RESUMEN
BACKGROUND: The impact of glycemic control in patients with pancreatic cancer treated with neoadjuvant therapy is unclear. METHODS: Glycated hemoglobin (HbA1c) values were measured in patients with localized pancreatic cancer prior to any therapy (pretreatment) and after neoadjuvant therapy prior to surgery (preoperative). HbA1c levels greater than 6.5% were classified as abnormal. Patients were categorized based on the change in HbA1c levels from pretreatment to preoperative: GrpA, always normal; Gr B, worsened; GrpC, improved; and GrpD, always abnormal. RESULTS: Pretreatment HbA1c levels were evaluable in 123 patients; there were 67 (55%) patients in GrpA, 8 (6%) in GrpB, 22 (18%) in GrpC, and 26 (21%) in GrpD. Of the 123 patients, 92 (75%) completed all intended therapy to include surgery; 57 (85%) patients in GrpA, 4 (50%) patients in GrpB, 16 (72%) patients in GrpC, and 15 (58%) patients in GrpD (p = 0.01). Elevated preoperative carbohydrate antigen 19-9 (CA19-9) (OR 0.22;[0.07-0.66]), borderline resectable (BLR) disease stage (OR 0.20;[0.01-0.45]) and abnormal preoperative HbA1c (OR 0.30;[0.11-0.90]) were negatively associated with completion of all intended therapy. Abnormal preoperative HbA1c was associated with a 2.74-fold increased odds of metastatic progression during neoadjuvant therapy (p = 0.08). CONCLUSIONS: Elevated preoperative HbA1c is associated with failure to complete neoadjuvant therapy and surgery and a trend for increased risk of metastatic progression.
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Hemoglobina Glucada/metabolismo , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/terapia , Anciano , Anciano de 80 o más Años , Antígeno CA-19-9/sangre , Quimioradioterapia Adyuvante , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Metástasis de la Neoplasia , Pancreatectomía , Neoplasias Pancreáticas/patología , Resultado del TratamientoRESUMEN
The lethal effects of combinations of adriamycin (ADR) and either hydroxyurea (HU) or 1-beta-d-arabinofuranosylcytosine (ara-C) were studied in relation to drug-scheduling interval in Sarcoma 180 cells grown in vitro. Drug lethality was determined by cell cloning in soft agar. Serial kinetic changes induced by a priming dose of HU or ara-C were monitored by flow cytometry and related to schedule-dependent cell killing by ADR. All drug exposures were for 1 hr. When ADR was given together with either HU or ara-C, cell log kill was additive. However, when ADR was given after exposure to either HU or ara-C, cell killing was increased up to 200- to 500-fold, respectively. Maximum schedule-dependent synergism was observed at a drug-scheduling interval of 2 hr; schedule-dependent synergism decreased as the interval between drugs was increased beyond 2 hr. Schedule-dependent synergism was not observed when the same drug combinations were given in reversed order. Drug-induced changes in the DNA histogram were not seen until 5 hr after HU exposure and 8 hr after ara-C exposure. Thus, the schedule-dependent synergism between ADR and either HU or ara-C cannot be explained by cell cycle blockade with synchronization of cells in S phase.
Asunto(s)
Citarabina/administración & dosificación , Doxorrubicina/administración & dosificación , Hidroxiurea/administración & dosificación , Sarcoma 180/tratamiento farmacológico , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Sinergismo Farmacológico , Quimioterapia Combinada , RatonesRESUMEN
The lethal and sublethal effects of sangivamycin (SGM) were studied in sarcoma 180 in vitro in relation to drug concentration and duration of drug exposure. SGM lethality was found to be dependent on both drug concentration and duration of drug exposure. Pronounced effects on cell survival were observed only when SGM exposure was prolonged; with prolonged drug exposure, small increments in SGM concentration resulted in large increases in cell killing. Log-phase cells were more susceptible to the lethal effects of SGM than were early-plateau-phase cells. Measurements of incorporation of [3H]thymidine and [3H]uridine into the acid-insoluble cell fraction demonstrated inhibition of both DNA and RNA synthesis by SGM which was also dependent on drug concentration and duration of drug exposure, reflecting the lethality characteristics of SGM. As SGM concentration was increased, DNA synthesis was inhibited more rapidly than was RNA synthesis. Flow cytometry demonstrated a concentration- and time-dependent accumulation of cells in the late S and G2-M region of the DNA histogram. Our findings indicate that maximum lethality is obtained by prolongation of SGM exposure, and they suggest that pharmacokinetic studies may be important for determining regimens which provide such exposure in humans.
