RESUMO
Background Despite professional recommendations malnutrition is not adequately addressed in cancer patients. Here, we explored whether nutritional status (NS) is associated with HRQoL in men with metastatic castrate-resistant prostate cancer (mCRPC). Methods: Men with mCRPC enrolled into this prospective observational study were allocated to one of the four NS categories based on clinical, laboratory, and patient self-reported criteria: well-nourished (WN), nutritional risk without criteria for cachexia/sarcopenia (NR), sarcopenia, and cachexia. The HRQoL was evaluated by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Association between NS and self-reported HRQoL was sought by the linear regression model, which was adjusted for known prognostic variables and body mass index. Results: Over the period of two years, 141 patients were enrolled. Their median age was 74.1 years (IQR 68.6-79.4 years) and majority of them were minimally symptomatic. Fifty-nine patients (41.8%) were WN, followed by 24 (17%), 42 (29.8%), and 16 (11.4%) patients with NR, sarcopenia, and cachexia, respectively. As compared to WN patients, all three other NS categories were significant negative predictors of HRQoL (P < 0.04). Conclusions: Abnormal NS is highly prevalent in men with mCRPC and is negatively associated with their HRQoL, which supports the recommendation for management of malnutrition in these patients.
Assuntos
Desnutrição , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Sarcopenia , Idoso , Humanos , Masculino , Desnutrição/complicações , Estado Nutricional , Qualidade de Vida , Sarcopenia/etiologiaRESUMO
BACKGROUND: The aim of the study was to investigate how the expression of tumor markers p21, p27, p53, cyclin D1, EGFR, Ki-67, and CD31 influenced the outcome of advanced inoperable oropharyngeal carcinoma patients, treated with concomitant radiochemotherapy. PATIENTS AND METHODS: The pretreatment biopsy specimens of 74 consecutive patients with inoperable stage IV oropharyngeal squamous cell carcinoma treated with concomitant radiochemotherapy were in retrospective study processed by immunochemistry for p21, p27, p53, cyclin D1, EGFR, Ki-67, and CD31. Disease-free survival (DFS) was assessed according to the expression of tumor markers. RESULTS: Patients with a high expression of p21 (≥10%), p27 (>50%), Ki-67 (>50%), CD31 (>130 vessels/mm2) and low expression of p53 (<10%), cyclin D1 (<10%) and EGFR (<10%) (favorable levels - FL) had better DFS than patients with a low expression of p21 (<10%), p27 (≤50%), Ki-67 (≤50%), CD31 (<130 vessels/mm2) and high expression of p53 (≥10%), cyclin D1 (≥10%) and EGFR (≥10%) (unfavorable levels - UL). However, statistical significance in survival between FL and UL was achieved only for p27 and cyclin D1. DFS significantly decreased with an increasing number of markers with an unfavorable level per tumor (1-4 vs. 5-7) (78% vs. 32%, respectively; p = 0.004). The number of markers per tumor with UL of expression retained prognostic significance also in multivariate analysis. CONCLUSIONS: Statistical significance in survival between FL and UL emerged only for p27 and cyclin D1. The number of markers per tumor with UL of expression was an independent prognostic factor for an adverse outcome.
