Biomedical subjects

N J Meropol

Publications and source records attributed to N J Meropol.

At least 37 records · Page 2Linked to original sources

PubMed2000

Oral therapy for colorectal cancer: how to choose.

Either alone or in combination with other antineoplastics, fluorouracil (5-FU) has been the mainstay of treatment of gastrointestinal, breast, and head and neck cancers for the past 40 years. Numerous active 5-FU schedules are in clinical use, but erratic oral bioavailability has historically mandated intravenous administration. Recently, two methods have been used to overcome the poor oral bioavailability of 5-FU. The first involves the use of prodrugs that are absorbed intact in the gastrointestinal tract and are ultimately converted to 5-FU in normal or tumor tissues. An alternate approach involves the inhibition of gastrointestinal degradation via coadministration of an inhibitor of dihydropyrimidine dehydrogenase, the rate-limiting enzyme in 5-FU catabolism. The oral fluoropyrimidines currently in development result in prolonged exposure to 5-FU and, therefore, have the potential to achieve clinical benefits similar to those seen with protracted intravenous infusions of 5-FU, but without the cost, complications, and inconvenience of ambulatory infusion pumps. This review describes several oral fluoropyrimidine regimens with activity in colorectal cancer: capecitabine (Xeloda), tegafur, UFT, S-1, and eniluracil plus 5-FU. An understanding of the distinct mechanisms of action and toxicity patterns of each regimen may ultimately guide treatment selection when multiple choices become available.

Administration, Oral↗

PubMed1999

Bioavailability and phase II study of oral UFT plus leucovorin in patients with relapsed or refractory colorectal cancer.

PURPOSE: This study was undertaken to address the influence of concurrent administration on the pharmacokinetics of UFT (uracil plus tegafur) and leucovorin (LV), and to measure the antitumor activity of a 28-consecutive-day oral regimen of UFT plus LV in patients with relapsed or refractory colorectal cancer. METHODS: Patients with advanced measurable colorectal cancer who had failed previous therapy with intravenous bolus 5-fluorouracil (5-FU) were eligible. Patients were treated with UFT 300 mg/m2 per day plus LV 90 mg per day in three divided doses every 8 h for 28 days, repeated at 35-day intervals. In addition, a three-treatment by three-period crossover bioavailability comparison of oral LV 30 mg plus UFT 200 mg versus either LV or UFT alone was scheduled for the 8 days preceding the first cycle of therapy. RESULTS: Of 19 patients enrolled, 18 were assessable for pharmacokinetics and response. When LV was coadministered with UFT, there were no statistically significant effects on tegafur, uracil, or 5-FU Cmax, AUC, or Tmax with the exception of a delayed Tmax for tegafur (P=0.03). No statistically significant differences were found in LV and 5-methyltetrahydrofolate plasma levels when LV was administered alone or with UFT. However, wide interpatient variability was observed for all parameters. There were no antitumor responses seen. CONCLUSIONS: Although the Tmax for tegafur is delayed with the concurrent administration of LV, there were no differences (P > 0.05) in any pharmacologic parameters that are of likely clinical significance. However, the great interpatient variability observed in UFT and LV pharmacology may have obscured true bioavailability effects in this small patient population. Daily oral UFT plus LV is inactive as second-line therapy in patients who have failed bolus 5-FU.

Adult↗

PubMed1999

American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants.

