RESUMEN
BACKGROUND: More than half of colorectal tumors harbor activating mutations in RAS/RAF proteins. Selumetinib (AZD6244, ARRY-142886) is a small molecule kinase inhibitor targeting MEK kinase, downstream of RAS. We examined the efficacy and safety of selumetinib with irinotecan in second-line therapy. METHODS: Patients with K-RAS mutated colorectal cancer, progressing on first-line oxaliplatin-based chemotherapy with bevacizumab, were eligible for this multicenter open-label phase I/II trial. In part A, a dose was determined using a standard "3 + 3" design; in part B, efficacy was determined. The primary endpoint was RECIST response rate. Historical data for irinotecan were used as reference. Secondary endpoints included progression-free survival and overall survival. RESULTS: Thirty-two patients entered the study, and 31 were treated. All had K-RAS exon 2 mutated tumors. In phase I, the recommended oral dose of selumetinib was 75 mg twice per day with intravenous (IV) irinotecan, 180 mg/m² every 2 weeks. Three patients (9.7 %) had partial response . Sixteen patients (51.6 %) had stable disease for ≥4 weeks, including three >1 year. The most common grade 3 adverse events included diarrhea, neutropenia, fatigue, anemia, nausea, and dehydration. The study was terminated before a pre-planned accrual of 45 subjects. CONCLUSIONS: Despite termination before full accrual, the point estimates of RR and median PFS show promising results, suggesting that further investigations of MEK inhibition in the treatment of metastatic colorectal cancer are warranted. Studies combining MEK inhibitors with cytotoxics or other targeted agents may lead to improved clinical activity based on the emerging preclinical data.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Topoisomerasa I/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/uso terapéutico , Estudios de Cohortes , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Terminación Anticipada de los Ensayos Clínicos , Femenino , Humanos , Irinotecán , Quinasas Quinasa Quinasa PAM/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Proyectos Piloto , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Análisis de Supervivencia , Inhibidores de Topoisomerasa I/administración & dosificación , Inhibidores de Topoisomerasa I/efectos adversos , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
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.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Paclitaxel/administración & dosificación , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/efectos adversos , Artralgia/inducido químicamente , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Esquema de Medicación , Neoplasias Esofágicas/patología , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Paclitaxel/efectos adversos , Análisis de Supervivencia , Trombocitopenia/inducido químicamente , Factores de Tiempo , Resultado del TratamientoRESUMEN
With a goal of identifying relations between gene expression and response (mucosal or pathological) or survival in esophageal cancer patients (stages II to IV) receiving oxaliplatin, 5-fluorouracil (5FU) and radiation, we measured in endoscopic primary tumor biopsies from 38 patients, the expression of seven genes (gammaGCS, gammaGT, MRP-2, ERCC-1, XPA, TS and DPD) prior to treatment, 1 week following oxaliplatin alone and at the end of the combined radio-chemotherapy cycle using real time QRT-PCR. A higher pretreatment level of XPA was related to shorter survival with a hazard ratio of 2.43 (90% confidence interval 1.09 to 5.43) using Cox regression modeling. However, multivariate analysis with a Cox model indicated low expression of XPA or TS and combined stages II and III had a higher probability of survival (for XPA: hazard ratio 3.0 and 90% C.I. of 1.3 to 6.9, with adjustment for stage included; for TS: hazard ratio is 1.98 with 90% C.I. of 0.94 to 4.20. The expression of TS, gammaGCS, ERCC-1 and MRP-2 declined from D 1 to the end of the cycle (p<0.05, sign test). A validation and further understanding of the findings need to be carried out in a larger study with a more homogeneous population of patients.
