RESUMO
BACKGROUND: Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment. PATIENTS AND METHODS: Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m2 twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function. RESULTS: TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function. CONCLUSIONS: These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Demência Frontotemporal , Neutropenia , Neoplasias Gástricas , Adulto , Humanos , Trifluridina/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Demência Frontotemporal/induzido quimicamente , Uracila/efeitos adversos , Timina/efeitos adversos , Pirrolidinas/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Junção Esofagogástrica/patologia , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológicoRESUMO
BACKGROUND: Trials typically group cancers of the gastro-oesophageal junction (GOJ) with oesophageal or gastric cancer when studying neoadjuvant chemoradiation and perioperative chemotherapy, so the results may not be fully applicable to GOJ cancer. Because optimal neoadjuvant treatment for GOJ cancer remains controversial, outcomes with neoadjuvant chemoradiation versus chemotherapy for locally advanced GOJ adenocarcinoma were compared retrospectively. METHODS: Data were collected from all patients who underwent neoadjuvant treatment followed by surgery for adenocarcinoma located at the GOJ at a single high-volume institution between 2002 and 2017. Postoperative major complications and mortality were compared between groups using Fisher's exact test. Overall survival (OS) and disease-free survival (DFS) were assessed by log rank test and multivariable Cox regression analyses. Cumulative incidence functions were used to estimate recurrence, and groups were compared using Gray's test. RESULTS: Of 775 patients, 650 had neoadjuvant chemoradiation and 125 had chemotherapy. These groups were comparable in terms of clinical tumour and lymph node categories, although the chemoradiation group had greater proportions of white men, complete pathological response to chemotherapy, and smaller proportions of diffuse cancer, poor differentiation, and neurovascular invasion. Postoperative major complications (20.0 versus 17.6 per cent) and 30-day mortality (1.7 versus 1.6 per cent) were not significantly different between the chemoradiation and chemotherapy groups. After adjustment, type of therapy (chemoradiation versus chemotherapy) was not significantly associated with OS (hazard ratio (HR) 1.26, 95 per cent c.i. 0.96 to 1.67) or DFS (HR 1.27, 0.98 to 1.64). Type of recurrence (local, regional, or distant) did not differ after neoadjuvant chemoradiation versus chemotherapy. CONCLUSION: In patients undergoing surgical resection for locally advanced adenocarcinoma of the GOJ, OS and DFS did not differ significantly between patients who had neoadjuvant chemoradiation compared with chemotherapy.
Treating advanced cancer of the gastro-oesophageal junction (GOJ) poses a challenge given its location in the distal oesophagus and proximal stomach, and whether it should be treated as oesophageal or gastric cancer. Given the indistinct location, it is unclear whether GOJ cancer should be treated with neoadjuvant chemoradiation, which is the treatment of choice for advanced oesophageal cancers, or perioperative chemotherapy, which is the treatment of choice for advanced gastric cancers. Few studies have addressed treatment options specifically for GOJ cancers. This study investigated whether there was a difference in survival between patients with GOJ cancer who were treated with chemoradiation versus chemotherapy.