PURPOSE: Because toxicities associated with chemotherapy and radiotherapy can adversely affect short- and long-term patient quality of life, can limit the dose and duration of treatment, and may be life-threatening, specific agents designed to ameliorate or eliminate certain chemotherapy and radiotherapy toxicities have been developed. Variability in interpretation of the available data pertaining to the efficacy of the three United States Food and Drug Administration-approved agents that have potential chemotherapy- and radiotherapy-protectant activity-dexrazoxane, mesna, and amifostine-and questions about the role of these protectant agents in cancer care led to concern about the appropriate use of these agents. The American Society of Clinical Oncology sought to establish evidence-based, clinical practice guidelines for the use of dexrazoxane, mesna, and amifostine in patients who are not enrolled on clinical treatment trials. METHODS: A multidisciplinary Expert Panel reviewed the clinical data regarding the activity of dexrazoxane, mesna, and amifostine. A computerized literature search was performed using MEDLINE. In addition to reports collected by individual Panel members, all articles published in the English-speaking literature from June 1997 through December 1998 were collected for review by the Panel chairpersons, and appropriate articles were distributed to the entire Panel for review. Guidelines for use, levels of evidence, and grades of recommendation were reviewed and approved by the Panel. Outcomes considered in evaluating the benefit of a chemotherapy- or radiotherapy-protectant agent included amelioration of short- and long-term chemotherapy- or radiotherapy-related toxicities, risk of tumor protection by the agent, toxicity of the protectant agent itself, quality of life, and economic impact. To the extent that these data were available, the Panel placed the greatest value on lesser toxicity that did not carry a concomitant risk of tumor protection. RESULTS AND CONCLUSION: Mesna: (1) Mesna, dosed as detailed in these guidelines, is recommended to decrease the incidence of standard-dose ifosfamide-associated urothelial toxicity. (2) There is insufficient evidence on which to base a guideline for the use of mesna to prevent urothelial toxicity with ifosfamide doses that exceed 2.5 g/m(2)/d. (3) Either mesna or forced saline diuresis is recommended to decrease the incidence of urothelial toxicity associated with high-dose cyclophosphamide use in the stem-cell transplantation setting. Dexrazoxane: (1) The use of dexrazoxane is not routinely recommended for patients with metastatic breast cancer who receive initial doxorubicin-based chemotherapy. (2) The use of dexrazoxane may be considered for patients with metastatic breast cancer who have received a cumulative dosage of 300 mg/m(2) or greater of doxorubicin in the metastatic setting and who may benefit from continued doxorubicin-containing therapy. (3) The use of dexrazoxane in the adjuvant setting is not recommended outside of a clinical trial. (4) The use of dexrazoxane can be considered in adult patients who have received more than 300 mg/m(2) of doxorubicin-based therapy for tumors other than breast cancer, although caution should be used in settings in which doxorubicin-based therapy has been shown to improve survival because of concerns of tumor protection by dexrazoxane. (5) There is insufficient evidence to make a guideline for the use of dexrazoxane in the treatment of pediatric malignancies, with epirubicin-based regimens, or with high-dose anthracycline-containing regimens. Similarly, there is insufficient evidence on which to base a guideline for the use of dexrazoxane in patients with cardiac risk factors or underlying cardiac disease. (6) Patients receiving dexrazoxane should continue to be monitored for cardiac toxicity. Amifostine: (1) Amifostine may be considered for the reduction of nephrotoxicity in patients receiving cisplatin-based chemoth

Adult↗

PubMed1999

Prognostic factors affecting survival in patients with colorectal carcinomatosis.