RESUMO
OBJECTIVES: Osteosarcoma is the most common primary bone malignancy that occurs mostly in adolescents. Treatment protocols usually include multiagent preoperative and postoperative chemotherapy based on methotrexate, cisplatin, doxorubicin and ifosfamide. Despite a favourable prognosis, there are considerable interindividual differences in treatment outcome. Genetic variability of enzymes involved in the metabolism and transport of methotrexate could contribute towards observed differences in response to chemotherapy. Our aim was to evaluate how polymorphisms in the folate pathway and transporter genes influence treatment outcome in osteosarcoma patients. PATIENTS AND METHODS: In total, 44 osteosarcoma patients treated with methotrexate were genotyped for eleven polymorphisms in four folate pathway and five folate transporter genes. Cox regression was used in survival analysis. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity and nonparametric tests were used to determine the influence on serum methotrexate levels. RESULTS: Polymorphic SLCO1B1 rs4149056 and rs11045879 alleles were associated with significantly higher serum methotrexate area under the curve (P=0.001 and 0.011, respectively). Carriers of at least one polymorphic SLCO1B1 rs4149056 and rs11045879 allele tended to have longer event-free survival compared with patients with two wild-type alleles [P=0.040, hazard ratio (HR)=0.26, 95% confidence interval (CI)=0.07-0.94; and P=0.034, HR=0.20, 95% CI=0.05-0.89, respectively]. Compared with the most common haplotype, carriers of both polymorphic alleles had significantly longer event-free survival (P=0.009, HR=0.27, 95% CI=0.10-0.72). CONCLUSION: We have shown that SLCO1B1 polymorphisms influence methotrexate disposition and survival in methotrexate-treated osteosarcoma patients and therefore might serve as pharmacogenetic markers of treatment outcome.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Ácido Fólico/metabolismo , Metotrexato/administração & dosagem , Transportadores de Ânions Orgânicos/genética , Osteossarcoma/tratamento farmacológico , Adolescente , Adulto , Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Criança , Feminino , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Osteossarcoma/genética , Osteossarcoma/mortalidade , Polimorfismo de Nucleotídeo Único , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Human epidermal growth factor receptor 2 (HER2) positive breast cancer is an entity with aggressive behaviour. One year of adjuvant trastuzumab significantly improves the disease free survival in the range of 40-50% and reduces the risk of dying from HER2 positive breast cancer by one third. Adjuvant treatment with trastuzumab became available in Slovenia in 2005 and the aim of this study is to explore, if the exceptional results reported in adjuvant clinical trials are achieved also in daily clinical practice. PATIENTS AND METHODS: An analysis of tumour and patient characteristics, type of treatment and outcome (relapse free and overall survival) of 313 patients (median age 52 years) treated at the Institute of Oncology Ljubljana in years 2005-2009 was performed. RESULTS: Median follow-up was 4.4 years. Sixty-one patients relapsed and 24 died. Three and four years relapse free survival was 84.2% and 80.8% and the overall survival was 94.4% and 92.5%, respectively. Independent prognostic factors for relapse were tumour grade (HR 2.10; 95% CI 1.07-4.14; p = 0.031) and nodal stage (HR 1.35; 1.16-1.56; p < 0.0001) and for the overall survival nodal stage only (HR 1.36; 1.05-1.78; p = 0.021). CONCLUSIONS: The outcome in patients with adjuvant trastuzumab in daily clinical practice, treated by medical oncologists, is comparable to results obtained in international adjuvant studies.
RESUMO
ABSTRACT: Metastatic salivary duct carcinomas (SDC) are rare tumors and evidence-based guidelines for their treatment have not yet been established. Reports of such cases like ours could be beneficial in the decision-making in the similar clinical circumstances. Here we present the 64-year-old Caucasian man with bone pain and pancytopenia two years after local treatment of SDC, in whom a bone marrow biopsy revealed poorly differentiated carcinoma of salivary origin with nuclear androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2/neu) positivity. Clinical response was achieved with cis-platin based cytotoxic therapy and maintenance hormonal treatment. At progression after 12 months, he was treated with anti-HER2 therapy combined with taxanes. The response lasted for 14 months. Then palliative therapy with capecitabine was introduced. With a relatively sustained quality of life, the response lasted for 15 months.
Assuntos
Carcinoma , Neoplasias das Glândulas Salivares , Masculino , Humanos , Pessoa de Meia-Idade , Receptores Androgênicos/genética , Capecitabina/uso terapêutico , Qualidade de Vida , Ductos Salivares , Neoplasias das Glândulas Salivares/tratamento farmacológicoRESUMO
Patients with recurrent or metastatic squamous cell head and neck cancer (R/M SCHNC) exhibit a poor prognosis with a median overall survival (OS) time of <1 year. Platinum-based chemotherapy with or without cetuximab has been the standard of care in the last decade. The aim of the current retrospective study was to evaluate the outcome and tolerability of treatment in patients with R/M SCHNC receiving platinum/5-fluorouracil/cetuximab (PFE) chemotherapy compared with platinum/5-fluorouracil (PF) chemotherapy in daily clinical practice. A retrospective analysis was performed using the data of patients treated at the Institute of Oncology Ljubljana between April 2008 and May 2018. Progression-free survival (PFS) and OS were calculated with the Kaplan-Meier method and compared with the log-rank test. Multivariate regression Cox analysis was used to determine independent prognostic factors. A total of 67 patients were treated at the aforementioned Institute: 34 patients received the PF and 33 the PFE regimen. The mean age of patients was 54.6 years and 91% of patients were male. Median PFS time was 6.6 vs. 7.1 months for the PF vs. PFE groups, respectively (P=0.852). Median OS time was 9.6 vs. 11.5 months for the PF vs. PFE groups, respectively (P=0.029). The prognostic factor for PFS was partial remission [hazard ratio (HR), 0.32; 95% CI, 0.15-0.70; P=0.004]. Prognostic factors for OS were partial remission (HR, 0.15; 95% CI, 0.06-0.38; P<0.001) or stable disease (HR, 0.28; 95% CI, 0.13-0.64; P=0.002), and a subsequent line of treatment upon progression (HR, 0.28; 95% CI, 0.15-0.52; P<0.001). In the PFE group, 15.4% of patients had a grade >2 infusion reaction to cetuximab and 27.3% had grade 3 skin rash. There were no differences in diarrhoea, hypomagnesaemia, infections and febrile neutropenia; however, the mortality on active treatment was high (13.4%). In conclusion, patients treated with PFE had similar PFS, but improved OS compared with patients treated with the PF protocol. The proportion of patients who died under treatment due to disease progression and toxicity was high in both treatment arms. A thorough selection of patients for this treatment is crucial.