Assuntos
Adenocarcinoma/terapia , Antineoplásicos/uso terapêutico , Neoplasias Esofágicas/terapia , Esofagectomia/efeitos adversos , Junção Esofagogástrica , Estadiamento de Neoplasias , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Idoso , Quimiorradioterapia Adjuvante , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/mortalidade , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , New York/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida/tendênciasRESUMO
BACKGROUND: Metastatic gastric cancer and cancer of the esophagogastric junction (GC/EGJ) is an aggressive disease with poor prognosis. In the TAGS study, trifluridine/tipiracil (FTD/TPI) improved overall survival (OS) compared with placebo in heavily pre-treated patients. This unplanned, exploratory subgroup analysis of the TAGS study aimed to clarify outcomes when FTD/TPI was used as third-line (3L) treatment and fourth- or later-line (4L+) treatment. PATIENTS AND METHODS: Patients were divided into a 3L group (126 and 64 in FTD/TPI and placebo arms, respectively) and 4L+ group (211 and 106 in FTD/TPI and placebo arms, respectively). Endpoints included OS, progression-free survival (PFS), time to Eastern Cooperative Oncology Group performance status (ECOG PS) deterioration to ≥2, and safety. RESULTS: Baseline characteristics were generally well balanced between FTD/TPI and placebo for 3L and 4L+ treatment. Median OS (mOS) for FTD/TPI versus placebo was: 6.8 versus 3.2 months {hazard ratio (HR) [95% confidence interval (CI)] = 0.68 (0.47-0.97), P = 0.0318} in the 3L group; and 5.2 versus 3.7 months [0.73 (0.55-0.95), P = 0.0192] in the 4L+ group. Median PFS for FTD/TPI versus placebo was 3.1 versus 1.9 months [0.54 (0.38-0.77), P = 0.0004] in the 3L group; and 1.9 versus 1.8 months [0.57 (0.44-0.74), P < 0.0001] in the 4L+ group. Time to deterioration of ECOG PS to ≥2 for FTD/TPI versus placebo was 4.8 versus 2.0 months [HR (95% CI) = 0.60 (0.42-0.86), P = 0.0049] in the 3L group; and 4.0 versus 2.5 months [0.75 (0.57-0.98), P = 0.0329] in the 4L+ group. The safety of FTD/TPI was consistent in all subgroups. CONCLUSIONS: This analysis confirms the efficacy and safety of FTD/TPI in patients with GC/EGJ in third and later lines with a survival benefit that seems slightly superior in 3L treatment. When FTD/TPI is taken in 3L as recommended in the international guidelines, physicians can expect to provide patients with an mOS of 6.8 months.
Assuntos
Neoplasias Colorretais , Neoplasias Gástricas , Humanos , Pirrolidinas , Neoplasias Gástricas/tratamento farmacológico , Timina , Trifluridina/uso terapêutico , UracilaRESUMO
Chikungunya virus (CHIKV) is an important reemerging human pathogen transmitted by mosquitoes. The virus causes an acute febrile illness, chikungunya fever, which is characterized by headache, rash, and debilitating (poly)arthralgia that can reside for months to years after infection. Currently, effective antiviral therapies and vaccines are lacking. Due to the high morbidity and economic burden in the countries affected by CHIKV, there is a strong need for new strategies to inhibit CHIKV replication. The serotonergic drug 5-nonyloxytryptamine (5-NT) was previously identified as a potential host-directed inhibitor for CHIKV infection. In this study, we determined the mechanism of action by which the serotonin receptor agonist 5-NT controls CHIKV infection. Using time-of-addition and entry bypass assays, we found that 5-NT predominantly inhibits CHIKV in the early phases of the replication cycle, at a step prior to RNA translation and genome replication. Intriguingly, however, no effect was seen during virus-cell binding, internalization, membrane fusion and genomic RNA (gRNA) release into the cell cytosol. In addition, we show that the serotonin receptor antagonist methiothepin mesylate (MM) also has antiviral properties toward CHIKV and specifically interferes with the cell entry process and/or membrane fusion. Taken together, pharmacological targeting of 5-HT receptors may represent a potent way to limit viral spread and disease severity.IMPORTANCE The rapid spread of mosquito-borne viral diseases in humans puts a huge economic burden on developing countries. For many of these infections, including those caused by chikungunya virus (CHIKV), there are no specific treatment possibilities to alleviate disease symptoms. Understanding the virus-host interactions that are involved in the viral replication cycle is imperative for the rational design of therapeutic strategies. In this study, we discovered an antiviral compound, elucidated its mechanism of action, and propose serotonergic drugs as potential host-directed antivirals for CHIKV.