This study evaluates prognostic factors that may influence survival in patients who present with carcinomatosis from colorectal cancer. Patients may present with carcinomatosis as the pattern of metastases at the initial diagnosis of colorectal cancer. Little is known about the natural history of carcinomatosis and the prognostic factors affecting outcome. All patients treated at Roswell Park Cancer Institute from 1988 to 1994 who presented with carcinomatosis at the initial diagnosis of colorectal cancer were identified. A retrospective review of the medical records for patient and tumor demographics was performed. Estimated survival distributions were calculated by the method of Kaplan and Meier. Tests of significance with respect to survival distribution were based on the log-rank test. Cox proportional hazards model was used for the multivariate analysis. There were 31 males and 38 females. The median age was 61 years (range, 26-80). The primary cancers were in the sigmoid with 24 patients (35%), cecum with 14 patients (20%), and transverse colon with 11 patients (16%). The remainder were distributed throughout the colon and rectum. The most common presentation was large bowel obstruction in 29 patients (42%). T3 and T4 cancers were present in 39 (57%) and 13 patients (19%), respectively. Lymph nodes were positive in 39 patients (57%), and mucin-producing tumors were also present in 39 patients (57%). Twelve patients (17%) had one site of disease, 17 patients (25%) had two sites of disease, and 37 (54%) patients had three or more sites of disease. Ascites was present in 29 patients (42%). Residual disease was present at the completion of surgery in 45 patients, absent in 13 patients, and status unknown in 11. The presence of residual disease (p = 0.0001), presence of ascites (p = 0.02), stage greater than T3 (p = 0.02), and increasing number of carcinomatosis sites (p = 0.006) were found to have a negative impact on survival on univariate analysis. On multivariate analysis, only the presence of residual disease at the completion of surgery was found to be an independent predictor of survival (p = 0.04). Overall median survival was 14 months with a 26% estimated 2-year survival. The presence of gross residual disease at the completion of surgery was shown to be the only independent factor negatively affecting survival. This has potential implications for the operative management of patients presenting with colorectal carcinomatosis.

Adenocarcinoma↗

PubMed1999

Paradoxical correlations of cyclin-dependent kinase inhibitors p21waf1/cip1 and p27kip1 in metastatic colorectal carcinoma.

The cyclin-dependent kinase inhibitors (CDIs) p27kip1 and p21waf1/cip1 are key cell cycle-negative regulatory enzymes. The objective of this study was to correlate expression of p27kip1 and p21waf1/cip1 with survival, chemotherapy responsiveness, and expression of the proliferation marker Ki-67 in patients with advanced colorectal cancer. Immunohistochemistry was performed with antibodies to p27kip1, p21waf1/cip1, and Ki-67 on samples from 66 patients with metastatic colorectal carcinoma. Interpretation was performed by visual inspection and automated image analysis. Patients who obtained a response to chemotherapy had greater p21waf1/cip1 tumor staining with a mean of 10.0 positive cells/high-powered field, compared with 4.5 positive cells/high-powered field for nonresponders (P = 0.03). A positive Spearman correlation was seen between Ki-67 and p27kip1 (r = 0.48; P = 0.0001), as well as between Ki-67 and p21waf1/cip1 (r = 0.48; P = 0.0001). A trend toward shorter survival was seen in patients with positive specimens (median survival of 10 months for patients with both p27kip1- and p21waf1/cip1-positive specimens, compared with 22 months for patients with neither p27kip1- nor p21waf1/cip1-positive specimens). In contrast to that previously reported in normal colonic mucosa or early-stage colorectal cancer, we observed positive correlations of Ki-67 with both p27kip1 and p21waf1/cip1, a trend toward greater CDI staining indicating worse prognosis, and greater p21waf1/cip1 staining in tumors that were chemosensitive. These findings suggest that in the metastatic setting, CDIs may show altered function, compared with their role in the normal cell cycle.

Adenocarcinoma↗

PubMed1999

Phase I and pharmacokinetic study of weekly 5-fluorouracil administered with granulocyte-macrophage colony-stimulating factor and high-dose leucovorin: a potential role for growth factor as mucosal protectant.

Diarrhea is dose-limiting with weekly 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been associated with a decrease in chemotherapy-associated mucosal toxicity. This study was conducted to determine the maximum tolerated dose (MTD) of weekly 5-FU when administered with GM-CSF and high-dose LV. Patients were treated with intravenous LV 500 mg/m2 plus 5-FU weekly for six doses followed by a 2-week rest. GM-CSF 250 mg/m2 was administered subcutaneously 5 days each week. Cohorts were treated with 5-FU at 600, 700, and 800 mg/m2 weekly. Twenty-nine patients were treated. The MTD of 5-FU in this schedule was 700 mg/m2/week, with diarrhea dose-limiting. 5-FU delivered dose intensity at the MTD was 424 +/- 23.7 mg/m2/week, including rest periods. 5-FU and LV pharmacokinetics were not altered by concurrent treatment with GM-CSF. In a weekly schedule with high-dose LV and GM-CSF, the MTD of 5-FU and 5-FU delivered dose intensity were higher than previously reported with 5-FU and LV administered without GM-CSF.