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Antibióticos Antineoplásicos/farmacología , Nucleósidos de Pirimidina/farmacología , Sarcoma Experimental/tratamiento farmacológico , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Células Clonales/efectos de los fármacos , ADN de Neoplasias/biosíntesis , Cinética , Ratones , ARN Neoplásico/biosíntesisRESUMEN
Imiquimod [1-(2-methylpropyl)-1H-imidazo[4,5c]quinolin-4-amine] is a compound of low molecular weight that, when administered p.o., induces interferon-alpha in several animal species and inhibits tumor growth in mice. To determine maximum tolerated dose, toxicity, and biological response in humans, a phase I clinical trial was conducted with 14 eligible cancer patients who received 100-500 mg imiquimod p.o. either once or twice weekly. Imiquimod induced interferon-alpha in serum in 10 of 19 doses of 200-300 mg. Interferon serum levels peaked 8-24 h after treatment and reached a maximum of 23,000 IU/ml in one patient. Significant mean increases (P < 0.01) in serum beta 2-microglobulin (1.5-fold), serum neopterin (3.5-fold), and 2-5A synthetase activity in peripheral blood mononuclear cells (7.9-fold) indicated that 200-300 mg imiquimod had biological and immunological activity in all evaluable patients. Increases in serum interferon, beta 2-microglobulin, and neopterin correlated significantly with dose (P < 0.001). No patient developed measurable antibody to interferon-alpha. Dose-limiting side effects included fatigue, malaise, fever, headache, and lymphocytopenia; no hepatic or renal toxicity or other hematological changes exceeded the normal range. Patients tolerated weekly doses of up to 500 mg, with the longest treatment lasting 4 weeks at 200 mg weekly. Twice-weekly doses up to to 300 mg were tolerated, with the longest twice-weekly treatments being 200 mg for 9 weeks and 100 mg for 25 weeks. No clinical responses were observed. Imiquimod, as an oral inducer of interferon, may have therapeutic usefulness in human cancers, viral infections, and other diseases. However, before initiation of phase II trials, additional work will be required to establish a tolerated dose and schedule for continued administration.
Asunto(s)
Aminoquinolinas/toxicidad , Inductores de Interferón/toxicidad , Neoplasias/terapia , 2',5'-Oligoadenilato Sintetasa/sangre , Administración Oral , Aminoquinolinas/administración & dosificación , Autoanticuerpos/sangre , Biopterinas/análogos & derivados , Biopterinas/sangre , Esquema de Medicación , Monitoreo de Drogas , Humanos , Imiquimod , Inductores de Interferón/administración & dosificación , Interferón-alfa/sangre , Interferón-alfa/inmunología , Estadificación de Neoplasias , Neoplasias/sangre , Neoplasias/inmunología , Neoplasias/patología , Neopterin , Factor de Necrosis Tumoral alfa/análisis , Microglobulina beta-2/análisisRESUMEN
Conventional therapy for leukemic meningitis includes cranial irradiation and intrathecal chemotherapy administered by repeated lumbar punctures or direct intraventricular instillation via an Ommaya reservoir. Several clinical reports have indicated that high doses of cytosine arabinoside (ara-C) are effective in the treatment of acute leukemia refractory to standard induction therapy. Pharmacokinetic studies have demonstrated that high doses of ara-C given intravenously obtain sustained therapeutic drug concentrations in the cerebrospinal fluid, suggesting that this approach may be useful in the treatment of systemic disease associated with meningeal involvement. Five consecutive patients with overt meningeal leukemia were treated using only systemic chemotherapy containing high-dose ara-C. In all patients there was prompt resolution of neurologic symptoms and signs accompanied by cytologic clearing of leukemic cells from the cerebrospinal fluid.