Assuntos
Febre de Chikungunya/tratamento farmacológico , Febre de Chikungunya/virologia , Vírus Chikungunya/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Triptaminas/farmacologia , Animais , Antivirais/farmacologia , Linhagem Celular , Vírus Chikungunya/fisiologia , Chlorocebus aethiops , Humanos , Fusão de Membrana/efeitos dos fármacos , RNA Viral/genética , Serotonina/análogos & derivados , Serotonina/farmacologia , Serotoninérgicos/metabolismo , Serotoninérgicos/farmacologia , Células Vero , Ligação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosAssuntos
Receptores ErbB , Neoplasias Esofágicas , Cetuximab , Quimiorradioterapia , Humanos , Terapia NeoadjuvanteRESUMO
BACKGROUND AND SCOPE: The management of GOJ cancers remains controversial and may vary between countries. Evidence-based attitudes and guidelines are not easy to elaborate since most of the trials and studies reported mixed cases of oesophageal (both adenocarcinoma and squamous cell tumours), GOJ and gastric cancers. The aim of this expert discussion and position paper is to elaborate practical recommendations that integrate evidence-reported literature and experience-based attitude covering all clinical aspects of GOJ cancer across different specialities and countries in Europe. METHODOLOGY: Opinion leaders, selected on scientific merit were asked to answer to a prepared set of questions covering the approach of GOJ tumours from definition to therapeutic strategies. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine. RESULTS: Definition, classification, diagnosis and staging of GOJ tumours were updated and debated. Therapeutic aspects including endoscopic therapy, surgical management, both multimodal curative and palliative management were also reviewed for proposing practical and consensual positions and recommendations whenever possible. CONCLUSION: GOJ tumours deserve specific attention,not only for uniformising clinical management across countries but also for performing specific clinical and translational research,mainly in the curative perioperative setting.
Assuntos
Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Junção Esofagogástrica/patologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Congressos como Assunto , Tratamento Farmacológico , Endoscopia Gastrointestinal , Esofagostomia , Medicina Baseada em Evidências , Gastrectomia , Humanos , Oncologia , Estadiamento de Neoplasias , Apoio Nutricional , Cuidados Paliativos , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Sociedades Médicas , Espanha , Organização Mundial da SaúdeRESUMO
This study looks at toxicity and survival data when chemoradiation (CRT) is delivered using intensity-modulated radiation therapy (IMRT) after induction chemotherapy. Forty-one patients with esophageal adenocarcinoma treated with IMRT from March 2007 to May 2009 at Memorial Sloan-Kettering Cancer Center were analyzed. All patients received induction chemotherapy prior to CRT. Thirty-nine percent (n = 16) of patients underwent surgical resection less than 4 months after completing CRT. Patients were predominantly male (78%), with a median age of 68 years (range 32-85 years). The majority of acute treatment-related toxicity was hematologic or gastrointestinal, with 17% of patients having grade 3+ hematologic toxicity and 12% of patients having grade 3+ gastrointestinal toxicity. Only two patients developed grade 2-3 pneumonitis (5%) and 5 patients experienced post-operative pulmonary complications (29%). Eight patients (20%) required a treatment break. With a median follow up of 41 months for surviving patients, 2-year overall survival was 61%, and the cumulative incidences of local failure (LF) and distant metastases were 40% and 51%, respectively. This rate of LF was reduced to 13% in patients who underwent surgical resection. Surgery and younger age were significant predictors of decreased time to LF on univariate analysis. Induction chemotherapy followed by CRT using IMRT in the treatment of esophageal cancer is well tolerated and is not associated with an elevated risk of postoperative pulmonary complications. The use of IMRT may allow for integration of more intensified systemic therapy or radiation dose escalation for esophageal adenocarcinoma, ultimately improving outcomes for patients with this aggressive disease.