Adult↗

PubMed1998

Evaluation of natural killer cell expansion and activation in vivo with daily subcutaneous low-dose interleukin-2 plus periodic intermediate-dose pulsing.

Natural killer (NK) cells may be expanded in vivo with a prolonged course of daily subcutaneous interleukin-2 (IL-2). However, cellular activation requires higher concentrations of IL-2 than are achieved with low-dose therapy. The objective of the current trial was to determine the toxicity and immunological effects of periodic subcutaneous intermediate-dose IL-2 pulses in patients receiving daily low-dose therapy. A group of 19 patients were treated with daily subcutaneous low-dose IL-2 at 1.25 x 10(6) International Units (1.25 MIU) m(-2) day(-1). After 4-6 weeks, patients received escalating 3-day intermediate-dose IL-2 pulses administered as single daily subcutaneous injections, repeated at 2-week intervals. The maximum tolerated pulse dose was 15 MIU m(-2) day(-1), with transient hypotension, fatigue, and nausea/vomiting dose-limiting. Subcutaneous IL-2 resulted in in vivo expansion of CD56+ NK cells (796+/-210%) and CD56bright natural killer (NK) cells (3247+/-1382%). Expanded NK cells coexpressed CD16, and showed lymphokine-activated killer activity and antibody-dependent cellular cytotoxicity in vitro. Intermediate-dose pulsing resulted in serum IL-2 concentrations above 100 pM. Cellular activation was suggested by rapid margination of NK cells following pulsing, coincident with peak IL-2 levels, with return to baseline by 24 h. In.addition, interferon gamma production in response to lipopolysaccharide was augmented. Subcutaneous daily low-dose IL-2 with intermediate-dose pulsing is a well-tolerated outpatient regimen that results in in vivo expansion and potential activation of NK cells, with possible application in the treatment of malignancy and immunodeficiency.

Adult↗

PubMed1998

Initial clinical trial and pharmacokinetics of Thymitaq (AG337) by 10-day continuous infusion in patients with advanced solid tumors.

PURPOSE: To establish the maximum tolerated dose (MTD), dose-limiting and other major toxicities and the major pharmacokinetic parameters of a 10-day infusion of the nonclassical antifolate Thymitaq. METHODS: The drug was given by 10-day infusion via a portable pump. The starting dose was 286 mg/m2 per day with escalation to 572 and 716 mg/m2 per day. Thymitaq in plasma was assayed by a validated isocratic reverse-phase HPLC assay with detection at 273 nm. RESULTS: The dose of 716 mg/m2 per day x 10 was considered too high as none of three patients completed a 10-day infusion and two of three developed grade IV myelotoxicity. At 572 mg/m2 per day three of four patients completed a 10-day infusion. Dose-limiting myelosuppression was seen in one of four but owing to a high incidence of thrombotic phenomena, no further patients were added. CONCLUSION: Continuous 10-day infusions of Thymitaq should be limited to low doses until further studies can be done.

Adult↗

PubMed1998

Oral fluoropyrimidines in the treatment of colorectal cancer.

5-Fluorouracil (5-FU) has been the mainstay of systemic therapy for colorectal cancer since its initial development 40 years ago. Efforts to improve the therapeutic index of 5-FU have included alteration of schedule and addition of biochemical modulators. An understanding of 5-FU mechanisms of action has resulted in major therapeutic advances in the past 10 years; however, a plateau has been reached in the efficacy of 5-FU, mandating a paradigm shift for those involved in colorectal cancer drug development. One direction vigorously pursued is the development of orally administered fluoropyrimidines that maintain or improve upon the effectiveness of intravenous 5-FU. In this paper the preclinical and clinical development of oral fluoropyrimidines and their modulators is reviewed, including UFT, capecitabine, ethynyluracil and S-1.

