrence and survival.


Assuntos
Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante/métodos , Neoplasias do Colo/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Oxaliplatina/uso terapêutico , Idoso , Antineoplásicos/farmacologia , Neoplasias do Colo/patologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Fluoruracila/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade , Oxaliplatina/farmacologia , Fatores de Risco
3.
Cancer Med ; 13(12): e7345, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38924262

RESUMO

BACKGROUND: Pancreatic cancer (PC) first-line therapy often consists of polychemotherapy regimens, but choosing a second-line therapy after disease progression, especially following first-line FOLFIRINOX, remains a clinical challenge. This study presents results from a large, multicenter, retrospective analysis of Italian patients with metastatic PC (mPC) treated with Nab-paclitaxel/Gemcitabine (AG) as second or later line of treatment. Main objective of the study is to identify prognostic factors that could inform treatment decisions. METHODS: The study included 160 mPC patients treated with AG in 17 Italian institutions. AG was administered according to labelling dose, until disease progression, unacceptable toxicity or patient refusal. Variations in schedules, dose modifications, supportive measures, and response evaluation were determined by individual clinicians' practice. RESULTS: AG was well-tolerated and exhibited promising clinical activity. The overall response rate (ORR) and the disease control rate (DCR) were 22.5% and 45.6%, respectively. Median progression-free survival (PFS) and overall survival (OS) were 3.9 and 6.8 months, respectively. Among the patients who received AG as a second-line therapy (n = 111, 66.9%), median PFS and OS were 4.2 and 7.4 months, respectively. Notably, in the 76 patients (68%) receiving AG after first-line FOLFIRINOX, an ORR of 19.7% and a DCR of 46.0% were observed, resulting in a median PFS of 3.5 and median OS of 5.7 months. The study identified specific clinical or laboratory parameters (LDH, NLR, fasting serum glucose, liver metastases, ECOG PS, and first-line PFS) as independent prognostic factors at multivariate level. These factors were used to create a prognostic nomogram that divided patients into three risk classes, helping to predict second-line OS and PFS. CONCLUSIONS: This study represents the largest real-world population of mPC patients treated with AG as a second or later line of therapy. It supports the feasibility of this regimen following first-line FOLFIRINOX, particularly in patients with specific clinical and laboratory characteristics who derived prolonged benefit from first-line therapy.


Assuntos
Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina , Gencitabina , Paclitaxel , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/mortalidade , Masculino , Feminino , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Albuminas/administração & dosagem , Albuminas/uso terapêutico , Albuminas/efeitos adversos , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Paclitaxel/efeitos adversos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Estudos Retrospectivos , Prognóstico , Adulto , Idoso de 80 Anos ou mais , Resultado do Tratamento , Itália , Metástase Neoplásica
4.
J Neurooncol ; 107(1): 191-6, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21989810

RESUMO

Central nervous system (brain or leptomeningeal) metastases (BLm) are considered rare in castration-resistant prostate cancer (CRPC) patients. Now that docetaxel has become the reference drug for first-line treatment of CRPC, patients whose disease is not controlled by hormonal manipulations may live much longer than before and have higher risk of developing BLm. We retrospectively reviewed the records of all patients with CRPC attending our centres from 2002 to 2010, and identified all of those who were diagnosed as having BLm and received (or were considered to have been eligible to receive) docetaxel-based treatment. We identified 31 cases of BLm (22 brain metastases and 9 leptomeningeal metastases) with an incidence of 3.3%. BLm-free survival was 43.5 months, and survival after BLm discovery was 4 months. With six patients surviving for more than 1 year after developing BLm, the projected 1-year BL-S rate was 25.8%. The findings of our study may be relevant in clinical practice as they indicate that incidence of BLm in CRPC patients in the docetaxel era seems to be higher than in historical reports, meaning that special attention should be paid to the appearance of neurological symptoms in long-term CRPC survivors because they may be related to BLm.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Meníngeas/secundário , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Orquiectomia , Neoplasias da Próstata/tratamento farmacológico , Taxoides/efeitos adversos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/induzido quimicamente , Neoplasias Encefálicas/mortalidade , Docetaxel , Seguimentos , Humanos , Masculino , Neoplasias Meníngeas/induzido quimicamente , Neoplasias Meníngeas/mortalidade , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/mortalidade , Neoplasias Hormônio-Dependentes/patologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
5.
BJU Int ; 108(8 Pt 2): E250-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21599821

RESUMO

OBJECTIVE: •To conduct a retrospective, multicentre, cohort analysis to assess the sequential use of the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib. PATIENTS AND METHODS: •Records of 189 patients with renal-cell carcinoma (RCC) who were treated with sorafenib and sunitinib sequentially between March 2004 and April 2009 at 12 Italian study centres were analysed. •Patients were treated under European Expanded Access Programmes or, following market approval, in general clinical practice. •Interventions were sorafenib (800 mg/day) and sunitinib (50 mg every day; 4 weeks on and 2 weeks off). •Progression-free survival (PFS) during treatment with the first and second TKI was evaluated. RESULTS: •In all, 99 patients were treated with sunitinib followed by sorafenib (SuSo) and 90 were treated with sorafenib followed by sunitinib (SoSu); 104 (55%) patients had received prior systemic therapy, mostly with cytokines. •The median (range) PFS on the first TKI was similar between treatment groups [sorafenib 8.4 (1.1-28.9) months; sunitinib 7.8 (0.5-30.4) months; hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.78-1.40, P=0.758]. Multivariate analysis showed that good Memorial Sloan-Kettering Cancer Center status was associated with increased PFS. •After the second TKI, patients in the SoSu group had a longer median PFS than those in the SuSo group (7.9 months vs 4.2 months, respectively; HR 0.54, 95% CI 0.39-0.74, P<0.001). •Multivariate analysis showed only treatment and Eastern Cooperative Oncology Group performance status (and not age, gender, study centre or previous treatment) were significantly associated with duration of PFS. CONCLUSION: •Our findings suggest a limited cross-resistance between sorafenib and sunitinib and that the sequence SoSu may result in a longer combined PFS than SuSo. This is the largest retrospective study to date, though its findings are limited in part by the retrospective nature.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzenossulfonatos/administração & dosagem , Carcinoma de Células Renais/patologia , Quimioterapia Combinada , Feminino , Humanos , Indóis/administração & dosagem , Itália , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Estudos Retrospectivos , Sorafenibe , Sunitinibe
6.
Artigo em Inglês | MEDLINE | ID: mdl-24638867