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Citarabina/administración & dosificación , Leucemia/tratamiento farmacológico , Neoplasias Meníngeas/tratamiento farmacológico , Enfermedad Aguda , Adulto , Anciano , Evaluación de Medicamentos , Femenino , Humanos , Inyecciones Intravenosas , Leucemia/líquido cefalorraquídeo , Masculino , Neoplasias Meníngeas/líquido cefalorraquídeo , Persona de Mediana Edad , RecurrenciaRESUMEN
PURPOSE: Diethyldithiocarbamate (DDTC) blocks cisplatin-induced toxicities in animal models without inhibiting antitumor effects. DDTC chemoprotection was tested in a randomized, multicenter, double-blind comparison versus placebo (PB) in patients with lung or ovarian cancer. Primary end points were nephrotoxicity, ototoxicity, neuropathy, and completion of therapy. PATIENTS AND METHODS: Between April 1990 and February 1992, 221 patients were registered with small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), or ovarian cancer. Cisplatin (100 mg/m2) and cyclophosphamide (in ovarian cancer) or etoposide (in lung cancer) were administered with either DDTC (1.6 g/m2 over 4 hours) or PB intravenously, every 4 weeks for a planned six cycles. RESULTS: At an interim safety analysis, data were available for 195 patients from the combined lung and ovarian cancer populations (PB, 99 patients; DDTC, 96 patients). Withdrawal for chemotherapy-induced toxicities occurred in 9% of PB-treated patients and 23% of DDTC-treated patients (P = .008). The mean cisplatin delivered dose-intensity (DDI) was 23 mg/m2/wk on both arms. However, the mean cisplatin cumulative dose delivered (CDD) was 379 mg/m2 on the PB arm, compared with 247 mg/m2 on the DDTC arm (P = .0001). At the time of interim analysis, 28% of PB-treated patients had completed all six cycles of therapy, compared with only 6% of DDTC-treated patients (P < .001). Although, clinical hearing loss, neuropathy, emesis, and myelosuppression were equivalent in the two treatment arms, DDTC-treated patients had more nephrotoxicity as determined by changes in serum creatinine concentration. Toxicities related to DDTC infusion included transient hypertension, flushing, and hyperglycemia. DDTC did not compromise response rates in either tumor type. CONCLUSION: This study did not demonstrate a significant chemoprotective effect against cisplatin-induced toxicities with the DDTC dose schedule tested. Patients who received DDTC received lower cumulative doses of cisplatin, but were more likely to be withdrawn from treatment early due to chemotherapy-related toxicities.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Cisplatino/toxicidad , Ditiocarba/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Cisplatino/administración & dosificación , Ditiocarba/administración & dosificación , Ditiocarba/toxicidad , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , PlacebosRESUMEN
A patient with systemic recurrence of large-cell malignant lymphoma developed radiologic evidence of parenchymal brain metastasis. Treatment with systemic high-dose cytarabine resulted in complete regression of peripheral adenopathy and complete radiologic response in the central nervous system, with normalization of the brain computed tomographic scan. This case further demonstrates the ability of high-dose cytarabine to penetrate the blood-brain barrier and achieve therapeutic drug concentrations in the central nervous system, an area that might otherwise remain a pharmacologic sanctuary for tumor cells.
