RESUMO
The human papilloma virus (HPV) group comprises approximately 200 genetic types that have a special affinity for epithelial tissues and can vary from producing benign symptoms to developing into complicated pathologies, such as cancer. The HPV replicative cycle affects various cellular and molecular processes, including DNA insertions and methylation and relevant pathways related to pRb and p53, as well as ion channel expression or function. Ion channels are responsible for the flow of ions across cell membranes and play very important roles in human physiology, including the regulation of ion homeostasis, electrical excitability, and cell signaling. However, when ion channel function or expression is altered, the channels can trigger a wide range of channelopathies, including cancer. In consequence, the up- or down-regulation of ion channels in cancer makes them attractive molecular markers for the diagnosis, prognosis, and treatment of the disease. Interestingly, the activity or expression of several ion channels is dysregulated in HPV-associated cancers. Here, we review the status of ion channels and their regulation in HPV-associated cancers and discuss the potential molecular mechanisms involved. Understanding the dynamics of ion channels in these cancers should help to improve early diagnosis, prognosis, and treatment in the benefit of HPV-associated cancer patients.
Assuntos
Neoplasias , Infecções por Papillomavirus , Humanos , Papillomavirus Humano , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/diagnóstico , Neoplasias/diagnóstico , Neoplasias/terapia , Neoplasias/metabolismo , Canais Iônicos/metabolismo , Íons/metabolismoRESUMO
Targeted therapy against cancer plays a key role in delivering safer and more efficient treatments. In the last decades, ion channels have been studied for their participation in oncogenic processes because their aberrant expression and/or function have been associated with different types of malignancies, including ovarian, cervical, and endometrial cancer. The altered expression or function of several ion channels have been associated with tumor aggressiveness, increased proliferation, migration, invasion, and metastasis of cancer cells and with poor prognosis in gynecological cancer patients. Most ion channels are integral membrane proteins easily accessible by drugs. Interestingly, a plethora of ion channel blockers have demonstrated anticancer activity. Consequently, some ion channels have been proposed as oncogenes, cancer, and prognostic biomarkers, as well as therapeutic targets in gynecological cancers. Here, we review the association of ion channels with the properties of cancer cells in these tumors, which makes them very promising candidates to be exploited in personalized medicine. The detailed analysis of the expression pattern and function of ion channels could help to improve the clinical outcomes in gynecological cancer patients.
RESUMO
BACKGROUND: Tyrosine-kinase inhibitors (TKIs) have become the cornerstone treatment of patients with non-small cell lung cancer that harbor oncogenic EGFR mutations. The counterpart of these drugs is the financial burden that they impose, which often creates a barrier for accessing treatment in developing countries. The aim if the present study was to compare the cost-effectiveness of three different first and second generation TKIs. METHODS: We designed a retrospective cost-effectiveness analysis of three different TKIs (afatinib, erlotinib, and gefitinib) administered as first-line therapy for patients with NSCLC that harbor EGFR mutations. RESULTS: We included 99 patients with the following TKI treatment; 40 treated with afatinib, 33 with gefitinib, and 26 with erlotinib. Median PFS was not significantly different between treatment groups; 15.4 months (95% CI 9.3-19.5) for afatinib; 9.0 months (95% CI 6.3- NA) for erlotinib; and 10.0 months (95% CI 7.46-14.6) for gefitinib. Overall survival was also similar between groups: 29.1 months (95% CI 25.4-NA) for afatinib; 27.1 months (95% CI 17.1- NA) for erlotinib; and 23.7 months (95% CI 18.6-NA) for gefitinib. There was a statistically significant difference between the mean TKIs costs; being afatinib the most expensive treatment. This difference was observed in the daily cost of treatment (p < 0.01), as well as the total cost of treatment (p = 0.00095). Cost-effectiveness analysis determined that afatinib was a better cost-effective option when compared with first-generation TKIs (erlotinib and gefitinib). CONCLUSION: In our population, erlotinib, afatinib, and gefitinib were statistically equally effective in terms of OS and PFS for the treatment of patients with advanced EGFR-mutated NSCLC population. Owing to its marginally increased PFS and OS, the cost-effectiveness analysis determined that afatinib was a slightly better cost-effective option when compared with first-generation TKIs (erlotinib and gefitinib).