RESUMO
BACKGROUND: The aim of our study was to describe the survival of Slovenian cancer patients diagnosed in the last twenty years. An insight is given into the improvement made in different cancer types, population groups and prognostic factors. MATERIALS AND METHODS: The principal data source was the population-based Slovenian Cancer Registry. The survival analysis included patients diagnosed with cancer in twenty years period from 1997 to 2016, which has been divided into four consecutive five-year periods. In addition, the analysis was stratified by cancer type, gender, age and stage. The survival was estimated using net survival calculated by the Pohar-Perme method and the complete approach has been applied. RESULTS: The survival of Slovenian cancer patients has been increasing over time. During the 20 years observed, five-year net survival increased by 11 percentage points. Significantly higher growth was observed in men. Age and stage at diagnosis are still crucial for the survival of cancer patients. Five-year net survival is lowest in those over 75 years of age at diagnosis but has also improved by seven percentage points over the past 20 years. The five-year net survival of patients in the localized stage increased by ten percentage points over the 20 years under observation. Survival of patients in the distant stage has not been improving. In both sexes, survival for melanoma, colorectal and lung cancers have increased significantly over the last 20 years. Progress has also been made in the two most common gender specific cancers: breast cancer in women and prostate cancer in men. Still, the significant progress in prostate cancer is probably mostly due to lead-time bias as during the study period, Slovenia used indiscriminate PSA testing, which probably artificially prolonged survival. CONCLUSIONS: The survival of Slovenian cancer patients has been increasing over time, which gives us a basis and an incentive for future improvements. To monitor the effectiveness of managing the cancer epidemic, the cancer burden needs to be monitored also in the future, using quality data and scientifically justified methodological approaches. In this process a well organised population-based cancer registries should play a key role.
Assuntos
Neoplasias/mortalidade , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/patologia , Sistema de Registros , Fatores Sexuais , Eslovênia/epidemiologia , Análise de SobrevidaRESUMO
BACKGROUND AND PURPOSE: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results. MATERIALS AND METHODS: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint. RESULTS: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005). CONCLUSION: The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Escamosas/tratamento farmacológico , Quimioterapia Adjuvante , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Quimioterapia de Indução , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
In total, ~85% of malignant gastrointestinal stromal tumours (GISTs) harbour activating mutations in one of the genes KIT or PDGFRA, while 1015% of all GISTs have no detectable KIT or PDGFRA mutations, but could have alterations in genes of the succinate dehydrogenase complex or in BRAF, PIK3CA or rarely RAS family genes. The clinical benefit of tyrosine kinase inhibitors, such as imatinib, depends on the GIST genotype, therefore molecular characterization of GIST has a crucial role in overall management of GIST. The aim of the present study was to molecularly characterize a cohort of 70 patients with metastatic GISTs from the Slovenian Cancer Registry (National Cancer Registry) treated between January 2002 and December 2011. Exons 9, 11, 13 and 17 of the KIT gene and exons 12, 14 and 18 of the PDGFRA gene were analysed by direct Sanger sequencing. All KIT/PDGFRA wildtype GISTs were tested for the presence of mutations in hot spot regions of KRAS, NRAS, BRAF, PIK3CA and AKT1 genes. Novel variants were characterized and classified using Cancer Genome Interpreter and according to The American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. In total, 60 (85.7%) patients had mutations in KIT and 2 (2.9%) in PDGFRA. Whereas, 8 (11.4%) patients with GIST had no mutation in either of the analysed genes. The majority of GIST cases (n=52) had a mutation in KIT exon 11, where 40 different mutations were detected. Eight of the variants were novel: c.1652_1672del, c.1653_1660delinsAA, c.1665_1672delinsCC, c.1668_1686del, c.1676_1720del, c.1715_1756dup, c.1721_1765dup, and c.1722_1766dup. Mutation frequencies of KIT and PDGFRA genes observed in Slovenian patients are comparable with those in other European populations. In the present group of patients analysed, the most frequently mutated region was exon 11 in the KIT gene, responsible for coding juxtamembrane domain of KIT protein. In this region, eight novel mutations were identified and classified as likely pathogenic driver variants. In addition, the present study identified 6 patients with secondary KIT mutation and 1 patient with double mutant GIST, who had two different mutations in PDGFRA exon 14.