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Cuerpo Calloso , Citarabina/uso terapéutico , Lóbulo Frontal , Linfoma/tratamiento farmacológico , Neoplasias de la Columna Vertebral , Neoplasias Encefálicas/secundario , Citarabina/administración & dosificación , Femenino , Humanos , Infusiones Parenterales , Linfoma/secundario , Persona de Mediana EdadRESUMEN
A prospective, randomized, controlled, double-blind study was performed between 1982 and 1985 to assess the ability of ketoconazole to prevent fungal infections in selected patients with cancer. Fifty-six patients receiving induction chemotherapy for acute leukemia, autologous bone marrow transplant for refractory nonhematopoietic malignant neoplasms, multidrug chemotherapy for malignant lymphoma, or corticosteroids for brain metastases were randomized to receive either oral ketoconazole, 400 mg/d, or placebo and observed until leukopenia resolved or corticosteroid therapy was stopped. Oral candidiasis developed in eight (28%) of 29 patients receiving placebo compared with none of 27 receiving ketoconazole. However, ketoconazole failed to prevent Candida esophagitis and vulvovaginitis in two patients and one patient, respectively. Furthermore, prophylactic use of ketoconazole did not significantly alter the total number of hospital days, febrile days, or antibiotic days or the requirement for amphotericin B in patients with acute leukemia and autologous bone marrow transplant. Since oral candidiasis can be successfully managed by several different treatment modalities when it does occur, we do not think that the routine prophylactic use of ketoconazole is justified.
Asunto(s)
Candidiasis/prevención & control , Cetoconazol/uso terapéutico , Neoplasias/complicaciones , Candidiasis/etiología , Candidiasis Bucal/prevención & control , Ensayos Clínicos como Asunto , Método Doble Ciego , Humanos , Terapia de Inmunosupresión/efectos adversos , Estudios Prospectivos , Distribución AleatoriaRESUMEN
In a prospective, randomized, double-blind, multicenter study, 202 patients with cancer from 19 medical centers were treated for hypercalcemia of malignancy with daily intravenous infusions of etidronate disodium (136 patients) or saline alone (66 patients) for 3 consecutive days. Patients also received up to 3.25 L of saline daily during the treatment period. Of 157 patients for whom data could be evaluated for efficacy, 63% (72/114) of etidronate-treated and 33% (14/43) of saline-treated patients had a normalization of total serum calcium levels. When serum calcium levels were adjusted for albumin (147 assessable patients), 24% of the etidronate- and 7% of the saline-treated patients responded to treatment. No serious side effects or treatment-related deaths occurred. When accompanied by adequate hydration and diuresis, intravenous etidronate was safe and more effective than hydration and diuresis alone in controlling hypercalcemia of malignancy.
Asunto(s)
Ácido Etidrónico/uso terapéutico , Hipercalcemia/tratamiento farmacológico , Neoplasias/complicaciones , Método Doble Ciego , Ácido Etidrónico/administración & dosificación , Femenino , Fluidoterapia , Humanos , Hipercalcemia/etiología , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The synthetic polynucleotide polyadenylic-polyuridylic acid (polyA:polyU) has shown antitumor activity in murine studies and human breast cancer. PolyA:polyU was evaluated in 25 cancer patients receiving weekly intravenous doses between 3 and 600 mg/m2. PolyA:polyU was well tolerated up to 600 mg/m2, with no doselimiting toxicity (all < grade 3). Side effects included mild elevation in temperature, fatigue, and mild hyperglycemia. No changes outside of the normal range in hematocrit, WBC count, platelet count, total bilirubin, or alkaline phosphatase were observed. Of 25 patients, 18 completed at least one cycle of 6 weeks, and 5 completed two cycles (median 6 weeks). Four patients had stable disease over 11-13 weeks of treatment, and no clinical responses were observed. At 24 h after the first treatment, there were no significant increases in biologic response (beta 2-microglobulin and neopterin in serum, or 2',5'-oligoadenylate synthetase in peripheral blood mononuclear cells). A small increase in beta 2-microglobulin was observed 24 h after the week 3 treatment (1.1-fold, p < 0.01). By the third week of treatment, 2-5A synthetase levels decreased slightly (to 80% of baseline, p < 0.01). No changes in cytokines IL-6, IL-12, tumor necrosis factor (TNF), or IL-2 receptor in serum were detected after 24 h of treatment. Thus, at these doses, polyA:polyU had no marked modulation on biologic responses in vivo, although this preparation significantly induced 2-5A synthetase in peripheral blood mononuclear cells in vitro. PolyA:polyU was well tolerated. An MTD was not reached but was greater than 600 mg/m2 on this weekly schedule.