Asunto(s)
Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Fluorouracilo/farmacología , Compuestos Organoplatinos/farmacología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia/métodos , Terapia Combinada , Endoscopía del Sistema Digestivo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/radioterapia , Femenino , Fluorouracilo/administración & dosificación , Expresión Génica/efectos de los fármacos , Humanos , Mucosa Laríngea/efectos de los fármacos , Mucosa Laríngea/metabolismo , Masculino , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Dosis de Radiación , Análisis de Supervivencia , Resultado del TratamientoAsunto(s)
Adenocarcinoma/radioterapia , Neoplasias Esofágicas/radioterapia , Derrame Pericárdico/diagnóstico , Traumatismos por Radiación , Adenocarcinoma/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Diagnóstico Diferencial , Electrocardiografía , Neoplasias Esofágicas/tratamiento farmacológico , Humanos , Masculino , Derrame Pericárdico/diagnóstico por imagen , Derrame Pericárdico/etiología , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Chemotherapy represents the standard treatment for patients with metastatic stomach cancer. Conflicting results have been published regarding the activity of paclitaxel in this setting. Therefore, we developed a phase II study to evaluate an outpatient 3 h infusion of paclitaxel. METHODS: Patients with chemonaive metastatic stomach cancer received paclitaxel 210 mg/m(2) every 3 weeks. Patients with esophageal cancer were not eligible. RESULTS: Twenty-one patients were enrolled. The median age was 55.5 years (range 37-81 years). Two partial responses were observed among the 18 patients evaluable for response and toxicity (response rate 11%, 95% CI: 2-33%). The median time to progression was 10.5 weeks and median survival 23 weeks. There was only one episode of grade IV neutropenia and no episodes of grade 3-4 non-hematological toxicity were observed. CONCLUSION: Paclitaxel exhibited minimal activity in this patient population.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Atención Ambulatoria , Antineoplásicos Fitogénicos/uso terapéutico , Paclitaxel/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/efectos adversos , Esquema de Medicación , Femenino , Humanos , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Paclitaxel/efectos adversos , Neoplasias Gástricas/patologíaRESUMEN
We had previously shown that high gene expressions (mRNA levels) of thymidylate synthase (TS; Leichman et al., J. Clin. Oncol., 15: 3223-3229, 1997) and thymidine phosphorylase (TP; Metzger et al., Clin. Cancer Res., 4: 2371-2376, 1998) in pretreatment tumor biopsies could identify tumors that would be nonresponsive to 5-fluorouracil (5-FU)-based therapy. In this study, we investigated the association between intratumoral gene expression of the pyrimidine catabolism enzyme dihydropyrimidine dehydrogenase (DPD) and the response of colorectal tumors to the same 5-FU-based protocol. DPD expressions were measured by quantitative reverse transcription-PCR in 33 pretreatment biopsies of colorectal tumors from patients who went on to receive treatment with 5-FU and leucovorin (LV). The range of DPD gene expression in those tumors that were nonresponsive to 5-FU was much broader than that of the responding tumors. None of the tumors with basal-level DPD expressions above a DPD:beta-actin ratio of 2.5 x 10(-3) (14 of 33) were responders to 5-FU/LV therapy, whereas those tumors with DPD gene expressions below DPD: beta-actin ratio of 2.5 x 10(-3) had a response rate of 50%. There was no correlation among DPD, TS, and TP expression values in this set of colorectal tumors, which indicated that these gene expressions are independent variables. All of the tumors that responded to 5-FU therapy (11 of 33) had expression values of all three of the genes, TS, TP, and DPD, below their respective nonresponse cutoff values, whereas, in each of the nonresponding tumors, at least one of these gene expressions was high. The patients with low expression of all three of the genes had significantly longer survival than patients with a high value of any one of the gene expressions. The results of this study show that intratumoral gene expression level of DPD is associated with tumor response to 5-FU and that the use of more than one independent determinant of response permits the identification of a high percentage of responding patients.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Enzimas/genética , Fluorouracilo/uso terapéutico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Dihidrouracilo Deshidrogenasa (NADP) , Esquema de Medicación , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Infusiones Intravenosas , Oxidorreductasas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Supervivencia , Timidina Fosforilasa/genética , Timidilato Sintasa/genéticaRESUMEN
