ABSTRACT
PURPOSE: To date, studies regarding the use of prophylactic cranial irradiation (PCI) versus standard of care (SoC) for patients with non-small cell lung cancer (NSCLC) have not shown a significant effect in terms of overall survival (OS). Additionally, the effect of PCI among high-risk patients has been scarcely studied. The objective of this randomized phase 2 study was to evaluate the role of PCI in a population of patients at high risk for development of brain metastases (BM). METHODS AND MATERIALS: Eligible patients had histologically confirmed NSCLC without baseline BM, harboring epidermal growth factor receptor mutations, anaplastic lymphoma kinase rearrangements, or elevated carcinoembryonic antigen levels at the time of diagnosis. Participants received systemic therapy according to molecular status, those without progressive disease were then assigned to receive SoC or SoC + PCI (25 Gy in 10 fractions). The primary outcome was cumulative incidence of brain metastases (CBM). The secondary endpoints included progression-free survival and OS. Quality of life and neurocognitive function are discussed in a separate article (Clinicaltrials.gov: NCT01603849). RESULTS: From May 2012 to December 2017, 84 patients were enrolled in the study, with 41 patients allocated to receive PCI and 43 received SoC. Patients allocated to receive PCI had a CBM at 24 months of 7% versus 38% in those allocated to the SoC arm. PCI was associated with a hazard ratio of 0.12 (95% confidence interval, 0.035-0.42) for developing BM. A benefit in OS was also observed (64.5 vs 19.8 months; hazard ratio: 0.41 (95% confidence interval, 0.22-0.78; P =â007). CONCLUSIONS: Among a selected population at high risk for developing BM, PCI significantly decreased CBM in addition to increasing progression-free survival and OS. To our knowledge, this is the first study to evaluate PCI in epidermal growth factor receptor mutations, anaplastic lymphoma kinase rearrangements, or elevated carcinoembryonic antigen levels in patients with NSCLC, showing a significant improvement in CBM. This relevant information should be of particular importance in the context of patients without access to third-generation targeted agents. Further studies are warranted to ascertain this effect.
Subject(s)
Brain Neoplasms/prevention & control , Carcinoma, Non-Small-Cell Lung/prevention & control , Cranial Irradiation , Lung Neoplasms/pathology , Anaplastic Lymphoma Kinase/genetics , Brain Neoplasms/epidemiology , Brain Neoplasms/mortality , Brain Neoplasms/secondary , Carcinoembryonic Antigen/blood , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/secondary , Confidence Intervals , Female , Genes, erbB-1 , Humans , Incidence , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Male , Middle Aged , Progression-Free Survival , Proportional Hazards Models , Quality of Life , Radiation Dose Hypofractionation , Standard of CareABSTRACT
The purpose of this study was to evaluate the role of adjuvant chemotherapy in malignant phyllodes tumors of the breast treated at the Instituto Nacional de Cancerología of Mexico. Twenty-eight patients with malignant phyllodes tumors of the breast enrolled in a observational study from January 1993 to December 2003 to receive four cycles of adjuvant chemotherapy with doxorubicin 65 mg/m(2) over 48 hours intravenous infusion and dacarbazine 960 mg/m(2) over 48 hours intravenous infusion (n = 17) versus observation (n = 11). All patients had surgical resection, and 38% had an axillary dissection. Seven patients (25%) received adjuvant radiotherapy. Log-rank test was used to test for differences in recurrence-free survival (RFS). The median patient age was 42 years (range, 23-76 years). The median tumor size was 13 cm (range, 3-30 cm), and 46% of the tumors were in the left breast. At a median follow-up of 15 months (range, 2-81 months), there were seven recurrences and five deaths. The 5 year RFS rate was 58% (95% CI = 36% and 92%) for the patients who received adjuvant therapy and 86% (95% CI = 63% and 100%) for the patients who did not (p = 0.17). The median survival after recurrence was 6.5 months. Adjuvant chemotherapy with doxorubicin and dacarbazine did not affect patient survival. Future studies to identify relevant molecular targets should be implemented in order to define effective therapies for phyllodes tumors of the breast.
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Breast Neoplasms/drug therapy , Dacarbazine/administration & dosage , Doxorubicin/administration & dosage , Phyllodes Tumor/drug therapy , Adult , Aged , Antineoplastic Agents, Alkylating/administration & dosage , Breast Neoplasms/pathology , Chemotherapy, Adjuvant , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasm Recurrence, Local/prevention & control , Neoplasm Staging , Phyllodes Tumor/pathology , Treatment OutcomeABSTRACT
BACKGROUND: In a recent pilot report, we showed that Smac/DIABLO mRNA is expressed de novo in a subset of cervical cancer patients. We have now expanded this study and analyzed Smac/DIABLO expression in the primary lesions in 109 cervical cancer patients. METHODS: We used immunohistochemistry of formalin-fixed, paraffin-embedded tissue sections to analyze Smac/DIABLO expression in the 109 primary lesions. Seventy-eight samples corresponded to epidermoid cervical cancer and 31 to cervical adenocarcinoma. The median follow up was 46.86 months (range 10-186). RESULTS: Smac/DIABLO was expressed in more adenocarcinoma samples than squamous tumours (71% vs 50%; p = 0.037). Among the pathological variables, a positive correlation was found between Smac/DIABLO immunoreactivity and microvascular density, a marker for angiogenesis (p = 0.04). Most importantly, Smac/DIABLO immunoreactivity was associated with a higher rate of local recurrence in squamous cell carcinoma (p = 0.002, log rank test). No association was found between Smac/DIABLO and survival rates. CONCLUSION: Smac/DIABLO expression is a potential marker for local recurrence in cervical squamous cell carcinoma patients.