Assuntos
Adenocarcinoma/secundário , Adenocarcinoma/terapia , Quimiorradioterapia Adjuvante/efeitos adversos , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Recidiva Local de Neoplasia , Radioterapia de Intensidade Modulada , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Quimiorradioterapia Adjuvante/métodos , Esofagectomia/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Humanos , Quimioterapia de Indução/efeitos adversos , Irinotecano , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Compostos de Platina/administração & dosagem , Radioterapia de Intensidade Modulada/efeitos adversos , Taxa de Sobrevida , Carga TumoralRESUMO
Chemoradiotherapy for locally advanced esophageal squamous cell carcinoma is associated with high rates of pathological complete response. A pathological complete response is recognized to be an important predictor of improved survival, to the extent that observation rather than surgery is advocated by some in patients with presumed pathological complete response based on their clinical response. The goal of this study was to look at the ability of clinical variables to predict pathological complete response after chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. We reviewed retrospectively patients with locally advanced esophageal squamous cell carcinoma who underwent chemoradiotherapy followed by surgery and compared those with pathological complete response to patients with residual disease. Between January 1996 and December 2010, 116 patients met inclusion criteria. Fifty-six percent of patients had a pathological complete response and a median survival of 128.1 months versus 28.4 months in patients with residual disease. When compared with patients with residual disease, patients with a pathological complete response had a lower post-neoadjuvant positron emission tomography (PET) maximum standardized uptake value (SUVmax), a larger decrease in PET SUVmax, a less thick tumor on post-chemoradiotherapy computed tomography and a higher rate of normal appearing post-chemoradiotherapy endoscopy with benign biopsy of the tumor bed. However, none of these characteristics alone was able to correctly identify patients with a pathological complete response, and none has significant specificity. Although the rate of pathological complete response after chemoradiotherapy is high in patients with esophageal squamous cell carcinoma, the ability of identifying patients with pathological complete response is limited. A reduction of the PET SUVmax by >70%, a normal appearing endoscopic examination, and no residual disease on biopsy all were seen in >65% of the patients with a pathological complete response. Even if these findings were unable to confirm the absence of residual disease in the primary tumor, they can help guide expectant management in high-risk patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Técnicas de Apoio para a Decisão , Neoplasias Esofágicas/terapia , Terapia Neoadjuvante , Idoso , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Esofagectomia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Indução de Remissão , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: To characterise recurrence patterns and survival following pathologic complete response (pCR) in patients who received preoperative therapy for localised gastric or gastrooesophageal junction (GEJ) adenocarcinoma. METHODS: A retrospective review of a prospective database identified patients with pCR after preoperative chemotherapy for gastric or preoperative chemoradiation for GEJ (Siewert II/III) adenocarcinoma. Recurrence patterns, overall survival, recurrence-free survival, and disease-specific survival were analysed. RESULTS: From 1985 to 2009, 714 patients received preoperative therapy for localised gastric/GEJ adenocarcinoma, and 609 (85%) underwent a subsequent R0 resection. There were 60 patients (8.4%) with a pCR. Median follow-up was 46 months. Recurrence at 5 years was significantly lower for pCR vs non-pCR patients (27% and 51%, respectively, P=0.01). The probability of recurrence for patients with pCR was similar to non-pCR patients with pathologic stage I or II disease. Although the overall pattern of local/regional (LR) vs distant recurrence was comparable (43% LR vs 57% distant) between pCR and non-pCR groups, there was a significantly higher incidence of central nervous system (CNS) first recurrences in pCR patients (36 vs 4%, P=0.01). CONCLUSION: Patients with gastric or GEJ adenocarcinoma who achieve a pCR following preoperative therapy still have a significant risk of recurrence and cancer-specific death following resection. One third of the recurrences in the pCR group were symptomatic CNS recurrences. Increased awareness of the risk of CNS metastases and selective brain imaging in patients who achieve a pCR following preoperative therapy for gastric/GEJ adenocarcinoma is warranted.
Assuntos
Adenocarcinoma/mortalidade , Neoplasias Esofágicas/mortalidade , Junção Esofagogástrica , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Gástricas/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Idoso , Neoplasias Encefálicas/secundário , Terapia Combinada , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapiaRESUMO
Pre- and peri-operative strategies are becoming standard for the management of localized gastro-esophageal cancer. For localized gastric/gastro-esophageal junction (GEJ) cancer there are conflicting data that a peri-operative approach with cisplatin-based chemotherapy improves survival, with the benefits seen in esophageal cancer likely less than a 5-10% incremental improvement. Further trends toward improvement in local control and survival, when combined chemotherapy and radiation therapy are given pre-operatively, are suggested by recent phase III trials. In fit patients, a significant survival benefit with pre-operative chemoradiation is seen in those patients who achieve a pathologic complete response. In esophageal/GEJ cancer, definitive chemoradiation is now considered in medically inoperable patients. In squamous cell carcinoma of the esophagus, surgery after primary chemoradiation is not clearly associated with an improved overall survival, however, local control may be better. In localized gastric/GEJ cancer, the integration of bevacizumab with pre-operative chemotherapy is being explored in large randomized studies, and with chemoradiotherapy in pilot trials. The addition of anti-epidermal growth factor receptor and anti-human epidermal growth factor receptor-2 antibody treatment to pre-operative chemoradiation continues to be explored. Early results show the integration of targeted therapy is feasible. Metabolic imaging can predict early response to pre-operative chemotherapy and biomarkers may further predict response to pre-operative chemo-targeted therapy. A multimodality approach to localized gastro-esophageal cancer has resulted in better outcomes. For T3 or node-positive disease, surgery alone is no longer considered appropriate and neo-adjuvant therapy is recommended. The future of neo-adjuvant strategies in this disease will involve the individualization of therapy with the integration of molecular signatures, targeted therapy, metabolic imaging and predictive biomarkers.