Assuntos
Tumores do Estroma Gastrointestinal/genética , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Análise de Sequência de DNA/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Éxons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , EslovêniaRESUMO
PURPOSE: To evaluate the toxicity and efficacy of concomitant chemoradiotherapy with mitomycin C and cisplatin in the treatment of advanced unresectable squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Treatment consisted of conventional radiotherapy (70 Gy in 35 fractions), mitomycin C 15 mg/m(2) IV, applied after the delivery of 10 Gy, and cisplatin at an initial dose of 10 mg/m(2)/d IV, applied during the last 10 fractions of irradiation ("chemoboost"). The cisplatin dose was escalated with respect to the toxic side effects by 2 mg/m(2)/d up to the maximum tolerated dose (MTD) or at the most 14 mg/m(2)/d (Phase I study), which was tested in the subsequent Phase II study. RESULTS: All 36 patients had Stage T4 and/or N3 disease, and the majority had oropharyngeal (50%) or hypopharyngeal (39%) primary tumors. Six patients were treated at each of the three cisplatin dose levels tested (Phase I study). Dose-limiting toxicity was not reached even at 14 mg/m(2)/d of cisplatin, which was determined as the MTD and tested in an additional 18 patients (Phase II study). After a median follow-up time of 48 months, 4-year locoregional control, failure-free, and overall survival rates were 30%, 14%, and 20%, respectively. In 24 patients treated at the cisplatin dose level of 14 mg/m(2)/d, the corresponding rates were 40%, 20%, and 22%, respectively. CONCLUSION: Concomitant chemoradiotherapy with mitomycin C and cisplatin "chemoboost" at 14 mg/m(2)/d is feasible, with encouraging survival results if the extremely poor disease profile of the treated patients is considered.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/secundário , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada/métodos , Estudos de Viabilidade , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Mitomicina/efeitos adversos , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Dosagem Radioterapêutica , Análise de SobrevidaRESUMO
In advanced squamous cell carcinoma of the head and neck, concomitant radiotherapy with cisplatin and/or cetuximab is frequently combined with cisplatin-based induction chemotherapy, which can cause severe hypomagnesemia, hypocalcemia, and hypokalemia. The aim of our study was to analyze the effects of magnesium sulfate supplementation on the incidence of hypomagnesemia, hypokalemia, and hypocalcemia during four cycles of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy followed by concomitant radiotherapy (CRT) with cisplatin and cetuximab. Twenty-five patients included in a phase II prospective study received routine magnesium sulfate infusions before each cycle of cisplatin, and additional supplementation based on laboratory findings. During TPF, the incidence of grade 1/2 and grade 3/4 hypomagnesemia was 16% and 4%, respectively; and increased despite magnesium supplementation during CRT to 72% and 8%, respectively. During TPF, a grade 2 and grade 4 hypocalcemia occurred in 8% and 4%, respectively; and during CRT, it reached 36% (grade 1/2). Grade 1 hypokalemia only was observed during TPF (4%) and CRT (8%). The median amounts of supplemented magnesium sulfate during TPF and CRT were 20 mEq and 50 mEq, respectively. It appears that a low incidence of grade 3/4 hypomagnesemia and hypocalcemia in our patients resulted from intensive magnesium supplementation. Thorough measurements of magnesium and calcium during cisplatin-based chemoradiation protocols in patients with head and neck cancer are crucial in preventing the development of grade 3/4 hypomagnesemia and hypocalcemia.