Assuntos
Afatinib/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Análise Custo-Benefício/métodos , Cloridrato de Erlotinib/administração & dosagem , Gefitinibe/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Adulto , Afatinib/economia , Idoso , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/economia , Feminino , Gefitinibe/economia , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/economia , Estudos RetrospectivosRESUMO
BACKGROUND: Up-to-date oncological therapy has been accomplished through the results of clinical trials (CTs). We analyzed the overall survival (OS) of patients with non-small cell lung cancer (NSCLC) and its relation to CT enrollment. METHODS: The study included 1,042 patients with advanced NSCLC treated at the Instituto Nacional de Cancerología. All patients received treatment according to the national and international guidelines. Data were collected from medical records. Patients were subgrouped on the basis of their CT enrollment as follows: participants in any CT (ACT), exclusively intervention CTs (ICT) or exclusively pharmaceutical-sponsored CTs (PCT). RESULTS: The CT enrollment effect was assessed through a multivariate Cox proportional hazards model. Thirty percent of the patients were in ACT, 28.3% in ICT and 13.7% in PCT. Female gender (p = 0.001), adenocarcinoma histology (p = 0.018), positive EGFR mutation (p = 0.006), and better ECOG performance status (<2) (p ≤ 0.0001) were more frequent in patients enrolled in CT; further, tobacco smoking (p ≤ 0.0001) and KRAS mutation (p = 0.001) were more frequent in patients who were not enrolled in a CT. CONCLUSION: Enrollment in ACT was associated with a better OS (hazard ratio: 0.47-0.74). NSCLC patients enrolled in a CT have an improved survival in an independent manner to other prognostic factors.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos como Assunto , Neoplasias Pulmonares/mortalidade , Participação do Paciente , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores Sexuais , Fumar , Taxa de SobrevidaRESUMO
BACKGROUND: Brain metastases occur in 30-50% of Non-small cell lung cancer (NSCLC) patients and confer a worse prognosis and quality of life. These patients are usually treated with Whole-brain radiotherapy (WBRT) followed by systemic therapy. Few studies have evaluated the role of chemoradiotherapy to the primary tumor after WBRT as definitive treatment in the management of these patients. METHODS: We reviewed the outcome of 30 patients with primary NSCLC and brain metastasis at diagnosis without evidence of other metastatic sites. Patients were treated with WBRT and after induction chemotherapy with paclitaxel and cisplatin for two cycles. In the absence of progression, concurrent chemoradiotherapy for the primary tumor with weekly paclitaxel and carboplatin was indicated, with a total effective dose of 60 Gy. If disease progression was ruled out, four chemotherapy cycles followed. RESULTS: Median Progression-free survival (PFS) and Overall survival (OS) were 8.43 ± 1.5 and 31.8 ± 15.8 months, respectively. PFS was 39.5% at 1 year and 24.7% at 2 years. The 1- and 2-year OS rates were 71.1 and 60.2%, respectively. Three-year OS was significantly superior for patients with N0-N1 stage disease vs. N2-N3 (60 vs. 24%, respectively; Response rate [RR], 0.03; p= 0.038). CONCLUSIONS: Patients with NSCLC and brain metastasis might benefit from treatment with WBRT and concurrent thoracic chemoradiotherapy. The subgroup of N0-N1 patients appears to achieve the greatest benefit. The result of this study warrants a prospective trial to confirm the benefit of this treatment.