RESUMO
BACKGROUND: Esophageal small-cell carcinoma (SCC) is rare, highly malignant and the optimal treatment approach has not been defined. PATIENTS AND METHODS: We report the largest single-institution retrospective review of patients with esophageal and gastroesophageal (GE) junction SCC. RESULTS: Twenty-five patients were identified, with complete records available for 22. Eighty-two percent were male, 82% had pure SCC histology and 86% of tumors were in the lower esophagus or GE junction. On the basis of the Veterans' Administration Lung Study Group criteria, 14 patients (64%) presented with limited disease (LD). Median survival was 19.8 months (range, 1.5 months to 11.2+ years); for LD patients, 22.3 months (range, 6 months to 11.2+ years); for extensive disease (ED) patients, 8.5 months (range, 1.5 months to 2.2 years, P = 0.02). With a median follow-up of 38 months, six patients (27%) are alive, one with ED and five with LD. Two LD patients are alive and free of disease for >5 years. Four of the five LD patients who are long-term survivors received induction chemotherapy followed by chemoradiotherapy without surgery. CONCLUSIONS: Our data indicate that patients with LD esophageal SCC treated with induction chemotherapy followed by consolidative chemoradiation can achieve long-term survival. The contribution of surgery remains unclear.
Assuntos
Carcinoma de Células Pequenas/mortalidade , Carcinoma de Células Pequenas/terapia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/terapia , Junção Esofagogástrica , Idoso , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Pequenas/secundário , Terapia Combinada , Neoplasias Esofágicas/patologia , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: This study evaluated the long-term effects of high-glucose (GLU) and high-sucrose (SUC) diets on the development of obesity, abdominal fat deposition, glucose intolerance, oxidative stress and effects on delta-aminolevulinate dehydratase (delta-ALA-D) activity in various organs. In particular, the effect of aging on these parameters was evaluated. METHODS: Mice were assigned to a baseline, control, or experimental group. The control group was provided with tap water and experimental groups with solutions of glucose or sucrose for 30 wk. To verify the effect of aging, young mice (baseline group, 8 wk old) were compared with aged animals (control and experimental groups, 38 wk old). RESULTS: Consumption of GLU or SUC diets caused increases in body weight, abdominal fat index, and fasting plasma glucose levels. A positive correlation was observed between the abdominal fat index and fasting glucose levels. There was a significant increase in levels of thiobarbituric acid-reactive species (TBARS) and a significant decrease in delta-ALA-D activity in various tissues of GLU and SUC feeding mice. Importantly, the dithiothreitol-induced enzymatic reactivation in the GLU and SUC groups was significantly higher than in the control group, and in the aged group it was significantly higher than in the baseline group. After 30 wk, the experimental groups had a decrease in delta-ALA-D activity and an increase in TBARS levels in relation to the baseline group. CONCLUSION: Alterations in the activity of the delta-ALA-D found in this work demonstrate the possible contributions of hyperglycemia and aging for protein oxidation, leading to impairment of its biologic function.
