RESUMO
BACKGROUND: Observational studies suggest that higher levels of 25-hydroxyvitamin D3 (25(OH)D) are associated with a reduced risk of colorectal cancer and improved survival of colorectal cancer patients. However, the influence of vitamin D status on cancer recurrence and survival of patients with stage III colon cancer is unknown. PATIENTS AND METHODS: We prospectively examined the influence of post-diagnosis predicted plasma 25(OH)D on outcome among 1016 patients with stage III colon cancer who were enrolled in a National Cancer Institute-sponsored adjuvant therapy trial (CALGB 89803). Predicted 25(OH)D scores were computed using validated regression models. We examined the influence of predicted 25(OH)D scores on cancer recurrence and mortality (disease-free survival; DFS) using Cox proportional hazards. RESULTS: Patients in the highest quintile of predicted 25(OH)D score had an adjusted hazard ratio (HR) for colon cancer recurrence or mortality (DFS) of 0.62 (95% confidence interval [CI], 0.44-0.86), compared with those in the lowest quintile (Ptrend = 0.005). Higher predicted 25(OH)D score was also associated with a significant improvement in recurrence-free survival and overall survival (Ptrend = 0.01 and 0.0004, respectively). The benefit associated with higher predicted 25(OH)D score appeared consistent across predictors of cancer outcome and strata of molecular tumor characteristics, including microsatellite instability and KRAS, BRAF, PIK3CA, and TP53 mutation status. CONCLUSION: Higher predicted 25(OH)D levels after a diagnosis of stage III colon cancer may be associated with decreased recurrence and improved survival. Clinical trials assessing the benefit of vitamin D supplementation in the adjuvant setting are warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT00003835.
Assuntos
Neoplasias do Colo/patologia , Recidiva Local de Neoplasia , Vitamina D/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/sangue , Neoplasias do Colo/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Dichloromethotrexate (DCMTX) has been the subject of sporadic clinical development for the last 30 years. Although DCMTX was developed in hopes of discovering a more potent antifolate, the potential pharmacologic and toxicologic advantages of the analog have become of greater interest. This phase I and pharmacokinetic trial of DCMTX given on days 1, 8, and 15 every 28 days was undertaken to test these potential advantages. The maximally tolerated dose on this schedule was 980 mg/m2. Hepatic toxicity was dose limiting. Malaise, myelosuppression, and mucositis were also major toxic effects. The recommended dose for subsequent phase II studies of DCMTX administered on this schedule is 785 mg/m2 with a reduction to 625 mg/m2 for patients with a poor performance status or extensive prior therapy. Plasma disappearance curves for most patients were biphasic or triphasic, although several demonstrated more complex kinetic patterns that suggested significant enterohepatic circulation. The magnitude of the area under the plasma disappearance curve was related to the severity of DCMTX-induced hepatotoxicity. The elimination kinetics were linear, with a mean plasma clearance of 294 mL/min (range, 128-715). The pharmacokinetic behavior of DCMTX does not support its use over methotrexate in regional perfusion. DCMTX's primarily nonrenal elimination suggests that it may have an advantage over methotrexate when combined with nephrotoxic drugs such as cisplatin. However, there is little reason to commit major resources to further evaluation of DCMTX unless significant advantages in antineoplastic activity are identified.