CONTEXT: Carcinoma of the esophagus traditionally has been treated by surgery or radiation therapy (RT), but 5-year overall survival rates have been only 5% to 10%. We previously reported results of a study conducted from January 1986 to April 1990 of combined chemotherapy and RT vs RT alone when an interim analysis revealed significant benefit for combined therapy. OBJECTIVE: To report the long-term outcomes of a previously reported trial designed to determine if adding chemotherapy during RT improves the survival rate of patients with esophageal carcinoma. DESIGN: Randomized controlled trial conducted 1985 to 1990 with follow-up of at least 5 years, followed by a prospective cohort study conducted between May 1990 and April 1991. SETTING: Multi-institution participation, ranging from tertiary academic referral centers to general community practices. PATIENTS: Patients had squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, adequate renal and bone marrow reserve, and a Karnofsky score of at least 50. Interventions Combined modality therapy (n = 134): 50 Gy in 25 fractions over 5 weeks, plus cisplatin intravenously on the first day of weeks 1, 5, 8, and 11, and fluorouracil, 1 g/m2 per day by continuous infusion on the first 4 days of weeks 1, 5, 8, and 11. In the randomized study, combined therapy was compared with RT only (n = 62): 64 Gy in 32 fractions over 6.4 weeks. MAIN OUTCOME MEASURES: Overall survival, patterns of failure, and toxic effects. RESULTS: Combined therapy significantly increased overall survival compared with RT alone. In the randomized part of the trial, at 5 years of follow-up the overall survival for combined therapy was 26% (95% confidence interval [CI], 15%-37%) compared with 0% following RT. In the succeeding nonrandomized part, combined therapy produced a 5-year overall survival of 14% (95% CI, 6%-23%). Persistence of disease (despite therapy) was the most common mode of treatment failure; however, it was less common in the groups receiving combined therapy (34/130 [26%]) than in the group treated with RT only (23/62 [37%]). Severe acute toxic effects also were greater in the combined therapy groups. There were no significant differences in severe late toxic effects between the groups. However, chemotherapy could be administered as planned in only 89 (68%) of 130 patients (10% had life-threatening toxic effects with combined therapy vs 2% in the RT only group). CONCLUSION: Combined therapy increases the survival of patients who have squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, compared with RT alone.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Estudios de Seguimiento , Humanos , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
PURPOSE: This was a phase I study of AG 331 to determine systemic tolerance and pharmacokinetics following single and multiple escalating intravenous doses. METHODS: The study was an open-label phase I trial that was divided into two components. In phase IA (single dose), six dose levels from 12.5 to 225 mg/m2 were administered to 18 patients (3 at each dose level) and serial blood samples were collected for 72 h. Upon achieving satisfactory pharmacologic parameters, the multiple dosing component (phase IB) was initiated. Six dose levels from 50 to 800 mg/m2 per day were administered for 5 consecutive days to 18 patients. Pre- and postdose blood samples were obtained on days 1-4 and serial blood samples were collected over 24 h following dose 5. Nonhematologic and hepatic toxicities were assessed, serum AG 331 concentrations were measured and pharmacokinetic parameters determined. RESULTS: Other than fatigue, no severe toxicities were encountered in phase IA. Liver toxicity was manifested by elevations in transaminase first noted at multiple doses of 200 mg/m2 per day for 5 days. Fever and malaise but no myelosuppression were noted. The mean terminal t1/2 following single doses was significantly shorter than the t1/2 following multiple dosing (6.8 vs 9.9 h) and clearance was significantly faster following single doses than following multiple dosing (81.7 vs 30.4 l/h), but no significant difference in Vd was noted. CONCLUSIONS: The dose-related toxicity profile precludes further clinical development at this time. The pharmacokinetics of AG 331 following single and multiple doses showed significant differences.
Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Inhibidores Enzimáticos/efectos adversos , Indoles/efectos adversos , Neoplasias/tratamiento farmacológico , Timidilato Sintasa/antagonistas & inhibidores , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Indoles/farmacocinética , Masculino , Persona de Mediana EdadRESUMEN
The gene expression levels of the nucleoside cleavage enzyme/angiogenic factor thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor, were measured by quantitative reverse transcription-PCR in 38 pretreatment biopsies of colorectal tumors from patients who were subsequently treated with 5-fluorouracil (5-FUra) and leucovorin (LV). The range of TP gene expression (relative mRNA levels) in those tumors nonresponsive to 5-FUra was much broader than that of the responding tumors. In contrast to in vitro studies that had shown that an increased intracellular level of TP potentiates the activity of 5-FUra by converting it to the more cytotoxic nucleoside form 5-fluoro-2'deoxyuridine, tumors with the highest basal TP expressions were nonresponders to 5-FUra/LV therapy. The mean TP mRNA level in the nonresponding tumors was 2.6-fold higher than that of the responding patients. We had shown previously that high expression of thymidylate synthase (TS), the target enzyme of 5-FUra, was also a predictor of nonresponse to 5-FUra (L. Leichman et al, J. Clin. Oncol., 15: 3223-3229, 1997). TP and TS expressions were found to be independent variables in these tumors, so that low expression levels of both TS and TP in tumors predicted a very high response rate (11 of 14) to 5-FUra/LV as well as a significantly longer survival, whereas none (0 of 24) of the patients with high expression of either TP or TS were responders.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Timidina Fosforilasa/genética , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Neoplasias Colorrectales/metabolismo , Humanos , Irinotecán , ARN Mensajero/análisis , Timidilato Sintasa/genéticaRESUMEN
We initiated a retrospective study to determine whether p53 status and thymidylate synthase (TS) protein expression in primary colon tumors influence recurrence and survival for patients with stage II colon cancer. Tumor specimens from 45 consecutive untreated patients with stage II colon cancer were examined for p53 and TS protein expression using immunohistochemistry. The median follow-up was 5.1 years. Eighteen patients had left-sided tumors, and 27 had right-sided tumors. Fourteen of 45 patients (31%) developed recurrence. p53 overexpression was detected in the tumors of 18 patients (40%); 10 patients (55%) with p53 overexpression recurred; and 4 of 27 (15%) without evidence of p53 overexpression recurred (P = 0.002). High TS expression was detected in the tumors of 16 patients (36%): 8 patients (50%) with high TS expression recurred, and 6 patients (21%) with low TS expression recurred (P = 0.027). Patients with p53 overexpression had a significantly poorer survival than did those patients without p53 overexpression (P < 0.001). High TS expression was associated with poor survival (P = 0.004). p53 overexpression and high TS expression were significantly associated with left-sided tumors (P = 0.003 and P = 0.022). Thirteen of 16 patients (81%) with high TS expression also overexpressed p53, and 24 of 29 patients (81%) with low TS expression did not manifest p53 overexpression (P < 0.001). p53 and TS expression in primary stage II colon cancer are associated and appear to influence recurrence and survival. In this pilot study, left-sided tumors demonstrate significantly more p53 overexpression and significantly higher TS expression than do right-sided tumors, which may explain the significantly poorer survival for patients with left-sided tumors.
Asunto(s)
Neoplasias del Colon/metabolismo , Proteínas de Neoplasias/metabolismo , Timidilato Sintasa/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/enzimología , Neoplasias del Colon/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Recent studies suggest that there may be a strong correlation between the p53 status of a tumor and a patient's response to chemotherapy. Therefore, we determined p53 status in 36 patients with disseminated colorectal cancer by cDNA sequencing and immunohistochemical staining, as well as by the gene expression level of thymidylate synthase (TS), the target enzyme of 5-fluorouracil (5-FU), by reverse transcription-PCR. Ten patients (28%) experienced a clinical response to 5-FU chemotherapy. Overall, TS expression and response to chemotherapy were associated: 9 of 18 (50%) patients with TS < or = 3.0 x 10(-3) responded, compared to 1 of 18 (6%) patients with TS > 3.0 x 10(-3) (P = 0.003). p53 mutations were found in 21 of 36 patients (58%) using cDNA cycle sequencing, and p53 protein overexpression was found in 20 of 32 patients (62%) using immunohistochemistry staining. Overall p53 status and response to chemotherapy were associated: 5 of 10 (50%) patients with wild-type p53 or negative p53 staining experienced a response, but only 5 of 26 (19%) patients with mutant p53 or p53 overexpression responded. TS expression, but not expression of p53, was significantly associated with overall survival (P = 0.002). Patients with wild-type p53 had significantly lower TS levels compared to patients with mutated p53 (P = 0.044). In this study, we also present data linking specific p53 point mutations to TS expression levels and resistance to 5-FU. Although the number of patients is relatively small, these results identify p53 status and TS gene expression as associated with response in disseminated colorectal cancer; independent studies are needed to confirm these findings and to provide information leading to a better understanding of the role of 5-FU-based chemotherapy in the treatment of colorectal cancer.