Assuntos
Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Pulmonares/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia , Cisplatino/administração & dosagem , Irradiação Craniana , Intervalo Livre de Doença , Feminino , Humanos , Quimioterapia de Indução , Estimativa de Kaplan-Meier , Pulmão/efeitos da radiação , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Estudos RetrospectivosRESUMO
PURPOSE: This randomized phase II trial evaluated whether the combination of cisplatin and paclitaxel (PC) plus all-trans retinoic acid (ATRA) increases response rate (RR) and progression-free survival (PFS) in patients with advanced non-small-cell lung cancer (NSCLC) with an acceptable toxicity profile and its association with the expression of retinoic acid receptor beta 2 (RAR-beta2) as a response biomarker. PATIENTS AND METHODS: Patients with stages IIIB with pleural effusion and IV NSCLC were included to receive PC, and randomly assigned to receive ATRA 20 mg/m(2)/d (RA/PC) or placebo (P/PC) 1 week before treatment until two cycles were completed. RAR-beta2 expression was analyzed in tumor and adjacent lung tissue. RESULTS: One hundred seven patients were included, 55 in the P/PC group and 52 in the RA/PC group. RR for RA/PC was 55.8% (95% CI, 46.6% to 64.9%) and for P/PC, 25.4% (95% CI, 21.3 to 29.5%; P = .001). The RA/PC group had a longer median PFS (8.9 v 6.0 months; P = .008). Multivariate analysis of PFS showed significant differences for the RA/PC group (hazard ratio, 0.62; 95% CI, 0.4 to 0.95). No significant differences in toxicity grade 3/4 were found between groups, except for hypertriglyceridemia (10% v 0%) in RA/PC (P = .05). Immunohistochemistry and reverse-transcriptase polymerase chain reaction assays showed expression of RAR-beta2 in normal tissues of all tumor samples, but only 10% of samples in the tumor tissue. CONCLUSION: Adding ATRA to chemotherapy could increase RR and PFS in patients with advanced NSCLC with an acceptable toxicity profile. A phase III clinical trial is warranted to confirm these findings.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Cisplatino/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Receptores do Ácido Retinoico/análise , Tretinoína/administração & dosagemRESUMO
INTRODUCTION: The combination of chemotherapy and thoracic radiation is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). However, most favorable chemotherapy regimen, timing of full-dose chemotherapy, and optimal combination of chemotherapy with radiation remain to be determined. Our primary objective was to evaluate the efficacy and safety of gemcitabine concurrent with radiotherapy after induction chemotherapy with gemcitabine plus carboplatin for locally advanced NSCLC. PATIENTS AND METHODS: Patients with histologically proven NSCLC stage IIIA and -B received carboplatin (area under the curve of 2.5) and gemcitabine (800 mg/m) on days 1 and 8, every 21 days for two cycles, followed by conventional fractioned thoracic radiotherapy and concomitant weekly gemcitabine 200 mg/m, and finally, consolidation chemotherapy. RESULTS: Inclusion was discontinued because of high-grade 3 to 5 radiation-pneumonitis events (6 of 19 patients, 31.6%), including one treatment-related death associated with radiation pneumonitis. Median follow-up was 11.9 months. Most common grades 3/4 hematological side effects comprised anemia, neutropenia 3 of 19 patients, each (15.8%), and thrombocytopenia (4 of 19, 21.1%) during induction. Partial response was observed in 10 patients (52.6%) following induction chemotherapy. After concurrent chemo-radiotherapy, overall response was 68.4%. Four patients (21.1%) underwent surgical resection. Median progression-free survival and overall survival were 12 +/- 1 month (95% confidence interval [CI], 9.8-14.1) and 21 +/- 3.5 months (95% CI, 14-27.9 months), respectively. CONCLUSION: Concurrent radiotherapy with gemcitabine after induction with gemcitabine and carboplatin showed a high-response rate; however, it is associated with excessive pulmonary toxicity. Adjustments in gemcitabine dosage during radiotherapy or changes in radiotherapy planning could reduce toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Pneumonite por Radiação/epidemiologia , Adulto , Idoso , Área Sob a Curva , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/efeitos adversos , Dosagem Radioterapêutica , Taxa de Sobrevida , GencitabinaRESUMO