Assuntos
Envelhecimento/metabolismo , Sacarose Alimentar/administração & dosagem , Glucose/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Sintase do Porfobilinogênio/metabolismo , Gordura Abdominal/metabolismo , Animais , Glicemia/metabolismo , Masculino , Camundongos , Sintase do Porfobilinogênio/antagonistas & inibidores , Distribuição Aleatória , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Aumento de Peso/efeitos dos fármacos , Aumento de Peso/fisiologiaRESUMO
We present a single institution experience with 5-FU, mitomycin-C based chemoradiation for the primary treatment of elderly patients with oesophageal cancer. Twenty-five patients with a median age of 77 years (range 66-88) with a diagnosis of stage II-III squamous cell or adenocarcinoma of the oesophagus were treated at Memorial Sloan Kettering from 1996 to 2001 with two cycles of concurrent 5-FU, mitomycin-C and 50.4 Gy. Owing to age and comorbidity, these patients were not considered surgical candidates. The Charlson comorbidity score was used to evaluate patient comorbidity. Nine patients (36%) experienced grade 3-4 haematologic toxicity. Of the 23 patients evaluable for response, 17 patients (68%) had a negative post-treatment endoscopy and CT scan without evidence of progressive disease. Eleven patients (44%) are alive and 10 (40%) remain without evidence of recurrent or progressive oesophageal cancer at a median follow-up of 35 months. The median overall survival was 35 months and 2-year survival 64%. There was no significant difference in overall survival between Charlson score =2 and those with a score >/=2 (P=0.10). Similar survival was observed for patients with adenocarcinoma or squamous carcinoma. Primary chemoradiation with two cycles of 5-FU, mitomycin-C, and 50.4 Gy in elderly patients is an active regimen with moderate toxicity, despite the advanced age and heavy comorbidity burden of this cohort. Patients with local/regional oesophageal cancer with adequate functional status should not be excluded from potentially curative treatment based on age alone.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Adenocarcinoma/mortalidade , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/mortalidade , Terapia Combinada , Neoplasias Esofágicas/mortalidade , Fluoruracila/administração & dosagem , Humanos , Mitomicina/administração & dosagem , Análise de SobrevidaRESUMO
BACKGROUND: The purpose of the study was to evaluate the efficacy of weekly paclitaxel (Taxol) in advanced esophageal cancer. PATIENTS AND METHODS: One hundred and two patients with advanced esophageal cancer were treated with paclitaxel 80 mg/m2 weekly over a 1-h infusion. One cycle was defined as 4 weeks of therapy. Ninety-five patients were assessable for toxicity and 86 patients who completed at least two cycles of treatment were assessable for response. Sixty-six patients had adenocarcinoma (66%) and 65 patients (68%) had no prior chemotherapy. RESULTS: A median of three cycles was delivered (range 1-11). Partial responses (PRs) were seen in 11 patients [13%, 95% confidence interval (CI) 6% to 20%]. In patients without prior chemotherapy, PRs were seen in 10 patients (15%, 95% CI 6% to 24%), with comparable response in adenocarcinoma (8/50, 16%) and squamous carcinoma (2/15, 13%). Limited response was seen in patients with prior chemotherapy (1/21, 5%). The median duration of response was 172 days. The median survival was 274 days. Therapy was well tolerated with minimal hematologic or grade 3 or 4 toxicity. CONCLUSION: Weekly paclitaxel has limited activity in esophageal cancer. The median survival, modest activity, and tolerance of therapy indicate that weekly paclitaxel may be an option in patients unable to tolerate combination chemotherapy.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Paclitaxel/administração & dosagem , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/efeitos adversos , Artralgia/induzido quimicamente , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Esquema de Medicação , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Paclitaxel/efeitos adversos , Análise de Sobrevida , Trombocitopenia/induzido quimicamente , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Accurate response assessment is essential for evaluating new cancer treatments. We evaluated the impact of Response Evaluation Criteria in Solid Tumors (RECIST), World Health Organization (WHO) criteria and tumor shape on response assessment in patients with metastatic esophageal cancer. PATIENTS