Asunto(s)
Neoplasias Colorrectales/genética , Genes p53/genética , Proteínas de Neoplasias/metabolismo , Mutación Puntual/genética , ARN Mensajero/metabolismo , Timidilato Sintasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Análisis de Supervivencia , Timidilato Sintasa/genéticaRESUMEN
PURPOSE: We have previously shown that relative thymidylate synthase (TS) mRNA levels in primary gastric adenocarcinomas treated with fluorouracil (5-FU) and cisplatin are inversely associated with response and survival. This is a presumed function of TS as a target for 5-FU activity. We now test the hypotheses that the relative mRNA level of the excision repair cross-complementing (ERCC1) gene is inversely associated with response and survival as an independent function of cisplatin efficacy. PATIENTS AND METHODS: Patients had intact, untreated, primary gastric adenocarcinoma cancer and were evaluated for eligibility on a preoperative cisplatin infusion-5-FU protocol. cDNA, derived from primary gastric tumors before chemotherapy, was used to determine ERCC1 mRNA levels, expressed as the ratio of polymerase chain reaction (PCR) product of the ERCC1 gene and the beta-actin gene. RESULTS: The median ERCC1 mRNA level from 38 primary gastric cancers (33 assessable for response) was 5.8 x 10(-3) (range, 1.8 x 10(-3) to 19.5 x 10(-3)). Of 17 responding patients, 13 (76%) were less than or equal to 5.8 x 10(-3) and four were greater than 5.8 x 10(-3) (P = .003). The median survival for patients with ERCC1 mRNA levels less than or equal to 5.8 x 10(-3) has not been reached, whereas for those greater than 5.8 x 10(-3) it was 5.4 months (P = .034). The median TS mRNA level, 3.7 x 10(-3) (range, 0.9 to 18.9) also segregated responsive versus resistant tumors (P = .024). With both ERCC1 and TS mRNA levels below their medians, 11 of 13 patients (85%) responded; with both ERCC1 and TS mRNA levels above their medians, two of 10 patients (20%) responded (P = .003). CONCLUSION: Considered separately, either ERCC1 or TS mRNA levels in a primary gastric adenocarcinoma has a statistically significant relationship to response. ERCC1 mRNA levels have a statistically significant association with survival; in this cohort TS mRNA levels did not reach statistically significant association with survival as in our previous publication. Whether these molecular parameters are independent of each other as predictors of outcome remains to be determined.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Proteínas de Unión al ADN , Endonucleasas , Proteínas/análisis , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Timidilato Sintasa/análisis , Adenocarcinoma/química , Adenocarcinoma/cirugía , Cisplatino/administración & dosificación , Terapia Combinada , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/métodos , Estudios Prospectivos , Proteínas/genética , ARN Mensajero/análisis , Neoplasias Gástricas/química , Neoplasias Gástricas/cirugía , Timidilato Sintasa/genéticaRESUMEN
PURPOSE: Response rates to fluorouracil (5-FU)-based therapy remain low. As new, active agents are being tested, information regarding specific intratumoral genetic determinants of chemotherapy sensitivity or resistance can be used to plan therapy rationally. Intratumoral thymidylate synthase (TS) quantitation may be among the most important determinants of sensitivity or resistance to 5-FU. MATERIALS AND METHODS: Forty-six disseminated colorectal cancer patients had measurable tumor biopsies for polymerase chain reaction (PCR)-based determination of TS mRNA pretreatment. Protracted infusion of 5-FU 200 mg/m2/d for 21 days with weekly intravenous leucovorin 20 mg/m2 each cycle was given. After two cycles, responses were evaluated. Response data were correlated with independently determined intratumoral ratios of TS/beta-actin mRNA for each patient. RESULTS: TS/beta-actin ratios were successfully obtained for 42 patients (91%). TS/beta-actin ratios ranged from 0.3 x 10(-3) to 18.2 x 10(-3) (median, 3.5 x 10[-3]). Twelve patients (26%) responded to treatment (median TS/beta-actin ratio, 1.7 x 10[+3]). Thirty-four patients did not respond (median TS/beta-actin ratio, 5.6 x 10[-3]). No patient with a TS mRNA level greater than 4.1 x 10(-3) responded. The median TS/beta-actin ratio (3.5 x 10[-3]) significantly segregated responders from nonresponders (P = .001). Median survival for patients with TS/beta-actin ratios < or = 3.5 x 10(-3) was 13.6 months; for patients with TS/beta-actin ratios greater than 3.5 x 10(-3), it was 8.2 months (P = .02). CONCLUSION: For this cohort, the intratumoral TS/beta-actin ratio had a statistically significant association with response and survival. This relationship for other 5-FU schedules remains unknown. Confirmation of these data in a larger patient population could lead to determination of therapy for disseminated colorectal cancer based on a specific intratumoral molecular parameter.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Leucovorina/administración & dosificación , Timidilato Sintasa/análisis , Actinas/análisis , Anciano , Antídotos/administración & dosificación , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/patología , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