BACKGROUND: Central nervous system is a common site of metastasis in NSCLC and confers worse prognosis and quality of life. The aim of this prospective study was to evaluate the prognostic significance of clinical-pathological factors (CPF), serum CEA levels, and EGFR and HER2 tissue-expression in brain metastasis (BM) and overall survival (OS) in patients with advanced NSCLC. METHODS: In a prospective manner, we studied 293 patients with NSCLC in IIIB-IV clinical stage. They received standard chemotherapy. CEA was measured prior to treatment; EGFR and HER2 were evaluated by immunohistochemistry. BM development was confirmed by MRI in symptomatic patients. RESULTS: BM developed in 27, and 32% of patients at 1 and 2 years of diagnosis with adenocarcinoma (RR 5.2; 95% CI, 1.002-29; p = 0.05) and CEA > or = 40 ng/mL (RR 11.4; 95% CI, 1.7-74; p < 0.01) as independent associated factors. EGFR and HER2 were not statistically significant. Masculine gender (RR 1.4; 95% CI, 1.002-1.9; p = 0.048), poor performance status (RR 1.8; 95% CI, 1.5-2.3; p = 0.002), advanced clinical stage (RR 1.44; 95% CI, 1.02-2; p = 0.04), CEA > or = 40 ng/mL (RR 1.5; 95% CI, 1.09-2.2; p = 0.014) and EGFR expression (RR 1.6; 95% CI, 1.4-1.9; p = 0.012) were independent associated factors to worse OS. CONCLUSION: High CEA serum level is a risk factor for BM development and is associated with poor prognosis in patients with advanced NSCLC. Surface expression of CEA in tumor cells could be the physiopathological mechanism for invasion to CNS.
Assuntos
Neoplasias Encefálicas/secundário , Antígeno Carcinoembrionário/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Neoplasias Encefálicas/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/análise , Feminino , Seguimentos , Humanos , Imunoensaio/métodos , Imuno-Histoquímica , Medições Luminescentes/métodos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Receptor ErbB-2/análise , Análise de SobrevidaRESUMO
The incidence of breast cancer in Latin American countries is lower than that in more developed countries, whereas the mortality rate is higher. These differences probably are related to differences in screening strategies and access to treatment. Population-based data are needed to make informed decisions. A 65-question telephone survey that included 100 breast cancer experts from 12 Latin American countries was conducted in 2006 as an exploratory analysis of the current state of breast cancer treatment in these regions at both at the country level and at the center level. Greater than 90% of countries had no national law or guideline for mammography screening. The access rate to mammography was 66.3% at the country level and 47% at the center level. Variation in care based on level (country vs center) was indicated for the timing of treatment after diagnosis, timing from initial diagnosis to treatment, and the time from surgery to initial chemotherapy. However, the more sophisticated diagnostic testing for hormone receptors and biomarkers were available at most centers (>80%), and, overall, nearly 80% of patients started treatment within 3 months of diagnosis. Variation in care between breast cancer care at the center level versus the country level indicated a need for national cancer care programs. Alternative data collection strategies for understanding the state of breast cancer control programs in developing countries can help identify areas of improvement.
Assuntos
Neoplasias da Mama/epidemiologia , Coleta de Dados/estatística & dados numéricos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/economia , Neoplasias da Mama/terapia , Região do Caribe/epidemiologia , Humanos , América Latina/epidemiologia , Programas de Rastreamento , Oncologia , Sociedades Médicas , Inquéritos e QuestionáriosRESUMO
Renal cell carcinoma represents nearly 3% of all cancers, predominantly affecting individuals >or=50 years of age, and until recently, few treatments options were available for metastatic disease. The 5-year median survival for these patients with metastatic renal cell carcinoma has been estimated at <10%. This review explores the data of the most relevant trials focusing on new approaches with novel agents, including sunitinib, sorafenib, bevacizumab, temsirolimus, as well as their combinations with traditional agents. We describe mechanisms of action, activity, and toxicity profile of those agents, as well as administration schedules that have been studied in clinical trials.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Neoplasias Renais/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzenossulfonatos/efeitos adversos , Benzenossulfonatos/uso terapêutico , Bevacizumab , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/cirurgia , Quimioterapia Adjuvante , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Indóis/efeitos adversos , Indóis/uso terapêutico , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Nefrectomia/métodos , Niacinamida/análogos & derivados , Compostos de Fenilureia , Prognóstico , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Sirolimo/efeitos adversos , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Sorafenibe , Sunitinibe , Análise de Sobrevida , Resultado do TratamentoRESUMO