Assuntos
Quimiorradioterapia/efeitos adversos , Hipercalciúria/prevenção & controle , Hipocalcemia/prevenção & controle , Sulfato de Magnésio/uso terapêutico , Nefrocalcinose/prevenção & controle , Erros Inatos do Transporte Tubular Renal/prevenção & controle , Cetuximab/efeitos adversos , Cetuximab/uso terapêutico , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Masculino , Estudos ProspectivosRESUMO
BACKGROUND/AIM: It can be hypothesized that in patients with locally advanced head and neck cancer and prominent cetuximab (CMb)-induced skin rash, immunoradiotherapy would result in a survival advantage over chemoradiotherapy with cisplatin (CP). PATIENTS AND METHODS: After a loading dose of CMb, one weekly cycle of CMb and CP concurrently with RT, patients who developed a grade ≥2 rash proceeded with immunoradiotherapy, and those with a grade 0-1 rash had chemoradiotherapy. RESULTS: A grade 3-4 allergic reaction to CMb developed in 11/39 (28.2%) patients and further recruitment was stopped. These patients proceeded treatment with CP. In early assessment of skin rash 10/28 patients qualified for chemoradiotherapy and 18/28 patients for immunoradiotherapy. There was no difference in survival between the two groups. CONCLUSION: Rate of serious CMb-induced hypersensitivity reactions was unacceptably high. Even though immunoradiotherapy was administered only to the prognostically most favorable group of patients, it resulted in no advantage over chemoradiotherapy.
Assuntos
Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia/métodos , Seleção de Pacientes , Radioterapia/métodos , Adulto , Idoso , Antineoplásicos/efeitos adversos , Cetuximab/efeitos adversos , Toxidermias , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
PURPOSE: The long term results and patterns of failure in patients with squamous cell head and neck carcinoma (SCHNC) treated in a prospective randomized trial in which concomitant postoperative radiochemotherapy with Mitomycin C and Bleomycin (CRT) was compared with radiotherapy only (RT), were analyzed. PATIENTS AND METHODS: Between March 1997 and December 2001, 114 eligible patients with Stage III or IV SCHNC were randomized. Primary surgical treatment was performed with curative intent in all patients. Patients in both groups were postoperatively irradiated to the total dose of 56-70 Gy. Chemotherapy included Mitomycin C 15 mg/m2 after 10 Gy and 5 mg of Bleomycin twice weekly during irradiation. Median follow-up was 76 months (48-103 months). RESULTS: At 5 years in the RT and CRT arms, the locoregional control was 65% and 88% (p = 0.026), disease-free survival 33% and 53% (p = 0.035), and overall survival 37% and 55% (p = 0.091) respectively. Patients who benefited from chemotherapy were those with high-risk factors. The probability of distant metastases was 22% in RT and 20% in CRT arm (p = 0.913), of grade III or higher late toxicity 19% in RT and 26% in CRT arm (p = 0.52) and of thyroid dysfunction 36% in RT and 56% in CRT arm (p = 0.24). The probability to develop a second primary malignancy (SPM) was 34% in the RT and 8% in the CRT arm (p = 0.023). One third of deaths were due to infection, but there was no difference between the 2 groups. CONCLUSION: With concomitant radiochemotherapy, locoregional control and disease free survival were significantly improved. Second primary malignancies in the CRT arm compared to RT arm were significantly less frequent. The high probability of post treatment hypothyroidism in both arms warrants regular laboratory evaluation.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/administração & dosagem , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/cirurgia , Terapia Combinada/métodos , Intervalo Livre de Doença , Seguimentos , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Mitomicina/administração & dosagem , Segunda Neoplasia Primária/etiologia , Probabilidade , Estudos Prospectivos , Dosagem Radioterapêutica , Falha de TratamentoRESUMO
BACKGROUND: Guidance on cardiac surveillance during adjuvant trastuzumab therapy remains elusive. The recommended methods are two-dimensional echocardiography (2D-ECHO) and electrocardiography gated equilibrium radionuclide ventriculography (RNV). We assessed the correlation and possible specific merits of these two methods. METHODS: In a prospective cohort study in patients undergoing post-anthracycline adjuvant trastuzumab therapy, clinical assessment, 2D-ECHO and RNV were performed at baseline, 4, 8 and 12 months. The correlation between used methods was estimated with Pearson's correlation coefficient and Bland-Altman analysis. RESULTS: Ninety-two patients (mean age 53.6±9.0 years) were included. The correlation of LVEF measured by ECHO and RNV at each time point was statistically insignificant. Values obtained by ECHO were on average higher (3.7% to 4.5%). A decline in LVEF of ≥10% from baseline was noticed in 19 (24.4%) and 13 (14.9%) patients with ECHO and RNV, respectively, however in only one patient by both methods simultaneously. A decline in LVEF of ≥10% to below 50% was found in three and none patients according to RNV and ECHO measurements, respectively. CONCLUSIONS: There is a weak correlation of ECHO and RNV measurements in individual patient, the results obtained by the methods are not interchangeable. LVEF values determined by 2D-ECHO were on average higher compared to RNV determined ones. When in an asymptomatic patient a decline in LVEF requiring treatment interruption is detected by RNV ECHO re-evaluation and referral to a cardiologist is advised.