Assuntos
Antineoplásicos/uso terapêutico , Metotrexato/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Medula Óssea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Fígado/efeitos dos fármacos , Masculino , Taxa de Depuração Metabólica , Metotrexato/efeitos adversos , Metotrexato/farmacocinética , Metotrexato/uso terapêutico , Pessoa de Meia-IdadeRESUMO
Piroxantrone (PRX, NSC 349174) is one of the first of a new class of intercalating agents, the anthrapyrazoles, to undergo clinical evaluation. Additionally, it is the first drug trial to prospectively test a new pharmacology-based dose escalation schema proposed for Phase I trials of anticancer compounds. In this Phase I trial, PRX was administered as a 1-h infusion every 3 weeks to patients with advanced cancer. Forty-four evaluable patients received 116 courses at doses ranging from 7.5 to 190 mg/m2. The dose-limiting toxicity was myelosuppression with leukopenia predominating. Nonhematological toxicities were minimal and consisted of nausea and vomiting, alopecia, mucositis, and phlebitis. Based on this trial, the maximum tolerated and recommended Phase II doses for PRX administered on this schedule are 190 and 150 mg/m2, respectively. PRX plasma elimination was rapid and best fit by a two-compartment model for 17 of 24 patients receiving greater than or equal to 90 mg/m2. The plasma clearance rate was 1290 +/- 484 ml/min (720 +/- 210 ml/min/m2) and did not vary with dose. The t1/2 alpha was 2.9 +/- 5.3 (SD) min and the t1/2 beta was 18.7 +/- 36.5 min. Area under the concentration versus time curve (AUC) at the maximal tolerated dose (MTD) was 435 mumol.min/liter, 40% higher than the predicted AUC from preclinical testing. The percentage decrease in WBC and neutrophil count was correlated with the AUC. The potential advantage of pharmacology-based dose escalation was limited in this study by assay insensitivity, extremely rapid plasma elimination, and the proximity of the starting dose to the dose where the target AUC was achieved and standard dose escalations were to begin. Consequently, there was no reduction in the number of dose escalations required to define the maximum tolerated dose. However, the practical aspects of this approach have been established and its use is recommended for further trials where detailed preclinical pharmacological studies are available.
Assuntos
Antraquinonas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazóis/uso terapêutico , Adulto , Idoso , Antraquinonas/administração & dosagem , Antraquinonas/efeitos adversos , Antraquinonas/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Coração/efeitos dos fármacos , Humanos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirazóis/farmacocinéticaRESUMO
Brequinar sodium is a quinoline carboxylic acid derivative that has shown antitumor activity in a number of in vivo murine and human tumor xenograft models. Its mechanism of action is blockade of de novo pyrimidine biosynthesis by inhibition of dihydroorotic acid dehydrogenase. In vitro and in vivo studies demonstrate the superiority of prolonged drug exposure in achieving tumor growth inhibition. This phase I study evaluated the administration of brequinar sodium by short, daily i.v. infusion for 5 days repeated every 4 weeks. Fifty-four subjects were enrolled in the study and received drug in doses ranging from 36-300 mg/m2. The dose-limiting toxicities were mucositis and diffuse skin rash. Other toxicities included myelosuppression, nausea, vomiting, malaise, and burning at the infusion site. The maximum tolerated dose on the "daily times 5" schedule was 300 mg/m2. The recommended phase II dose is 250 mg/m2. Pharmacokinetic analysis of the day 1 drug clearance curves in 51 subjects showed slight nonlinearity in the relationship between dose and area under the clearance curve (AUC). The dose versus AUC relationship was well described using a Michaelis-Menten model of brequinar elimination kinetics with Vmax = 45 (micrograms/ml)/h and Km = 123 micrograms. Analysis of the day 5 drug clearance curves revealed a diminution in Vmax to 30 (micrograms/ml)/h. As a consequence of the reduction in Vmax brequinar plasma concentrations on day 5 were higher than predicted from day 1 drug kinetics. Pharmacodynamic analysis of the day 1 kinetic parameters and the toxicities occurring during the first cycle of drug therapy revealed significant correlations between mucositis and dose, AUC, and peak brequinar concentration; between leukopenia and AUC and peak drug concentration; and between thrombocytopenia and beta elimination rate.