AND METHODS: In 19 patients with metastatic esophageal cancer in a phase II trial of bryostatin-1 and paclitaxel, response was retrospectively assessed for 89 lesions with RECIST and WHO criteria on baseline and serial follow-up CT scans. The eccentricity factor (EF) was introduced for measuring the degree to which tumor shape diverges from a perfect sphere [EF = radical1-(LPD/MD)(2), where LPD is the largest perpendicular diameter and MD is the maximal diameter]. RESULTS: The disagreement rate in best overall response categorization between RECIST (unidimensional) and WHO (bidimensional) criteria was 26.3%. Change in eccentricity was significantly greater (P < 0.01) for patients with disagreement (mean 0.31, range 0-0.91). When the short axis was used for unidimensional lymph node measurement, disagreement between WHO and RECIST lessened. CONCLUSIONS: Response assessment by WHO and RECIST differs substantially. Greater change in eccentricity is associated with greater discordance between WHO and RECIST. The discordance between WHO and RECIST may impact on how effective a therapy is judged to be.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/terapia , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Briostatinas , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Metástase Linfática , Macrolídeos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/patologia , Paclitaxel/administração & dosagem , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: ras genes encode Ras proteins that are important for signal transduction in cancer cells. Farnesyl protein transferase (FPTase) is an enzyme that is responsible for a critical post-translational modification of Ras. PATIENTS AND METHODS: We report the results of a phase II trial of SCH 66336, an FPTase inhibitor, in patients with metastatic colorectal cancer. This is the first reported experience of an FPTase inhibitor in this disease. All patients were considered refractory to first- and second-line therapy. A total of 21 evaluable patients were treated with a starting dose of 200 mg b.i.d. given continuously. RESULTS: The major side-effects were fatigue (grade 1 in 42%, grade 2 in 42% and grade 3 in 14%), diarrhea (grade 1 in 23% and grade 3 in 42%) and nausea (grade 2 in 16%). Elevations in serum creatinine (grade 2 or 3) were observed in 19% of patients and appeared to be related to dehydration induced by diarrhea. Significant hematological toxicity was not observed (only grade 1 thrombocytopenia in 19% and grade 2 or 3 anemia in 28%). Pharmacological studies revealed adequate mean pre-dose plasma concentrations in this group of patients on day 15 of therapy. No objective responses were observed, although stable disease was seen in three patients for several months. Administration of SCH 66336 was accompanied by gastrointestinal toxicity. CONCLUSIONS: Future development of this compound cannot be recommended as monotherapy in this disease.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/administração & dosagem , Fluoruracila/administração & dosagem , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistência a Medicamentos , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Resultado do TratamentoRESUMO
Exatecan mesylate (DX-8951f) is a topoisomerase I inhibitor that has increased solubility and antitumor activity compared with other topoisomerase I inhibitors. The purpose of this study was to establish a safe dose of DX-8951f given as a weekly 24-h infusion 3 of every 4 weeks. DX-8951f was administered as a 24-h continuous infusion in escalating doses. Twenty-seven patients were treated with 81 courses of the drug. Dose-limiting toxicities included neutropenia, thrombocytopenia, and inability to administer all three doses in the first cycle. In minimally pretreated patients, a dose of 0.8 mg/m(2) was tolerable. In patients who were heavily pretreated, a slightly lower dose, 0.53 mg/m(2), was tolerated without any severe toxicities. Nonhematological toxicities were mild and consisted of mild diarrhea, asthenia, mild nausea, and constipation. Pharmacokinetic parameters could be well described with a one-compartment model in most patients, although the application of the one-compartment model probably resulted in an underestimated elimination half-life. In conclusion, the recommended Phase II dose for DX-8951f administered as a weekly 24-h infusion on a 3-of-4 week schedule is 0.8 mg/m(2) in minimally pretreated patients and 0.53 mg/m(2) in patients who are heavily pretreated.
Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Camptotecina/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase I , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Infusões Intravenosas , Leucopenia/induzido quimicamente , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/urina , Neutropenia/induzido quimicamente , Trombocitopenia/induzido quimicamenteRESUMO
Cancers of the esophagus, stomach, and pancreas account for 11% of American cancer deaths and have a high case fatality rate. For esophageal cancer, the superiority of chemoradiotherapy rather than radiotherapy alone as a nonsurgical management was reaffirmed by a large pattern-of-care study in the United States. The study of preoperative chemoradiotherapy followed by surgery continues, with the investigation of newer chemotherapeutic agents combined with radiotherapy in an attempt to improve the therapeutic index of therapy. Trials attempting to intensify chemoradiotherapy treatments have included the addition of postoperative chemotherapy, the addition of brachytherapy, and the escalation of radiotherapy dose above the standard dose of 50.4 Gy. Neither brachytherapy nor an increase in external beam radiotherapy dose has been proven to improve local tumor control or patient survival. Adjuvant chemotherapy alone may have an impact on patient survival in one preliminary report, despite the results of earlier trials that failed to show a benefit for adjuvant chemotherapy alone. In the adjuvant treatment of gastric cancer, a meta-analysis of adjuvant chemotherapy trials suggested a survival benefit for adjuvant chemotherapy compared with surgery alone; however, preliminary reports of two large adjuvant chemotherapy trials using cisplatin-based chemotherapy failed to improve survival compared with surgery alone. The large Intergroup Trial 116, comparing surgery alone to surgery followed by postoperative fluorouracil, leucovorin, and radiotherapy, indicated a significant survival benefit for postoperative chemoradiotherapy. Postoperative chemoradiotherapy is the new standard of care for high-risk resected gastric cancer. Ongoing and future trials will address the inclusion of newer chemotherapeutic agents, the use of preoperative chemotherapy and radiotherapy, and the use of intraperitoneal therapy. In the adjuvant treatment of pancreatic cancer, clinical trials continue to evaluate the role of fluorouracil and radiotherapy, the use of preoperative chemoradiotherapy, and the incorporation of new therapeutic agents.
Assuntos
Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , HumanosRESUMO
PURPOSE: Flavopiridol is the first cyclin-dependent kinase inhibitor to enter clinical trials. Activity in gastric cancer xenografts and in a patient with gastric cancer on the phase I trial led to this phase II study of flavopiridol in patients with metastatic gastric cancer. PATIENTS AND METHODS: Sixteen patients were entered onto the study, and 14 were assessable for response. Flavopiridol was administered initially at a dose of 50 mg/m(2)/d by continuous infusion for 72 hours every 2 weeks. Assessment of plasma pharmacokinetics was performed in all patients. Peripheral mononuclear cells were collected throughout the 72-hour infusion for determinants of apoptosis. RESULTS: There were no major objective responses (exact confidence interval 0% to 23%). One patient achieved a minor response in his liver metastases, though the primary progressed. Other patients exhibited histologic and radiographic evidence of tumor necrosis. Common toxicities included fatigue in 93% of patients (grade 3 or 4 in 27%) and diarrhea in 73% of patients (grade 3 or 4 in 20%). Five patients (33%) developed venous thromboses at the central catheter tip. The studies performed on peripheral mononuclear cells indicated no induction of apoptosis. CONCLUSION: Flavopiridol administered as a single agent for 72 hours every 14 days is inactive in the treatment of gastric cancer. The drug also induced an unexpected higher incidence of vascular thrombosis and fatigue than was anticipated from the phase I trials. Future development of flavopiridol will depend on other doses and schedules in combination with chemotherapy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Flavonoides/uso terapêutico , Piperidinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Antineoplásicos/farmacologia , Fadiga/induzido quimicamente , Feminino , Flavonoides/farmacologia , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Piperidinas/farmacologia , Neoplasias Gástricas/patologia , Trombose Venosa/etiologiaRESUMO
Irinotecan (CPT-11, Camptosar) a topoisomerase I inhibitor derived from the Chinese shrub Camptotheca acuminata, has broad activity in varied gastrointestinal malignancies, including pancreatic, biliary, esophageal, and stomach cancers. Using cisplatin (Platinol) plus irinotecan as a backbone for chemotherapy, a combination for which in vitro synergy and possible sequence dependency have been identified, several clinical trials are being conducted combining these two drugs with other chemotherapeutic agents and radiation. This article reviews a recently reported phase II study of cisplatin and irinotecan in esophageal cancer, and provides a preliminary report of two ongoing phase I studies of cisplatin/irinotecan/paclitaxel (Taxol); and cisplatin/irinotecan/fluorouracil (5-FU) in advanced gastrointestinal malignancies. Early results of an ongoing phase I study of cisplatin, irinotecan, and radiation in resectable and locally advanced unresectable esophageal cancer is also discussed. Preliminary data on all of these combinations suggest promising activity in upper gastrointestinal malignancies.