Cervical cancer is the seventh most frequent cancer worldwide but more than 80% of cases occur in developing countries. Till date, radiation therapy with external beam and brachytherapy remains as the core treatment for most stages of cervical cancer. However, radiation treatment protocols and equipment modelled on the best developed countries can be seldom applied directly to developing countries owing to financial constraints and lack of qualified personnel, thus, a substantial proportion of patients do not have access to even palliative radiation therapy. Treatment options when the standard therapy is either not available or difficult to reproduce in particular settings is highly desirable with the potential to save lives that otherwise could be lost by the lack of adequate treatment. These options of treatment ideally had to have show, 1) that these are not inferior to the "standard" in terms of either survival or quality of life; 2) that these can be delivered in settings were the "standard" is not available or if available its quality is poor; and 3) that the treatment option be accepted by the population to be treated. Based on these considerations, it is obvious that cervical cancer patients, particularly those who live in countries with limited resources and therefore may not have sufficient radiation therapy resources are in need of newer therapeutical options. There is now a considerable amount of information emanating from clinical studies where surgery has a major role in treating this disease. These forms of "radiation-sparing" treatments include total mesometrial resection that could make unnecessary the use of adjuvant radiation; neoadjuvant chemotherapy that could avoid the use of adjuvant radiation in around 85% of patients and preoperative chemoradiation that could make brachytherapy dispensable. The feasibility and therapeutical value of these potential forms of management need to be prospectively evaluated.
RESUMO
BACKGROUND: It has been shown that IAPs, in particular XIAP, survivin and c-IAP1, are overexpressed in several malignancies. In the present study we investigate the expression of c-IAP1, c-IAP2, XIAP and survivin and its isoforms in cervical cancer. METHODS: We used semiquantitative RT-PCR assays to analyze 41 cancer and 6 normal tissues. The study included 8 stage I cases; 16 stage II; 17 stageIII; and a control group of 6 samples of normal cervical squamous epithelial tissue. RESULTS: c-IAP2 and XIAP mRNA levels were similar among the samples, cervical tumors had lower c-IAP1 mRNA levels. Unexpectedly, a clear positive association was found between low levels of XIAP and disease relapse. A log-rank test showed a significant inverse association (p = 0.02) between XIAP expression and tumor aggressiveness, as indicated by disease relapse rates. There were no statistically significant differences in the presence or expression levels of c-IAP1 and c-IAP2 among any of the clinical variables studied. Survivin and its isoforms were undetectable in normal cervical tissues, in contrast with the clear upregulation observed in cancer samples. We found no association between survivin expression and age, clinical stage, histology or menopausal state. Nevertheless, we found that adenocarcinoma tumors expressed higher levels of survivin 2B and DeltaEx3 (p = 0.001 and p = 0.04 respectively, by Kruskal-Wallis). A multivariate Cox's partial likelihood-based analysis showed that only FIGO stage was an independent predictor of outcome. CONCLUSION: There are no differences in the expression of c-IAP2 and XIAP between normal vs. cancer samples, but XIAP expression correlate in cervical cancer with relapse of this disease in the patients. Otherwise, c-IAP1 was downregulated in the cervical cancer samples. The expression of survivin was upregulated in the patients with cervical cancer. We have found that adenocarcinoma presented higher levels of survivin isoforms 2B and DeltaEx3.