Asunto(s)
Antineoplásicos/uso terapéutico , Inductores de Interferón/uso terapéutico , Neoplasias/terapia , Poli A-U/uso terapéutico , 2',5'-Oligoadenilato Sintetasa/sangre , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Biopterinas/análogos & derivados , Biopterinas/análisis , Citocinas/sangre , Fatiga/inducido químicamente , Femenino , Fiebre/inducido químicamente , Humanos , Hiperglucemia/inducido químicamente , Inductores de Interferón/efectos adversos , Inductores de Interferón/farmacología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/análisis , Neoplasias/sangre , Neoplasias/patología , Neopterin , Poli A-U/efectos adversos , Poli A-U/farmacología , Resultado del Tratamiento , Microglobulina beta-2/análisisRESUMEN
Hypercalcemia, a complication that develops in 10% to 20% of patients with cancer, results from disruption of the normal physiologic mechanisms that closely regulate calcium homeostasis. Most patients with hypercalcemia are seriously dehydrated, and this volume depletion further compromises the kidney's ability to excrete calcium. Replenishment of extracellular fluid, restoration of intravascular volume, and maintenance of saline diuresis are the cornerstones of initial therapy. In most patients, pharmacologic inhibition of abnormally increased osteoclastic resorption is necessary to normalize serum calcium and achieve long-term control. The severity of the hypercalcemia and the patient's renal function, bone marrow reserve, and anticipated response to specific antineoplastic agents can all influence the selection of an antihypercalcemic agent. Available drugs for initial therapy include calcitonin, plicamycin, and etidronate; several additional investigational agents have shown promising efficacy in controlling hypercalcemia of malignancy. The bisphosphonates have an excellent safety profile and appear to be the agents of choice for initial and long-term management of cancer-related hypercalcemia.
Asunto(s)
Hipercalcemia/terapia , Neoplasias/complicaciones , Humanos , Hipercalcemia/tratamiento farmacológico , Hipercalcemia/etiologíaRESUMEN
A prospective, randomized trial of induction chemotherapy in advanced squamous cell carcinomas of the upper aerodigestive tract (UAD) was conducted between July 1979 and September 1982. Eighty-three patients with locally advanced Stage III-IV tumors received standard treatment (STD RX; defined as preoperative irradiation and radical excision or irradiation alone), or induction chemotherapy (CTX) followed by STD RX. Chemotherapy consisted of two cycles of bleomycin (30 units/day by continuous infusions Days 1-4), cyclophosphamide (200 mg/m2 IV Days 1-5), methotrexate (30 mg/m2 Days 1 + 5), and 5-fluorouracil (400 mg/m2 IV Days 1-5). Response to CTX was complete in 2 and partial (greater than 50% reduction) in 27; the overall response rate was 68%. Tumor clearance was documented in 30/40 STD RX patients at completion of irradiation and/or surgery and in 24/43 CTX patients (17/29 responders, 7/14 non-responders). Freedom from local-regional disease was noted at 2 years in 53% STD RX and 35% CTX patients (p less than .06). CTX patients had a higher proportion of local-regional persistence and recurrence. The difference was apparent only in the subset of patients treated with primary irradiation; local-regional control following irradiation and surgery was equal in STD RX and CTX groups. Survival at 2 years was 43% STD RX and 31% CTX. Disease-free survival in those with clearance was 64% STD RX and 59% CTX. Induction chemotherapy did not improve tumor clearance or survival in this series. Caution regarding local-regional control with CTX and primary irradiation is noted.