Administration, Oral↗

PubMed1998

Octreotide does not prevent diarrhea in patients treated with weekly 5-fluorouracil plus high-dose leucovorin.

The somatostatin analog, octreotide, is effective in treating diarrhea associated with cancer chemotherapy. This study was undertaken to determine whether octreotide could be used as prophylaxis against chemotherapy-induced diarrhea and, thereby, permit increased dose intensity. Adult cancer patients were treated with a standard regimen of intravenous 5-fluorouracil (5-FU) (600 mg/m2) plus leucovorin (LV) (500 mg/m2) weekly x 6 weeks. In addition, 150 microg of octreotide was administered subcutaneously twice daily, beginning on the first day of chemotherapy and continuing for 43 days. Escalation of 5-FU was planned for successive cohorts based upon toxicity. Eleven patients were treated at the initial 5-FU dose level. In 10 evaluable patients, dose-limiting toxicities were diarrhea (two patients), fatigue (one patient), and hyperbilirubinemia (one patient). Diarrhea was experienced by six of 10 patients, and only three patients were able to receive six weekly chemotherapy treatments without dose reduction or delay. At a dose of 150 microg twice daily, octreotide did not prevent diarrhea associated with 5-FU plus LV, and 5-FU dose escalation was not possible. While octreotide is successful in the treatment of 5-FU-induced diarrhea, we were unable to demonstrate a role in toxicity prophylaxis.

Adenocarcinoma↗

PubMed1998

Randomized, placebo-controlled, multicenter trial of granulocyte-macrophage colony-stimulating factor as infection prophylaxis in oncologic surgery. Leukine Surgical Prophylaxis Research Group.

PURPOSE: Postoperative infections are a frequent source of preventable morbidity and mortality in the oncologic population. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent modulator of immune effector cells in vitro and in vivo. This study was conducted to determine whether GM-CSF, when administered perioperatively, could reduce the incidence of surgical infections in cancer patients. METHODS: This was a prospective, randomized, placebo-controlled, multicenter study. Cancer patients at high risk of infectious surgical morbidity were randomized to receive GM-CSF 125 microg/m2 per day or placebo subcutaneously for 8 days beginning 3 days preoperatively. Routine antibiotic prophylaxis was administered to all patients. RESULTS: Three hundred ninety-nine patients were enrolled, with 198 randomized to receive GM-CSF. Twenty-one percent of patients experienced infections during the first 2 weeks postoperatively, and there was no difference in infection rate between the study groups. The most common sites of infection were respiratory tract (53%) and surgical wound (25%). The duration of operation and American Society of Anesthesiology (ASA) physical status classification were the most significant predictors of infection in multivariate analysis. GM-CSF was well tolerated and was not associated with fever. CONCLUSION: The eligibility criteria for this study were successful at defining a patient subgroup at high risk for postoperative infections. At an immunomodulatory dose of 125 microg/m2 per day, GM-CSF was safe and well tolerated, but did not reduce the incidence of postoperative infections in this high-risk oncologic population. Infectious morbidity in surgical oncology remains an important subject for continued clinical investigation.

Adult↗

PubMed1998

Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine.