Assuntos
Proteínas Inibidoras de Apoptose/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/genética , Neoplasias do Colo do Útero/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Adenocarcinoma/química , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Survivina , Neoplasias do Colo do Útero/patologiaRESUMO
BACKGROUND: Globally, cervical cancer primarily affects socially disadvantaged women. Five randomized trials were the foundation for adopting cisplatin-based chemotherapy during radiation as the standard of care for high-risk patients after primary radical hysterectomy who require adjuvant radiation and for locally advanced patients treated with definitive radiation. These results were obtained in clinical trials performed in carefully prepared academic centers; hence, we sought to determine whether these results could be reproduced when patients were treated on an out-of-protocol basis. METHODS: We reviewed the files of 294 patients with locally advanced cervical cancer who received radiation plus weekly cisplatin as routine management between 1999 to 2003, and analyzed treatment compliance, response rate, toxicity, and survival. RESULTS: A total of 294 patients who received radiation and cisplatin were analyzed. Mean age was 43.8 years (range, 26-68 years). The majority of cases were squamous cell carcinoma (87.8%), and distribution according to International Federation of Gynecology and Obstetrics (FIGO) stage was as follows: IB2-IIA, 23%; IIB, 53.3%, and IIIB, 23%; there were only two IVA cases. Overall, 96% of patients completed external beam, and intracavitary therapy. The majority of patients (67%) received the planned six courses of weekly cisplatin. Complete responses were achieved in 243 (83%) patients, whereas 51 (17%) had either persistent (32 patients, 10.8%) or progressive (19 patients, 6.4%) disease. At median follow-up (28 months; range, 2-68 months), 36 patients (12.2%) have relapsed (locally 30.5, and systemically, 69.5%). The most common toxicities were hematologic and gastrointestinal, in the majority of cases considered mild-moderate. At median follow-up (28 months; range, 2-68 months), overall and progression-free survival are 76.5 and 67%, respectively. CONCLUSION: Our results support use of chemoradiation with six weekly applications of cisplatin at 40 mg/m2 during external radiation for routine management of locally advanced cervical cancer.
RESUMO
BACKGROUND: Most cervical cancer patients with pelvic recurrent or persistent disease are not candidates for exenteration, therefore, they only receive palliative chemotherapy. Here we report the results of a novel treatment modality for these patients pre-exenterative chemotherapy- under the rational that the shrinking of the pelvic tumor would allow its resection. METHODS: Patients with recurrent or persistent disease and no evidence of systemic disease, considered not be candidates for pelvic exenteration because of the extent of pelvic tumor, received 3-courses of platinum-based chemotherapy. Response was evaluated by CT scan and bimanual pelvic examination; however the decision to perform exenteration relied on the physical findings. Toxicity to chemotherapy was evaluated with standard criteria. Survival was analyzed with the Kaplan-Meier method. RESULTS: Seventeen patients were studied. The median number of chemotherapy courses was 4. There were 9 patients who responded to chemotherapy, evaluated by bimanual examination and underwent pelvic exenteration. Four of them had pathological complete response. Eight patients did not respond and were not subjected to surgery. One patient died due to exenteration complications. At a median follow-up of 11 months, the median survival for the whole group was 11 months, 3 months in the non-operated and 32 months in those subjected to exenteration. CONCLUSION: Pre-exenterative chemotherapy is an alternative for cervical cancer patients that are no candidates for exenteration because of the extent of the pelvic disease. Its place in the management of recurrent disease needs to be investigated in randomized studies, however, its value for offering long-term survival in some of these patients with no other option than palliative care must be stressed.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Área Sob a Curva , Carboplatina/farmacologia , Cisplatino/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Intervalo Livre de Doença , Feminino , Fluoruracila/farmacologia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Exenteração Pélvica , Projetos Piloto , Recidiva , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Neoplasias do Colo do Útero/mortalidade , GencitabinaRESUMO