RESUMO

Nevus spilus is the term usually given to a pigmented skin lesion, congenital or acquired, that may occur anywhere on the body, consisting of a large light tan patch with numerous superimposed darker scattered maculae or papulae that are flat or slightly raised. For a long time, nevus spilus was believed to be a benign lesion. However, in 1957 Perkinson reported a melanoma appearing on nevus spilus for the first time. Since then other reports about melanomas developing on nevus spilus have been published, sometimes with a fatal outcome. We describe the case of an 80-year-old male patient with a congenital nevus just above his left knee. The lesion had remained unchanged over time, but some months before his checkup the patient noticed a darker area in the lesion that had continued to enlarge. The lesion was removed and histological examination revealed an in situ malignant melanoma. Although nevus spilus is not normally considered a precursor of melanoma, the potentiality of malignant transformation requires regular monitoring, and careful checkups are recommended and justified.


Assuntos
Melanoma/patologia , Nevo Pigmentado/patologia , Neoplasias Cutâneas/patologia , Idoso de 80 Anos ou mais , Humanos , Masculino , Melanoma/cirurgia , Nevo Pigmentado/cirurgia , Neoplasias Cutâneas/cirurgia , Coxa da Perna , Melanoma Maligno Cutâneo
7.
Anticancer Res ; 33(3): 1041-4, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23482779

RESUMO

Endometrial cancer (EC) is usually diagnosed at an early stage, when surgery-alone may be curative, but 20-25% of patients with EC have higher-risk early-stage disease requiring radiation therapy alone or in combination with chemotherapy, in addition to surgery. Most EC relapses are either pelvic or distant metastases and occur within the first three years after hysterectomy. Laparotomy wound recurrences of EC are extremely rare, and only a few cases have been previously reported. We describe the unusual case of a late wound recurrence from an EC surgically removed 10 years previously which was successfully treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) after response to a hormonal therapy. Ten years after abdominal hysterectomy and bilateral salpingo-oophorectomy, on computed tomographic (CT) scan, a 70-year-old woman exhibited an abdominal mass of 3.5 cm, strictly adherent to the abdominal rectal muscle. CT-guided biopsy revealed estrogen- and progesterone receptor-positive metastasis from EC and the patient was treated with megestrole acetate. The whole body (18)F-fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET)/CT showed a marked metabolic response at the single metastatic site, with no further metastases, and the patient underwent surgical resection of the mass followed by immediate HIPEC perfusion with cisplatin. No residual macroscopic disease was present at the end of surgery and no complications occurred during the hospital stay. At 12-month follow-up, the patient is alive without evidence of disease. Although this approach is still being investigational for peritoneal recurrence of EC, our report confirms its feasibility and its promising results in highly selected patients.


Assuntos
Neoplasias do Endométrio/terapia , Hipertermia Induzida , Idoso , Terapia Combinada , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/patologia , Feminino , Fluordesoxiglucose F18 , Humanos , Infusões Parenterais , Laparotomia/efeitos adversos , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Recidiva , Terapia de Salvação , Tomografia Computadorizada por Raios X , Imagem Corporal Total
8.
J Immunother ; 33(7): 735-41, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20664353

RESUMO

The aim of this study was to look for the maximum tolerated dose (MTD) of gemcitabine and 5-fluorouracil in a new regimen also containing the antiangiogenic bevacizumab and immunotherapy (IT) for the treatment of metastatic renal cell cancer. The primary objective of this multicenter dose-finding study was to establish the MTD of chemotherapy (CT) in combination with fixed doses of IT and bevacizumab. The secondary objective was to assess the combination's activity. Five escalated dose levels of CT with intravenous gemcitabine and 5-fluorouracil (days 1 and 8 every 28 d), were associated together with intravenous bevacizumab (10 mg/kg on days 1 and 15 every 28 d), subcutaneous interleukin-2 (1 MIU/m² bid on days 8, 9, 15, 16, and 1 MIU/m²/d on days 10-12 and 17-19), and interferon-α-2a (3 MIU on days 10, 12, 17, 19). Of the 27 enrolled patients, 59% had been pretreated. The MTD was not reached. The highest CT dose studied was gemcitabine 1000 mg/m² and 5-fluorouracil 600 mg/m². More frequent grade 3 to 4 toxicities included neutropenia (63%), thrombocytopenia (33%), and fever (26%). The response rate was 33% according to the Response Evaluation Criteria in Solid Tumors. This is the first study that explored the feasibility and safety of combined bevacizumab, IT, and CT in metastatic renal cell cancer. The activity of this regimen is interesting and its efficacy warrants further trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renais/imunologia , Imunoterapia , Neoplasias Renais/imunologia , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Bevacizumab , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Seguimentos , Humanos , Análise de Intenção de Tratamento , Interferon-alfa/administração & dosagem , Interleucina-2/administração & dosagem , Itália , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Dose Máxima Tolerável , Oncologia , Pessoa de Meia-Idade , Metástase Neoplásica , Análise de Sobrevida , Gencitabina
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