Asunto(s)
Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeza y Cuello/terapia , Bleomicina/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirugía , Terapia Combinada , Ciclofosfamida/administración & dosificación , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Neoplasias Laríngeas/terapia , Metotrexato/administración & dosificación , Neoplasias de la Boca/terapia , Neoplasias Faríngeas/terapia , Factores de TiempoRESUMEN
BACKGROUND: Cell cycle arrest after DNA damage is partly mediated through the transcriptional activation of p21(WAF1) by the p53 tumor suppressor gene. p21(WAF1) and p53 are both critical in maintaining cell cycle control in response to DNA damage from radiation or chemotherapy. Therefore, we examined the role of p21(WAF1) and p53 in the determination of outcome for patients who receive radiation and/or chemotherapy for pancreatic cancer. METHODS: p21(WAF1) and p53 protein expression were determined (with the use of immunohistochemistry) in specimens from 90 patients with pancreatic cancer. Forty-four patients underwent surgical resection, and 46 patients had either locally unresectable tumors (n = 9 patients) or distant metastases (n = 37 patients). Seventy-three percent of the patients who underwent resection and 63% of the patients who did not undergo resection received radiation and/or chemotherapy. RESULTS: p21(WAF1) expression was present in 48 of 86 tumors (56%) and was significantly (P<.05) associated with advanced tumor stage. Median survival among patients with resected pancreatic cancer who received adjuvant chemoradiation with p21(WAF1)-positive tumors was significantly longer than in patients with no p21(WAF1) staining (25 vs. 11 months; P = .01). Fifty of 89 tumors (56%) stained positive for p53 protein. p53 overexpression was associated with decreased survival in patients who did not undergo resection. CONCLUSIONS: Normal p21(WAF1) expression may be necessary for a beneficial response to current adjuvant chemoradiation protocols for pancreatic cancer. Alternate strategies for adjuvant therapy should be explored for patients with pancreatic cancer who lack functional p21(WAF1).
Asunto(s)
Adenocarcinoma/radioterapia , Adenocarcinoma/cirugía , Ciclinas/biosíntesis , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/cirugía , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/biosíntesis , Terapia Combinada , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/análisis , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pancreatectomía , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/análisis , Proteína p53 Supresora de Tumor/biosíntesisRESUMEN
BACKGROUND: Reports of improved survival rates for patients with resected adenocarcinoma of the pancreas coincide with the adoption of adjuvant chemoradiation protocols. The impact of nodal micrometastases demonstrated by molecular assays and adjuvant therapy on survival of patients with stage I pancreatic cancer has not been adequately assessed. METHODS: A retrospective analysis of postoperative chemoradiation on survival in 61 patients undergoing resection of pancreatic adenocarcinomas from 1984 to 1997 was performed. Archival tumors and regional nodes from 25 patients with stage I cancers were tested for a Kiras oncogene mutation using polymerase chain reaction and analysis for restriction fragment length polymorphisms (PCR/RFLP). RESULTS: Adjuvant chemoradiation was associated with improved survival for stage I (P < .01), but not stage III, disease. Seventeen (68%) of 25 patients with stage I disease tested had evidence of mutant Kiras in one or more regional nodes. Survival did not differ for patients with molecular micrometastases. Six of 17 (35%) patients with micrometastases received adjuvant chemoradiation and had improved survival (P < .05). CONCLUSIONS: The majority of patients with stage I pancreatic cancer have PCR/RFLP evidence of lymph node micrometastases. Adjuvant chemoradiation improves survival in these patients by treating micrometastases not detected by histology. Adjuvant chemoradiation should be used for patients with stage I pancreatic cancers.