Assuntos
Antineoplásicos/efeitos adversos , Compostos de Bifenilo/efeitos adversos , Neoplasias/tratamento farmacológico , Compostos de Bifenilo/farmacocinética , Compostos de Bifenilo/uso terapêutico , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-IdadeRESUMO
UNLABELLED: Vinorelbine, cisplatin and docetaxel are known to be efficacious in non-small cell lung cancer (NSCLC). This limited institution pilot study evaluated the novel strategy of sequencing active first line agents prior to progression. The primary objective of this study was to assess the toxicity profile in anticipation of a larger cooperative group standard phase II study. Patients with selected stage IIIB and IV NSCLC, Southwest Oncology Group (SWOG) performance status (PS) of 1 or less and measurable or evaluable disease were eligible. Treatment was cisplatin 100 mg/m(2) day 1 and 29, vinorelbine 25 mg/m(2) weekly for 8 weeks, followed by docetaxel 100 mg/m(2) every 21 days for four cycles if no progression. If grade IV neutropenia developed, G-CSF 5 mcg/kg/day was used in subsequent cycles. Of 18 eligible patients, 17 patients had stage IV disease with a median age of 66 years (range 48-80). Eight patients had a SWOG PS of 1, 10 had a PS of zero. Six of eighteen patients received all 8 weeks of vinorelbine/cisplatin and six of eight patients who went on to receive docetaxel received all four planned cycles; only two patients overall received all planned therapy. One grade III/IV event each of cardiotoxicity (myocardial infarction), renal toxicity (acute renal failure), anemia and thrombocytopenia occurred with vinorelbine and cisplatin, and 2 Grade IV hypersensitivity reactions, manifested by severe back pain with docetaxel occurred. Three deaths occurred during the study, all during treatment with vinorelbine and cisplatin: one due to neutropenic sepsis; one from a pulmonary embolism; and one secondary to severe hypoglycemia in a diabetic patient. Of the 16 patients evaluable for response after vinorelbine/cisplatin, there were two complete responses (12.5%) and three partial responses (19%) for an overall response rate of 31% (95% CI 8-58). One additional patient who received docetaxel experienced a partial response. Two patients remain alive (21+ and 18+ months, respectively). The 1-year survival was 44%. CONCLUSION: This sequence, as defined, was tolerated marginally well in patients with advanced NSCLC. Granulocytopenia was the major toxicity requiring dose adjustments throughout the sequence. Based on response rates and tolerability that were somewhat comparable to other regimens in this disease setting, a modified version of this program, adjusted to decrease the incidence of grade III and IV toxicity, was selected as one arm of a recent randomized phase II trial in the Southwest Oncology Group (SWOG), S9806, evaluating sequential therapy in advanced NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/análogos & derivados , Taxoides , Vimblastina/análogos & derivados , Injúria Renal Aguda/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Agranulocitose/induzido quimicamente , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dor nas Costas/induzido quimicamente , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Progressão da Doença , Docetaxel , Esquema de Medicação , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/induzido quimicamente , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Análise de Sobrevida , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , VinorelbinaRESUMO
Thirteen cases of Listeria monocytogenes infection occurred at the Johns Hopkins Oncology Center over a 10-year period, representing 0.09% of all admissions. These cases principally occurred in patients with underlying hematologic of lymphoreticular malignancy, but in all patients other causes of immune suppression were also present. Corticosteroids were the most frequent exogenous cause of immune suppression. Bacteremia was detected more frequently than meningitis and in contrast to earlier reports, bacteriologic cure was achieved in 12 of 13 patients. Therapeutic success appeared to be related to early institution of effective antimicrobial agents. Despite eradication of infection, seven of the patients were dead within three months from progression of their underlying disease. The overall survival rate of cancer patients with listeriosis is therefore a function of the underlying malignancy and not the infection.
Assuntos
Listeriose/etiologia , Neoplasias/complicações , Adulto , Idoso , Feminino , Humanos , Tolerância Imunológica , Listeriose/diagnóstico , Listeriose/tratamento farmacológico , Masculino , Pessoa de Meia-IdadeRESUMO
Thirty-five evaluable patients with advanced adenocarcinoma of the pancreas were treated with piroxantrone at a dose of 150 mg/m2 intravenously every 21 days. No objective responses were observed (95% confidence interval 0%-10%). Toxicities of grade > or = 3 were primarily hematologic and were seen in 28 patients. Piroxantrone is inactive in pancreatic cancer and no further investigation of this agent in this tumor is recommended.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antraquinonas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Pirazóis/uso terapêutico , Adenocarcinoma/secundário , Adulto , Idoso , Antraquinonas/efeitos adversos , Antineoplásicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/efeitos adversosRESUMO
Twenty-one evaluable patients with advanced gastric adenocarcinoma were treated with piroxantrone at a dose of 150 mg/m2 intravenously every 21 days. One objective response was seen for an overall response rate of 5% (95% confidence interval 0-24%). Toxicities of grade > or = 3 were primarily hematologic and seen in 13/21 patients. Piroxantrone has minimal activity against gastric adenocarcinoma and no further investigation of this agent on this schedule in this disease is recommended.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antraquinonas/uso terapêutico , Antineoplásicos/uso terapêutico , Pirazóis/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Antraquinonas/efeitos adversos , Antineoplásicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/efeitos adversosRESUMO
Twenty-two patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with piroxantrone 150 mg/m2 intravenously every 21 days. There were no objective responses. The 95% upper confidence bound for response is 15%. Primary toxicity was hematologic.