Assuntos
Antineoplásicos/efeitos adversos , Ecocardiografia/métodos , Ventriculografia com Radionuclídeos/métodos , Trastuzumab/efeitos adversos , Adulto , Idoso , Antineoplásicos/administração & dosagem , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/etiologia , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Estudos de Coortes , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Trastuzumab/administração & dosagem , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/diagnóstico por imagem , Função Ventricular EsquerdaRESUMO
PURPOSE: Papillary renal-cell carcinoma type 1 (PRCC1) is associated with MET gene alterations. Our phase II trial prospectively assessed the efficacy and safety of crizotinib in patients with advanced/metastatic PRCC1 with or without MET mutations (MET+ and MET-). EXPERIMENTAL DESIGN: Eligible patients with reference pathology-confirmed PRCC1 received 250 mg oral crizotinib twice daily. Patients were attributed to MET+/MET- sub-cohorts by the sequencing of exons 16-19 of the MET gene in tumour tissue. The primary end-point was objective response rate (ORR). If at least two of the first 12 eligible and evaluable MET+ patients achieved a confirmed partial response (PR) or complete response (CR) (in accordance with the Response Evaluation Criteria in Solid Tumours, version 1.1), a maximum of 35 patients were enrolled. Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), PFS rate (PFSR), overall survival (OS) and safety. RESULTS: Forty-one patients provided consent, of whom 23 were eligible, treated and evaluable. In four MET+ patients, two achieved PR and one had stable disease (SD) (ORR 50%; 95% confidence interval [CI]: 6.8-93.2), DOR was 21.8 and 37.3 months, 1-year PFSR: 75.0% (95% CI: 12.8-96.1) and 1-year OS: 75.0% (95% CI: 12.8-96.1). Among 16 MET- patients, one achieved a PR lasting more than 9.9 months and 11 had SD (ORR: 6.3%; 95% CI: 0.2-30.2), 1-year PFSR: 27.3% (95% CI: 8.5-50.4) and 1-year OS: 71.8% (95% CI: 41.1-88.4). Among three patients with unknown MET status (MET?) due to technical failure, one achieved PR lasting more than 6.9 months, and one had SD (ORR 33.3%, 95% CI: 0.8-90.6), 1-year PFSR: 66.7% (95% CI: 5.4-94.5) and 1-year OS: 100%. MET amplification was found post hoc in one MET+ patient (PR, DOR: 37.3 months), and one MET- case who had SD. Common treatment-related adverse events were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%) and blurred vision (34.8%). CONCLUSION: Crizotinib is active and well tolerated in advanced, metastatic PRCC1, achieving objective responses and long-lasting disease control in patients with MET mutations or amplification. Sporadic, durable responses are also seen in MET- and MET? cases, suggesting the presence of other alterations of MET or alternative pathways.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/tratamento farmacológico , Amplificação de Genes , Neoplasias Renais/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/secundário , Crizotinibe , Intervalo Livre de Doença , Europa (Continente) , Feminino , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/enzimologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
AIM: To evaluate the efficacy and toxicity of preoperative chemoradiotherapy with capecitabine in locally advanced rectal cancer. METHODS: Between June 2004 and January 2005, 57 patients with operable, clinical stage II-III adenocarcinoma of the rectum entered the prospective phase II study. Radiation dose was 45 Gy (25x1.8 Gy). Concurrent chemotherapy with a daily dose of 1650 mg/m2 capecitabine was administered orally, divided into two equal doses per day, including weekends. Patients were evaluated weekly for acute toxicity and compliance with the protocol. Surgery was scheduled 6 weeks after the completion of the chemoradiotherapy. RESULTS: A single female patient died after receiving 27 Gy, because of pulmonary embolism. All other patients completed the preoperative chemoradiotherapy according to the protocol and a definitive operation was performed in all but one of these patients. The complete pathological response was recorded in 5 patients (9.1%). Tumor (T), lymph nodes (N), and overall downstaging rates were 40%, 52.9%, and 49.1%, respectively. Total sphincter preservation rate was 65.5% (36 out of 55 patients) and the rate in 27 patients with tumors located within 5 cm of the anal opening was 37% (10 out of 27 patients). The most frequent side-effect of the combined therapy was dermatitis (grade 3 in 19 patients). After surgery, a single patient died due to sepsis during the early perioperative period. Nonlethal perioperative complications were recorded in 24/55 patients. CONCLUSION: Preoperative chemoradiotherapy with oral capecitabine is safe and well tolerated. It has a downstaging potential and can increase the possibility for sphincter preservation surgery.