PURPOSE: To compare gemcitabine and cisplatin (GC) with cisplatin (C) concurrent with radiotherapy in International Federation of Gynecology and Obstetrics Stage IB2, IIA, and IIB cervical carcinoma in a preoperative setting. The main endpoints were the pathologic response rate and toxicity. METHODS AND MATERIALS: A total of 83 patients were randomized to either C or GC. Treatment consisted of six doses of cisplatin at 40 mg/m(2) every week for Arm 1 (C) and six doses of gemcitabine at 125 mg/m(2) plus cisplatin at 40 mg/m(2) every week for or Arm 2 (GC) Both regimens were administered concurrent with 50 Gy of external beam radiotherapy in 2-Gy fractions for 5 weeks. After chemoradiotherapy, patients underwent radical hysterectomy. RESULTS: All 83 patients were studied for toxicity and 80 for response. The complete pathologic response rate in the C arm and GC arm was 55% (95% confidence interval, 35.5-73%) and 77.5% (95% confidence interval, 57-90%; p = 0.0201). Among those with a partial response, 7 patients each had high and intermediate-high risk factors for recurrence in their surgical specimens in the C arm vs. 2 and 3 patients, respectively, with these characteristics in the CG arm. The number of weekly doses and the dose intensity of GC were lower than for C. The time to complete external beam radiotherapy also favored the C arm. The CG combination produced greater GI and hematologic toxicity. CONCLUSION: The radiosensitizing combination of GC achieved a greater pathologic response rate than C in the treatment of cervical cancer.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Radiossensibilizantes/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Adenoescamoso/tratamento farmacológico , Carcinoma Adenoescamoso/patologia , Carcinoma Adenoescamoso/radioterapia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada , Intervalos de Confiança , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Radiossensibilizantes/efeitos adversos , Dosagem Radioterapêutica , Neoplasias do Colo do Útero/patologia , GencitabinaRESUMO
Oxaliplatin (cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] [oxalato(2-)-O,O'] platinum; Eloxatin) is a third-generation platinum compound with a 1,2-diaminocyclohexane (DACH) carrier ligand, which has a wide spectrum of anticancer activity in vitro systems and has displayed preclinical and clinical activity in a wide variety of tumors. To investigate its in vitro activity against head and neck cancer, we exposed two head and neck cancer cell lines to the compound, created a variant resistant to cisplatin to study cross-resistance to the compound and analyzed the potential radiosensitizing effect of the drug. We report here that oxaliplatin was cytotoxic at similar doses to cisplatin in these cells. There was no cross-resistance to cisplatin, as demonstrated by different IC50 values in these cell lines and the sensitivity to oxaliplatin of the cisplatin-resistant cell line. There was an effective radiosensitizer effect of the compound in either cell line. Additional in vitro and in vivo experimentation is warranted in order to support the use of oxaliplatin as a radiosensitizer in head and neck cancer patients.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Radiossensibilizantes/uso terapêutico , Cisplatino/uso terapêutico , Reações Cruzadas , Resistencia a Medicamentos Antineoplásicos , Humanos , Oxaliplatina , Células Tumorais CultivadasRESUMO
The prognosis of cervical cancer patients with renal failure secondary to obstructive uropathy is poor. Our objective was to analyze our experience in the management with chemoradiation of untreated cervical cancer patients complicated by obstructive nephropathy and kidney dysfunction. Untreated patients with cervical cancer and renal failure as manifested by raised serum creatinine were treated with pelvic radiotherapy concurrently with weekly gemcitabine at 300 mg/m2. Response, toxicity and renal function pre- and post-therapy were evaluated. Eight FIGO stage IIIB and one IVB patients were treated. Pre-treatment serum creatinine ranged from 1.6 to 18.5 mg/100 ml (median 3.3, mean 6.8) and creatinine clearance varied from 4 to 57 mg/ml/min (median 17, mean 22.1). Four patients had a percutaneous nephrostomy placed and four patients had symptoms from kidney failure. All patient completed chemoradiation. Most patients had grade 3 leukopenia and neutropenia. Dermatitis, colitis and proctitis were common. All patients had improvement in creatinine clearance (pre-therapy 22.78, post-therapy 54.3 mg/ml/min) (p=0.0058) and all but one normalized serum creatinine. Eight (89%) of nine patients achieved complete response and one patient had persistence. At a median follow-up of 11 months (range 6-14), all patients are alive, one with pelvic and another with systemic disease. Ureteral obstruction causing any degree of renal insufficiency should not be a contraindication to receive chemoradiation to attempt cure. In this setting where cisplatin-based therapy is contraindicated, the use of gemcitabine may be considered.