Assuntos
Antraquinonas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Pirazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antraquinonas/efeitos adversos , Antineoplásicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Pirazóis/efeitos adversos , Vômito/induzido quimicamenteRESUMO
Twenty-three evaluable patients with advanced gastric adenocarcinoma were treated with trimetrexate at doses of 8-12 mg/m2 intravenously daily for five days, with cycles repeated every 21 days. One complete response was seen for an overall response rate of 4% (95% confidence interval 0-22%). Hematologic toxicities of grade > or = 3 were seen in 10/23 patients, and overall any grade 3 or greater toxicity was seen in 14/23 patients. Trimetrexate has minimal activity against gastric adenocarcinoma in this study, and no further investigation of this agent at this dose and schedule is recommended in this disease.
Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Trimetrexato/uso terapêutico , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Trimetrexato/efeitos adversosRESUMO
Piroxantrone is one of the anthrapyrazoles developed in an effort to combine the broad antitumor activity of the anthracyclines with decreased myocardial toxicity. It has shown activity in metastatic melanoma during phase I trials. The Southwest Oncology Group (SWOG) conducted a phase II trial in disseminated malignant melanoma with piroxantrone administered at 150 mg/m2 intravenously over 1 h every 21 days, based upon the phase I experience. Forty-six eligible patients were registered to the trial and 44 were evaluable for response. Two partial responses, Wayne of 6 and 9 months duration were observed for an overall response rate of 5% (95% confidence interval 1%-15%). Thirty-six of 46 eligible patients have died with an estimated median survival of 5 months (95% confidence interval 3-8 months). Toxicities were tolerable with granulocytopenia being the predominant toxicity. Based upon the observed response rate, it is concluded that piroxantrone administered at this dose and schedule has detectable but minimal activity, and does not warrant further investigation in this disease.
Assuntos
Antraquinonas/uso terapêutico , Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Pirazóis/uso terapêutico , Adulto , Idoso , Antraquinonas/efeitos adversos , Antineoplásicos/efeitos adversos , Estudos de Avaliação como Assunto , Feminino , Humanos , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Pirazóis/efeitos adversosRESUMO
This phase I study was conducted to reevaluate the dose-limiting toxicities, maximum tolerated (MTD) and recommended phase II doses of oral NMF administered on a three times weekly schedule for 4 out of every 6 weeks. This schedule was based on the observation that prolonged administration of NMF was associated with the most efficacious antitumor activity in preclinical studies. Phase II trials that employed a starting dose of 800 mg/m2, determined in a previous phase I trial, were suspended because of frequent and severe toxicities. In the current study, a symptom complex characterized by nausea, vomiting, and malaise was the dose-limiting toxicity of oral NMF administered on this schedule. Other toxicities included hepatic enzyme elevations, mild myelosuppression, and worsening of preexistent toxic peripheral neuropathies. Of interest, three patients who were asymptomatic prior to treatment, rapidly developed symptoms of increased intracranial pressure after starting NMF; and, computerized tomographic brain scans revealed metastatic tumors with significant peritumoral edema. NMF was well tolerated at 600 mg/m2, however, an abrupt increase in toxicity resulted when the dose was increased to 700 mg/m2. Although NMF peak plasma concentrations (Cmax) and areas under the plasma disappearance curves (AUC) differed between the 600 and 700 mg/m2 dose levels, these differences were not striking, and similar NMF plasma concentrations and exposures were well tolerated during intravenous trials. Based on this study, the recommended phase II dose for oral NMF administered three times weekly for 4 of 6 weeks was 600 mg/m2.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Antineoplásicos/uso terapêutico , Drogas em Investigação/uso terapêutico , Formamidas/uso terapêutico , Administração Oral , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Relação Dose-Resposta a Droga , Esquema de Medicação , Avaliação de Medicamentos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Feminino , Formamidas/administração & dosagem , Formamidas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Piroxantrone is an anthrapyrazole compound undergoing phase II testing in a variety of diseases. The anthrapyrazoles are a series of compounds synthesized with the intent of maintaining the broad antitumor activity of anthracyclines, but with lessened cardiac toxicity. The Southwest Oncology Group (SWOG) conducted a phase II trial of piroxantrone in advanced soft tissue sarcoma. Treatment consisted of piroxantrone 150 mg/M2 administered intravenously over 1 hour every 21 days. Twenty-five eligible patients were registered to the trial. Twenty-three patients received treatment and are fully evaluable for response and toxicity. Two partial responses were seen for an overall response rate of 9% (95% confidence limit 1%-28%). Abnormal cardiac ejection fraction occurred in five patients, and fatal congestive heart failure developed in one patient on study. Toxicities other than cardiac were tolerable. Based on the observed response rate and cardiac toxicity, further trials of piroxantrone in the treatment of soft tissue sarcoma do not appear warranted.