Quantitative reverse transcription PCR (RT-PCR) was used to measure gene expressions (relative mRNA levels) of p16 and the alternate transcript pl6beta in esophageal and gastric tumors. p16 gene expression was undetectable in 13 of 25 esophageal squamous cell carcinomas. In 11 of these tumors, pl6beta was simultaneously missing whereas two of the pl6-deficient tumors still expressed p16beta. Among 34 esophageal adenocarcinomas and 11 gastric adenocarcinomas, only one tumor lacked p16 expression and all tumors expressed p16beta. p16 sequences were not detectable by PCR in genomic DNA from tumors lacking both p16 and p16beta mRNA, suggesting that the simultaneous loss of both gene expressions resulted from homozygous genomic deletion of the p16 gene. However, DNA from tumors that lacked p16 mRNA but expressed pl6beta did contain the p16 gene, consistent with loss of p16 expression in these tumors by transcriptional suppression. No point mutations in p16 cDNA were detected among 12 that were sequenced, but one p16 cDNA from a squamous cell carcinoma had a 19-base deletion, possibly indicating a splice-site mutation. Among those tumors that expressed p16 mRNA, the gene expression values of both p16 and pl6beta varied over a wide range. In some cases, p16 expression was detectable but low, suggesting that down-regulation of p16 expression may be used in some cases to achieve the funtional equivalent of gene deletion or transcriptional silencing. These results demonstrate that p16 expression patterns differ based on tumor histology and origin. Homozygous deletion of p16 appears to be common in esophageal squamous cell carcinomas but in adenocarcinomas, both gene deletion and transcriptional silencing of p16 were infrequent.
Asunto(s)
Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/biosíntesis , Neoplasias Esofágicas/metabolismo , Genes p16 , Neoplasias Gástricas/metabolismo , Transcripción Genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Carcinoma de Células Escamosas/patología , Cartilla de ADN , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Humanos , Reacción en Cadena de la Polimerasa , ARN Mensajero/biosíntesis , Eliminación de Secuencia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Because only approximately 50% of gastric carcinomas are resectable for cure, the authors hypothesized that effective systemic preoperative (neoadjuvant) chemotherapy, aimed at decreasing the size and extent of the primary tumor and eradicating distant microscopic disease, may increase the rate of resectability and have a greater impact on survival than postoperative (adjuvant) treatment alone. In addition, because the peritoneal cavity is the most common site of first recurrence after successful gastric cancer resection, intraperitoneal (IP) chemotherapy seemed a logical choice for postoperative (adjuvant) treatment. METHODS: Fifty-nine patients with invasive primary gastric adenocarcinoma who were deemed resectable for cure entered a clinical trial that called for 2 cycles of protracted infusion 5-fluorouracil with weekly leucovorin and cisplatin chemotherapy followed by surgery. Approximately 3-4 weeks after potentially curative surgery, patients were scheduled to receive two cycles of IP 5-fluoro-2'deoxyuridine and cisplatin. RESULTS: Of the 59 patients studied, 58 (98%) received both cycles of systemic chemotherapy. Fifty-six patients (95%) underwent surgery: 40 patients (71%) had resections intended to cure for Stage 0-IIIB disease, 15 patients (27%) had palliative surgery for Stage IV gastric carcinoma, and one patient died intraoperatively without being staged. Two patients refused surgery, and the remaining patient died of progressive disease prior to surgery. Thirty-one of the 40 patients who underwent curative surgery completed both cycles of postoperative IP therapy; 4 patients received only 1 cycle. Three patients (5%) died secondary to treatment complications. There were two operative deaths, and one patient died of peritonitis associated with Grade 4 granulocytopenia. Nine of the 40 patients (23%) whose carcinomas were resected for cure had recurrent carcinoma. With a median follow-up period now exceeding 45 months, the calculated median survival for the 59 patients entered into the trial is >4 years. CONCLUSIONS: This program of preoperative systemic and postoperative IP chemotherapy has been found to be safe and appears to decrease gastric carcinoma recurrence rates and increase survival compared with historic controls.