PURPOSE: To evaluate the toxicology and pharmacology of an orally active fluoropyrimidine given as a continuous daily dose divided into two portions for 6 weeks, and to determine the maximal-tolerated daily dose (MTD) and the suggested phase II daily dose. PATIENTS AND METHODS: Solid-tumor patients with a Karnofsky performance status greater than 70 who had normal organ function and resolution of the effects of prior therapy, and who gave informed written consent, were enrolled. Oral capecitabine, as a divided morning and evening dose, was administered to cohorts of a minimum of 3 patients starting at 110 mg/m2 and escalating by means of a modified Fibonacci scheme to 1,657 mg/m2/d. Pharmacologic samples were obtained on days 1 and 15. Toxicity evaluations were performed approximately every 3 days for the first 43 days. Antitumor effect was evaluated at day 42 of therapy. RESULTS: Thirty-three patients entered the study. Few side effects occurred at or below 1,331 mg/m2/d. The MTD was 1,657 mg/m2/d with limiting toxicities of palmar-plantar erythrodysesthesia, nausea, vomiting, vertigo, abdominal pain, diarrhea, and thrombocytopenia. All toxicities were reversible. A mixed response was seen in one breast cancer patient. Pharmacologic studies showed rapid and extensive metabolism of the parent drug into cytotoxic metabolites with a maximum plasma concentration (Cmax) 1 hour after ingestion. Linear increases in the area under the concentration-time curve (AUC) and Cmax were seen with linear increases in administered dose. CONCLUSION: The suggested phase II dose on a continuous 42-day dosing schedule is 1,331 mg/m2/d. Linear pharmacologic parameters of the parent compound and metabolites are demonstrated.

Administration, Oral↗

PubMed1997

Unusual central nervous system toxicity in a phase I study of N1N11 diethylnorspermine in patients with advanced malignancy.

The objectives of this study were to determine the dose limiting toxicity (DLT) and other major toxicities, the maximum tolerated dose (MTD) and the human pharmacokinetics of N1N11 diethylnorspermine (DENSPM), a new polyamine analog which in experimental systems inhibits the biosynthesis of intracellular polyamines and promotes their degradation by inducing the enzyme spermine/spermidine N-acetyl transferase. These objectives were incompletely achieved because of the occurrence of an unusual syndrome of acute central nervous system toxicity which forms the basis of the present report. Fifteen patients with advanced solid tumors were entered into a phase I study of DENSPM given by a 1 h i.v. infusion every 12 h for 5 days (10 doses). The starting dose was 25 mg/m2/day (12.5 mg/m2/dose) with escalation by a modified Fibonacci search. Doses of 25 and 50 mg/m2/day were tolerated with only minor side effects of facial flushing, nausea, headache and dizziness (all grade I). At doses of 83 and 125 mg/m2/day, a symptom complex of headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia, was seen in 3 patients, one after 2 courses of 83 and 2 after 1 course of 125 mg/m2/day. This syndrome occurred after drug administration was complete and the patients had returned home. Lesser CNS toxicity was seen in 2 other patients at lower daily doses. Preliminary pharmacokinetics of DESPM measured in plasma by HPLC in 8 patients showed linearity with dose and a rapid plasma decay with a t1/2 of 0.12 h. We conclude that great caution is warranted in administering DENSPM on this schedule at doses of > or = 83 mg/m2/day.

Adenocarcinoma↗

PubMed1997

A phase II study of 5-fluorouracil, leucovorin, adriamycin, and cisplatin (FLAP) for metastatic gastric and gastroesophageal junction adenocarcinoma. A Penn Cancer Clinical Trial Group and Roswell Park Cancer Institute Community Oncology Research Program Trial.

A Phase II study was performed to evaluate the activity and toxicity of 5-fluorouracil, leucovorin, Adriamycin, and cisplatin combination chemotherapy (FLAP) in patients with previously untreated advanced gastric and gastroesophageal (GE) junction adenocarcinoma. Forty-two consecutive patients were enrolled to received FLAP in this multi-institutional trial. Response, toxicity, and survival data were noted. Fifteen of 42 (36%) patients demonstrated objective responses, with two complete responses (5%) and 13 partial responses (31%). The median time to disease progression was 17 weeks, and the overall survival duration was 30 weeks. Myelosuppression was significant, requiring dose modifications, but there were no treatment-related deaths. FLAP is an active regimen in the treatment of advanced gastric and GE junction adenocarcinoma. We are presently using this regimen in the neoadjuvant setting in patients with gastric and GE junction cancers.