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Radiossensibilizantes/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Capecitabina , Terapia Combinada , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Dosagem Radioterapêutica , Neoplasias Retais/cirurgiaRESUMO
BACKGROUND: Cardiotoxicity is an important side effect of trastuzumab therapy and cardiac surveillance is recommended. OBJECTIVES: The aim of our study was to prospectively assess baseline patients' characteristics, level of N-terminal pro-brain natriuretic peptide (NT-proBNP) and echocardiographic parameters as possible predictors of trastuzumab-related cardiac dysfunction. METHODS: In a prospective cohort study, clinical, echocardiographic and neurohumoral assessment was performed at baseline, after 4, 8 and 12 months in breast cancer patients undergoing post-anthracycline (3-4 cycles) adjuvant therapy with trastuzumab. Trastuzumab-related cardiac dysfunction was defined as a decline of ≥ 10% in left ventricular ejection fraction (LVEF). RESULTS: 92 patients (mean age, 53.6 ± 9.0 years) were included. Patients who developed trastuzumab-related LVEF decline ≥ 10% (20.6%) during treatment had significantly higher baseline LVEF (70.7 ± 4.4%) than those without (64.8 ± 5.5%) (p = 0.0035). All other measured baseline parameters (age, body mass index, arterial hypertension, level of NT-proBNP and other echocardiographic parameters) were not identified as significant. CONCLUSIONS: Our findings suggest that baseline patient' characteristics, level of NT-proBNP and echocardiographic parameters, as long as they are within normal range, are not a reliable tool to predict early trastuzumab-related cardiac dysfunction in patients undergoing post-low dose anthracycline adjuvant trastuzumab therapy. A LVEF decline in patients with high-normal baseline level although statistically significant is not clinically relevant.
Assuntos
Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Insuficiência Cardíaca/induzido quimicamente , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Trastuzumab/efeitos adversos , Adulto , Idoso , Animais , Pressão Sanguínea/efeitos dos fármacos , Índice de Massa Corporal , Cardiotoxicidade/etiologia , Quimioterapia Adjuvante/efeitos adversos , Ecocardiografia Doppler , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Receptor ErbB-2 , Valores de Referência , Fatores de Risco , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Osteosarcoma patients are commonly treated with cisplatin-based preoperative and postoperative chemotherapy. Cisplatin binds to DNA and forms both intrastrand and interstrand crosslinks, inhibiting DNA replication. Glutathione-S-transferases (GSTs) participate in cisplatin detoxification, while several independent DNA repair mechanisms repair cisplatin-induced lesions. The aim of our study was to investigate the influence of genetic variability of DNA repair mechanisms and GSTs on efficacy and toxicity of cisplatin-based chemotherapy in osteosarcoma patients. METHODS: A total of 66 osteosarcoma patients were genotyped for ERCC1, ERCC2, NBN, RAD51, XRCC3, and GSTP1 polymorphisms, as well as GSTM1 and GSTT1 gene deletion. We determined the influence of polymorphisms on survival and treatment outcome using Cox regression and logistic regression. RESULTS: Carriers of at least one polymorphic ERCC2 rs1799793 allele had longer event-free survival (EFS) (P=0.006; hazard ratio (HR)=0.28; 95% confidence interval (CI)=0.11-0.70). Polymorphic GSTP1 rs1138272 allele was associated with both shorter EFS and OS (P=0.005; HR=3.67; 95%CI=1.47-9.16; and P=0.004; HR=3.52; 95%CI=1.51-8.22, respectively). Compared to the reference NBN CAA haplotype, NBN CGA haplotype was associated with shorter EFS (P=0.001; HR=4.12; 95%CI=1.77-9.56). CONCLUSIONS: Our results suggest that DNA repair polymorphisms and GST polymorphisms could be used as predictive factors for cisplatin-based chemotherapy in osteosarcoma patients and could contribute to treatment personalization.