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Esquema de Medicación , Femenino , Floxuridina/administración & dosificación , Fluorouracilo/administración & dosificación , Humanos , Infusiones Intravenosas , Infusiones Parenterales , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: The present intergroup phase III randomized study compared combined chemotherapy (CT) plus radiotherapy (RT) treatment versus RT only in patients with locally advanced esophageal cancer. MATERIALS AND METHODS: Two courses of chemotherapy during 50 Gy RT followed by additional two courses of the same CT, versus 64 Gy RT alone were investigated. CT consisted of cisplatin 75 mg/m2 on day 1 [corrected] and fluorouracil (5FU) 1,000 mg/m2/d on days 1 to 4 every 4 weeks with RT and every 3 weeks post-RT. The main objective of the study was to compare overall survival between the two randomized treatment groups. Patients were stratified by tumor size, histology, and degree of weight loss. RESULTS: Sixty-two assessable patients were randomized to receive RT alone, and 61 to the combined arm. Patients characteristics were as follows: squamous cell cancer, 90% versus 85%; weight loss greater than 10 lb, 61% versus 69%; and tumor size, > or = 5 cm, 82% versus 80% on the RT and CT-RT arms, respectively. Systemic side effects, which consisted of nausea, vomiting, and renal and myelosuppression, occurred more frequently on the combined arm, while local side effects were similar in both groups. With a minimum follow-up time of 5 years for all patients, the median survival duration was 14.1 months and the 5-year survival rate was 27% in the combined treatment group, while the median survival duration was 9.3 months with no patients alive at 5 years in the RT-alone group (P < .0001). Additional patients (69) were treated with the same combined therapy and were analyzed. The results of the last group confirmed all of the results obtained with combined CT-RT in the randomized trial, with a median survival duration of 17.2 months and 3-year survival rate of 30%. CONCLUSION: We conclude that cisplatin and 5FU infusion given during and post-RT of 50 Gy is statistically superior to standard 64-Gy RT alone in patients with locally advanced esophageal cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Cisplatino/administración & dosificación , Terapia Combinada , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Dosificación Radioterapéutica , Análisis de SupervivenciaAsunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Antagonistas del Ácido Fólico/efectos adversos , Ácido Fólico/uso terapéutico , Pancitopenia/prevención & control , Estomatitis/prevención & control , Tetrahidrofolatos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Esquema de Medicación , Femenino , Ácido Fólico/administración & dosificación , Antagonistas del Ácido Fólico/farmacocinética , Humanos , Infusiones Intravenosas , Masculino , Neoplasias/tratamiento farmacológico , Pancitopenia/inducido químicamente , Estomatitis/inducido químicamente , Tetrahidrofolatos/farmacocinética , Insuficiencia del TratamientoRESUMEN
UFT is an oral preparation combining the 5-fluorouracil (FU) prodrug tegafur (FT) and uracil (U) in a 1:4 ratio, which is commercially available in Japan for the treatment of breast and gastrointestinal cancers. We sought to determine the tolerance of daily oral UFT and to relate this tolerance to the pharmacokinetics of FT and/or the derived FU, while exploring the possibility of circadian FU kinetics contributing to the results. A 28-day schedule followed by 2 weeks rest was began at the initial level of 300 mg/m2/day administered either at 8 a.m. or at 6 p.m. At the following level, 400 mg/m2/day patients were randomly assigned to a split-dose administration or to the above single, timed dose administration. Intolerance to single dosing was clearly demonstrated, and only the split dosing was advanced to 500 mg/m2/day. When this level proved too toxic, 400 mg/m2 was studied further on a 7 a.m., 3 p.m., and 11 p.m. (every 8 h) schedule. Pharmacology was determined on selected patients. In the single dose administration, areas under the curves of FU were higher following p.m. dosing, although substantial interpatient variation was present. Toxicities (diarrhea and neutropenia) were more severe in patients receiving the drug in single daily doses. We conclude that the kinetics of FT are saturable, with disproportionate increases in area under the curve (and toxicities) as dose levels are increased. With divided dosing, tolerance improves. UFT at a dose of 400 mg/m2/day administered as three divided doses (every 8 h) is suitable for Phase II studies, although toxicity requiring cessation of drug administration prior to completion of 28-day cycles will occur in some patients.