Assuntos
Antraquinonas/uso terapêutico , Antineoplásicos/uso terapêutico , Pirazóis/uso terapêutico , Sarcoma/tratamento farmacológico , Adulto , Idoso , Antraquinonas/administração & dosagem , Antraquinonas/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Sarcoma/secundárioRESUMO
A phase II trial of the new anthrapyrazole piroxantrone was carried out by the Southwest Oncology Group in patients with advanced metastatic or recurrent endometrial cancer. A two-stage statistical design targeted accrual of 20 eligible patients. The starting dose of piroxantrone was 150 mg/m2 in patients without prior radiation therapy (RT) and 120 mg/m2 in patients with prior RT. There were 15 eligible patients, six of whom had received prior hormonal therapy while nine patients had not received prior hormonal therapy. Eight patients had received prior RT while seven patients had not received any prior RT. One to seven cycles of piroxantrone were administered. Dose escalation was feasible in four patients. No grade 5 toxicity was experienced by any patients. Most of the grade 4 (granulocytopenia in one) and grade 3 (leukopenia in three, granulocytopenia in three, anemia in two and thrombocytopenia in one) toxicity was related to myelosuppression. Grade 3 non-hematologic toxicities were nausea, fatigue and SGOT elevation. There was one partial response for a response rate of 7% (95% CI 0.2-32%) and median survival was 11 months (95% CI 3-13 months). The study was prematurely terminated due to lack of patient accrual.
Assuntos
Antraquinonas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Pirazóis/uso terapêutico , Adulto , Idoso , Agranulocitose/induzido quimicamente , Antraquinonas/efeitos adversos , Feminino , Humanos , Leucopenia/induzido quimicamente , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Pirazóis/efeitos adversosRESUMO
A phase II trial of the new anthrapyrazole piroxantrone was conducted by the Southwest Oncology Group in advanced ovarian carcinoma. The objective were to evaluate its response rate and toxicity in patients who had disease persistence, progression, or recurrence either during or after platinum-containing chemotherapy. A two-stage statistical design targeted accrual to 15 eligible patients if no responses were observed. The piroxantrone starting dose was 120 mg/m2, with the provision to escalate to 150 and 180 mg/m2. There were 16 eligible patients, all of whom had received either one (12 patients) or two (4 patients) prior platinum-containing regimens; one patient had received doxorubicin. Fourteen of the 16 patients were enrolled either at the time of disease persistence/progression during initial chemotherapy or with recurrence or progression within 6 months of the previous platinum-based remain. One to 5 cycles of piroxantrone were given. Dose escalation was feasible in 7 patients but was prevented in the other 9 by neutropenia. Maximum toxicity for all cycles was none or grade 1 in 2 patients; grade 2, 5; grade 3, 8; and grade 4, 1. All but one of the grade 3 or 4 events was from myelosuppression; there were no adverse cardiac events. No responses were observed. Thus, piroxantrone appears inactive in patients with persistent, progressive, or recurrent ovarian cancer who recently had received a platinum-based regimen.