Assuntos
Glutationa Transferase/genética , Osteossarcoma/genética , Adolescente , Adulto , Cisplatino/administração & dosagem , Reparo do DNA , Feminino , Variação Genética , Humanos , Masculino , Polimorfismo Genético , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Cytotoxic activity of most chemotherapeutic agents is based on their ability to induce DNA damage. Interstrand crosslinks are among the most detrimental forms of DNA damage as both DNA strands are affected. As translesion polymerases participate in their repair, they may be important for response to chemotherapeutic agents that induce such lesions, including commonly used cisplatin. Altered expression of translesion polymerase genes REV1 and REV3L may modify sensitivity to cisplatin. As osteosarcoma patients are commonly treated with cisplatin-based chemotherapy, our aim was to investigate if REV1 and REV3L polymorphisms influence survival of osteosarcoma patients treated with cisplatin-based chemotherapy. We determined the genotypes of common functional tag REV1 and REV3L polymorphisms in 66 osteosarcoma patients. Cox regression was used for survival analysis. Carriers of at least one polymorphic REV1 rs3087403 allele had significantly shorter EFS and overall survival (OS) (p = 0.004; HR = 3.79; 95%CI = 1.53-9.35 and p < 0.001; HR = 4.44; 95%CI = 1.92-10.27, respectively). Combination of REV1 rs3087403 and REV3L rs462779 polymorphisms was also significantly associated with shorter OS (ptrend<0.001) and shorter EFS (ptrend = 0.003). The results of this first study on polymorphisms in translesion polymerase genes in osteosarcoma suggest they could help predict outcome of cisplatin-based chemotherapy in osteosarcoma patients.
Assuntos
Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Haplótipos , Nucleotidiltransferases/genética , Osteossarcoma/genética , Osteossarcoma/mortalidade , Polimorfismo Genético , Adolescente , Adulto , Alelos , Neoplasias Ósseas/patologia , Proteínas de Ligação a DNA/genética , DNA Polimerase Dirigida por DNA/genética , Feminino , Genótipo , Humanos , Masculino , Proteínas Nucleares/genética , Razão de Chances , Osteossarcoma/patologia , Prognóstico , Análise de Sobrevida , Adulto JovemRESUMO
PURPOSE: In a prospective randomized clinical study, simultaneous postoperative application of irradiation (RT), mitomycin C, and bleomycin was tested in a group of patients with operable advanced head-and-neck carcinoma. It was expected that the planned combined postoperative therapy would reduce the number of locoregional recurrences and prolong survival. METHODS AND MATERIALS: A total of 114 eligible patients with Stage III or IV squamous cell head-and-neck carcinoma were randomized to receive postoperative RT alone (Group 1) or RT combined with simultaneous mitomycin C and bleomycin (Group 2). Patients were stratified according to the stage and site of the primary tumor and the presence or absence of high-risk prognostic factors. Primary surgical treatment was performed with curative intent in all patients. Patients in both groups were postoperatively irradiated to the total dose of 56-70 Gy. Chemotherapy included mitomycin C 15 mg/m(2) after 10 Gy and 5 mg of bleomycin twice a week during RT to the planned total dose of 70 mg. RESULTS: At 2 years, patients in the radiochemotherapy group had better locoregional control (86%) than those in the RT alone group (69%; p = 0.037). Disease-free survival and overall survival was also better in the radiochemotherapy group compared with the RT-alone group (76% vs. 60%, p = 0.099; and 74% vs. 64%, p = 0.036, respectively). Patients who benefited from chemotherapy were those with high-risk factors. CONCLUSION: The results of the present study indicate that concomitant postoperative radiochemotherapy with mitomycin C and bleomycin improves locoregional control and survival in patients with advanced head-and-neck carcinoma. The patients who benefited from chemotherapy were those with high-risk factors.