Subject(s)
Adenocarcinoma/chemistry , Biomarkers, Tumor/analysis , Carcinoma, Squamous Cell/chemistry , Intracellular Signaling Peptides and Proteins/analysis , Mitochondrial Proteins/analysis , Neoplasm Proteins/analysis , Neoplasm Recurrence, Local/chemistry , Uterine Cervical Neoplasms/chemistry , Adenocarcinoma/blood supply , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Apoptosis , Apoptosis Regulatory Proteins , Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/genetics , Carcinoma, Squamous Cell/blood supply , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Intracellular Signaling Peptides and Proteins/genetics , Kaplan-Meier Estimate , Middle Aged , Mitochondrial Proteins/biosynthesis , Mitochondrial Proteins/genetics , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasm Recurrence, Local/blood supply , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Single-Blind Method , Uterine Cervical Neoplasms/blood supply , Uterine Cervical Neoplasms/mortality , Uterine Cervical Neoplasms/pathologyABSTRACT
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.
Subject(s)
Inhibitor of Apoptosis Proteins/genetics , Microtubule-Associated Proteins/genetics , Neoplasm Proteins/genetics , Uterine Cervical Neoplasms/metabolism , X-Linked Inhibitor of Apoptosis Protein/genetics , Adenocarcinoma/chemistry , Adenocarcinoma/pathology , Cell Line, Tumor , Female , Humans , Neoplasm Staging , Prognosis , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , Survivin , Uterine Cervical Neoplasms/pathologyABSTRACT
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.
Subject(s)
Antineoplastic Agents/therapeutic use , Head and Neck Neoplasms/drug therapy , Organoplatinum Compounds/therapeutic use , Radiation-Sensitizing Agents/therapeutic use , Cisplatin/therapeutic use , Cross Reactions , Drug Resistance, Neoplasm , Humans , Oxaliplatin , Tumor Cells, CulturedABSTRACT
BACKGROUND: Smac/Diablo is a recently identified protein that is released from mitochondria after apoptotic stimuli. It binds IAPs, allowing caspase activation and cell death. In view of its activity it might participate in carcinogenesis. In the present study, we analyzed Smac expression in a panel of cervical cancer patients. METHODS: We performed semi quantitative RT-PCR on 41 cervical tumor and 6 normal tissue samples. The study included 8 stage I cases; 16 stage II; 17 stage III; and a control group of 6 samples of normal cervical squamous epithelial tissue. RESULTS: Smac mRNA expression was below the detection limit in the normal cervical tissue samples. In contrast, 13 (31.7%) of the 41 cervical cancer biopsies showed detectable levels of this transcript. The samples expressing Smac were distributed equally among the stages (5 in stage I, 4 in stage II and 4 in stage III) with similar expression levels. We found no correlation between the presence of Smac mRNA and histology, menopause, WHO stage or disease status. CONCLUSIONS: Smac is expressed de novo in a subset of cervical cancer patients, reflecting a possible heterogeneity in the pathways leading to cervical cancer. There was no correlation with any clinical variable.
Subject(s)
Carrier Proteins/biosynthesis , Mitochondrial Proteins/biosynthesis , Neoplasms, Squamous Cell/genetics , Uterine Cervical Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Apoptosis Regulatory Proteins , Cell Line, Tumor , Female , HeLa Cells/chemistry , HeLa Cells/metabolism , Humans , Intracellular Signaling Peptides and Proteins , Menopause/genetics , Middle Aged , Neoplasm StagingABSTRACT
Objetivo. Realizar un análisis sobre la epidemiología descriptiva de cáncer en el Instituto Nacional de Cancerología de México y sobre las características de la creciente demanda de atención médica. Material y métodos. Se revisó la experiencia de 10 años del Registro Hospitalario de Cáncer en el periodo comprendido entre 1985 y 1994. Resultados. En el periodo de estudio se registraron 28,581 pacientes con confirmación histológica de cáncer. Hubo 8984 (31.4 por ciento) casos en hombres; los tumores más frecuentes fueron en testículo (8.3 por ciento), en pulmón (7.4 por ciento), linfoma no-Hodgkin (7.1 por ciento) y en próstata (5.5 por ciento). Entre las mujeres se presentaron 19597 (68.6 por ciento) casos; el cáncer de cérvix uterino invasor (30.6 por ciento) y el cáncer de mama (20.6 por ciento) representaron más de 50 por ciento del total de pacientes. En 1996 se dieron 108876 consultas; hubo 6492 hospitalizaciones, 36388 sesiones de radioterapia y 9116 administraciones de quimioterapia. Sólo 30 por ciento de la población atendida proviene del Distrito Federal, y la restante reside en los 31 estados de la República. Conclusiones. Es necesario fortalecer los Centros Estatales de Cancerología para la contrarreferencia de pacientes y evitar así la rápida saturación de los servicios médicos de este instituto; así como estimular la creación de registros hospitalarios y colaborar con la Secretaría de Salud para optimizar los programas de detección temprana de cáncer en México