Asunto(s)
Adenocarcinoma/patología , Adenocarcinoma/terapia , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Adenocarcinoma/mortalidad , Anciano , Quimioterapia Adyuvante , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Mutación Puntual , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Proteínas Proto-Oncogénicas p21(ras)/genética , Radioterapia Adyuvante , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
As part of a multicenter trial of etidronate disodium for control of hypercalcemia in patients with malignancies, patients achieving normocalcemia within seven days after starting intravenous therapy with etidronate disodium plus saline were enrolled into a double-blind, placebo-controlled trial of oral etidronate disodium to maintain normocalcemia. By random assignment, patients received either oral etidronate disodium, 20 mg/kg/day, or placebo for up to three months. Efficacy was evaluated after 30 days of maintenance therapy: patients who were normocalcemic on day 30 were considered treatment successes. Of 81 patients who entered this phase of the study, 63 were evaluable for efficacy. Analysis of this group revealed that significantly (P less than 0.01) more patients in the etidronate disodium group (35%) than in the placebo group (6%) were normocalcemic at day 30. Life-table analysis of response indicated that patients treated with etidronate disodium maintained normocalcemia significantly (P less than 0.01) longer than did patients receiving placebo (median, 29 days versus 11 days). These results suggest that in patients whose calcium levels were normalized with IV etidronate disodium, oral etidronate disodium maintained normocalcemia significantly longer than no maintenance therapy in patients treated for hypercalcemia secondary to malignancy.
Asunto(s)
Calcio/sangre , Ácido Etidrónico/uso terapéutico , Hipercalcemia/tratamiento farmacológico , Neoplasias/complicaciones , Administración Oral , Ensayos Clínicos como Asunto , Método Doble Ciego , Humanos , Hipercalcemia/etiología , Distribución Aleatoria , Factores de TiempoRESUMEN
Two patients receiving aminoglycosides via central venous Silastic catheters were noted to have serum drug concentrations markedly divergent from expected results. Study of these patients, and of four additional patients prospectively selected for study, demonstrated that three of five patients had higher peak and/or trough aminoglycoside serum concentrations--when blood was obtained from the central venous catheter--than were contained in simultaneous samples from peripheral blood; these divergent results were noted after the catheter had been in use for more than 1 week; divergent results were not improved by additional catheter flushing prior to central venous blood sampling. These observations suggest that spurious aminoglycoside serum concentration results may sometimes be obtained when blood sampling is performed from central venous Silastic catheters, and can result in improper drug dosage alterations. It is necessary to access the timing, processing, and reliability of serum drug-monitoring practices on a routine basis to preclude such problems, and to reassess individual patient-monitoring studies which are inconsistent with anticipated results.
Asunto(s)
Catéteres de Permanencia/efectos adversos , Errores de Medicación , Tobramicina/sangre , Adulto , Femenino , Humanos , Estudios Prospectivos , Elastómeros de Silicona , Tobramicina/administración & dosificación , VenasRESUMEN
Forty-four patients with locally recurrent or metastatic colorectal adenocarcinoma were treated with methotrexate (MTX) 100 mg/m2 i.v. followed 1 h later by 5-fluorouracil (5-FU) 600 mg/m2 i.v. Calcium leucovorin 10 mg/m2 p.o. q 6 h X four doses was given 24 h after MTX. The regimen was given on days 1 and 8 and repeated every 28 days. Six of 44 patients (14%) obtained either complete or partial response with a mean response duration of 6.8 months. Of 26 previously untreated patients there were one complete response (4%), four partial responses (15%), and 12 (46%) instances of stabilization of disease. Patients obtaining response or stabilization of disease experienced improved survival compared to those with progressive disease. Toxicity consisted of stomatitis and hematopoietic suppression requiring dose attenuation in six patients (14%); there were no treatment-related deaths. Sequenced MTX/5-FU is modestly active with acceptable toxicity in previously untreated patients with colorectal adenocarcinoma but offers no apparent advantage over single-agent 5-FU.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Adulto , Anciano , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Metotrexato/administración & dosificación , Persona de Mediana EdadRESUMEN