Assuntos
Quimioterapia Adjuvante/métodos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Radioterapia Adjuvante/métodos , Insuficiência Renal/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapia , Braquiterapia/métodos , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Creatinina/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/toxicidade , Esquema de Medicação , Avaliação de Medicamentos/métodos , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Testes de Função Renal/métodos , México , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/efeitos adversos , Radiossensibilizantes/uso terapêutico , Insuficiência Renal/complicações , Fatores de Tempo , Resultado do Tratamento , Obstrução Uretral/complicações , Neoplasias do Colo do Útero/complicações , GencitabinaRESUMO
Radiation was until recently the key and only modality for the routine treatment of locally advanced cervical carcinoma. However after years of studying multi-modality treatments as an alternative to radiation alone in randomized phase III trials, the standard treatment has changed to chemo-radiation based on cisplatin. Three recent meta-analyses have confirmed that cisplatin-based chemo-radiation adds an absolute 12% benefit in five-year survival over radiation therapy alone. Neoadjuvant chemotherapy followed by radiation has not been of proven benefit, but when neoadjuvant chemotherapy is followed by surgery, an absolute increase of 15% in five-year survival over radiation alone is seen. This benefit in survival is comparable to that obtained with the current chemo-radiation schedules based on cisplatin. Despite these encouraging results there remains room for improvement as the five-year survival of patients treated with chemo-radiation ranges from nearly 80% in bulky IB tumours to only 25% in stage IVA disease. Other therapeutic approaches need to be fully evaluated including the use of chemo-radiation after neoadjuvant chemotherapy; the use of new drug combinations and the multi-modality combination of neoadjuvant chemotherapy followed by radical surgery plus adjuvant chemo-radiation. Likewise, the addition of radiosensitizers to cisplatin, preoperative chemo-radiation and/or adjuvant chemotherapy may eventually improve the currents results of cisplatin-based chemo-radiation. Nevertheless, it is hard to foresee a dramatic increase in cure rate, even with the most optimal combination of cytotoxic drugs, surgery and radiation, and thus the testing of molecular targeted therapies against cervical cancer is a logical step to follow.
Assuntos
Invasividade Neoplásica/patologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia , Adulto , Idoso , Biópsia por Agulha , Quimioterapia Adjuvante , Ensaios Clínicos Fase III como Assunto , Terapia Combinada , Feminino , Humanos , Histerectomia/métodos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Prognóstico , Radioterapia Adjuvante , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento , Neoplasias do Colo do Útero/mortalidadeRESUMO
PURPOSE: Chemoradiation based on cisplatin, most commonly weekly, is the standard treatment of locally advanced cervical cancer; however, the nephrotoxic potential and the requirement for hydration of cisplatin somewhat restrains its use. The objective of this study was to determine the recommended dose of carboplatin when administered weekly during pelvic radiation (RT). METHODS AND MATERIALS: Twenty-four histologically proven, International Federation of Gynecology and Obstetrics Stage IIIB patients were treated with standard pelvic RT concurrently with six weekly applications of carboplatin at the following dose levels: 100 mg/m(2), 116 mg/m(2), 133 mg/m(2), and 150 mg/m(2). Six patients per level were treated. Acute toxicity was assessed according to the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria. The recommended dose was defined as the one that was one level below the level at which dose-limiting toxicity was present in more than one-third of patients. RESULTS: Between September 2001 and July 2002, 24 patients were accrued. All but two completed external beam radiotherapy and intracavitary treatment. The treatment was well tolerated. The median number of weekly applications of carboplatin was six, and the mean dose to points A and B was 85.6 Gy (range 75.2-91.6) and 62.9 Gy (range 58.2-74.6), respectively. RT was delivered within 41.7 days (range 33-70). Dose-limiting toxicity (leukopenia and/or neutropenia) was present in 50% of patients treated at the higher dose level (150 mg/m(2)). At the recommended dose of 133 mg/m(2), 33% of patients presented with Grade 3 leukopenia. At treatment completion, 75% of patients had a complete clinical response. CONCLUSION: Carboplatin at 133 mg/m(2), weekly for 6 weeks, is a well tolerated and effective radiosensitizer in cervical cancer patients.