Twenty-three patients with refractory, aggressive-histology, non-Hodgkin's lymphomas were treated with cytosine arabinoside (2.0 g/m2 i.v. every 12 h on days 1 and 2), etoposide (100 mg/m2 i.v. on days 1 and 2), and cisplatin (35 mg/m2 i.v. on days 1 and 2) every 3 weeks. All patients had received one or two prior chemotherapy regimens. Five of 19 (26%) evaluable patients responded, with a median duration of response of 9 weeks (90% confidence interval: 11-48%). One patient with a complete response remains free of disease over 31 months after completing six cycles of therapy. Six transient responses of less than 1-month duration were also observed. Hematological toxicity was significant: 73% of patients experienced grade 4 neutropenia, and 52% experienced grade 4 thrombocytopenia. Twenty patients (87%) underwent dose reductions following their first cycle of therapy for grade 3 or 4 myelosuppression. We conclude that this combination of drugs, when administered by this schedule, has limited antitumor activity; however, administering the regimen with a dose-intense schedule appears warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma no Hodgkin/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Cisplatino/administración & dosificación , Citarabina/administración & dosificación , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Humanos , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Proyectos Piloto , PronósticoRESUMEN
Based on preclinical studies demonstrating synergy between gallium and hydroxyurea, we evaluated the efficacy and toxicity of continuous intravenous gallium nitrate in combination with oral hydroxyurea in patients with refractory non-Hodgkin's lymphoma. Fourteen patients, median age 64 years (range 53-89), with stage III or IV low- or intermediate-grade lymphoma were treated with gallium nitrate and hydroxyurea in combination for 7 days at four different dose levels: (a) gallium nitrate, 200 mg/m2/day; hydroxyurea, 500 mg/day; (b) gallium nitrate, 250 mg/m2/day; hydroxyurea, 1,000 mg/day; (c) gallium nitrate, 300 mg/m2/day; hydroxyurea, 1,000 mg/day; and (d) gallium nitrate, 350 mg/m2/day, hydroxyurea, 1,000 mg/day. All patients had progressive disease and had been heavily pretreated. Six of 14 patients had objective tumor regression following treatment (one complete response, one near-complete response, and four partial responses) with a median duration of response of 7 weeks (range 3-38 weeks). An additional four patients had minor responses. Responses occurred at all dose levels and in both low- and intermediate-grade histologic subtypes. The predominant toxicities encountered were anemia and reversible nephrotoxicity. Combination gallium nitrate and hydroxyurea has significant activity in lymphoma and is well tolerated even by elderly patients. Because of the lack of cross-resistance to other drugs and the potential synergistic antineoplastic activity, gallium nitrate and hydroxyurea should be further evaluated in combination with other chemotherapeutic agents.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Galio/administración & dosificación , Hidroxiurea/administración & dosificación , Linfoma no Hodgkin/tratamiento farmacológico , Inhibidores de la Síntesis del Ácido Nucleico/administración & dosificación , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estudios de Evaluación como Asunto , Femenino , Galio/efectos adversos , Humanos , Hidroxiurea/efectos adversos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Inhibidores de la Síntesis del Ácido Nucleico/efectos adversos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Thirteen patients with metastatic colorectal adenocarcinoma underwent treatment with continuous ambulatory 5-fluorouracil (5-FU) infusion 300 mg/m2/day and intermittent bolus methotrexate (MTX) (200 mg/m2) with calcium leucovorin (LCV) 10 mg/m2 orally every 6 h X four to eight doses given 24 h after MTX. Although MTX administration was planned every 14 days, the average time between treatments exceeded 19 days (range 14-42) because of excessive toxicity. All patients experienced toxicity at some time in their treatment course, requiring interruption of 5-FU infusion in 12 of 13 patients. Significant toxicities included stomatitis (13 of 13 patients), hand-foot syndrome (8 of 13 patients), and diarrhea (3 of 13 patients). Toxicity did not appear to be minimized by attenuation of MTX and/or 5-FU dosage or by increasing the dose and/or duration of LCV. At this dosage schedule the addition of MTX/LCV to 5-FU infusion results in excessive and unacceptable toxicity and does not appear to improve treatment results.