Adenocarcinoma↗

PubMed1997

Phase I and pharmacokinetic study of etoposide phosphate by protracted venous infusion in patients with advanced cancer.

PURPOSE: Etoposide has schedule-dependent cytotoxic activity, and clinical resistance may be overcome with prolonged low-dose therapy. Oral bioavailability is variable, and protracted intravenous administration is limited by water insolubility, which requires large infusion volumes. Etoposide phosphate (EP) is a water-soluble prodrug that is rapidly converted in vivo to etoposide, and may be administered in concentrated solution. A phase I study was conducted to determine the toxicity, pharmacokinetics, and pharmacodynamics of EP administered as a protracted venous infusion in the ambulatory setting. METHODS: Twenty-three patients with advanced cancer were treated with a continuous infusion of EP using ambulatory pumps for 6 weeks followed by a 2-week rest. Cohorts were treated with EP at 10, 20, 25, and 30 mg/m2/d. Steady-state plasma etoposide levels (Css) and stability of EP in infusion pumps were measured using high performance liquid chromatography (HPLC). RESULTS: Myelosuppression, mucositis, and fatigue were dose-limiting. The maximum-tolerated dose (MTD) of EP was 20 mg/m2/d. The mean Css (+/- SD) of etoposide were 0.67 +/- 0.25, 1.14 +/- 0.24, 1.38 +/- 0.64, and 2.19 +/- 0.52 microg/mL at daily EP doses of 10, 20, 25, and 30 mg/m2, respectively. Neutropenia correlated with Css (r = 0.65, P = .008). EP was stable in infusion pumps for at least 7 days. Partial responses were observed in patients with hepatoma and non-small-cell lung cancer (one each). CONCLUSION: EP may be conveniently and safely administered as a low-volume protracted venous infusion in the ambulatory setting. Cytotoxic plasma concentrations of etoposide are obtained at the MTD. The pharmacodynamic relationships observed suggest the possibility of pharmacologically based dosing of EP.

Adult↗

PubMed1997

Oral UFT plus leucovorin in patients with relapsed or refractory colorectal cancer.

Therapeutic options for patients with advanced colorectal cancer who have failed treatment with fluorouracil (5-FU) are limited. Responses have been reported in this setting with a protracted venous infusion of 5-FU. Daily oral therapy with tegafur and uracil (UFT) plus leucovorin (LV) has the potential to mimic the pharmacology of continuous infusion 5-FU. Therefore, we undertook a phase II study of a 28-day schedule of a combination chemotherapy regimen containing oral UFT/leucovorin in patients with measurable metastatic colorectal cancer who had failed treatment with bolus 5-FU. In addition, we sought to determine whether coadministration of UFT and leucovorin alters the bioavailability of these agents. In a pretreatment phase, each patient underwent sequential pharmacokinetic sampling following a single dose of UFT alone, leucovorin alone, and the combination of UFT plus leucovorin. The preliminary results of this trial suggest that tegafur pharmacokinetics are not affected by coadministration of leucovorin and that folate pharmacokinetics are not affected by UFT.

Adult↗

PubMed1996

A pilot study of cryochemotherapy for hepatic metastases from colorectal cancer.

Cryosurgery of hepatic metastases from colorectal carcinoma is a form of local therapy for unresectable disease. After curative resection, failures occur in the liver, and at extrahepatic sites. This pilot study evaluated the toxicity and tolerance to cryotherapy and intraoperative chemotherapy for unresectable hepatic metastases from colorectal cancer. If after exploratory celiotomy for potential curative resection of hepatic metastases the patient was deemed unresectable because of location and/or number of lesions, cryosurgery and intraoperative chemotherapy with systemic 5-fluorouracil 600 mg/m2 and leucovorin 500 mg/m2 was performed. Four patients were treated with cryochemotherapy. All patients developed toxicity. Two patients developed grade II leukopenia on Postoperative Days 2 and 12, and grades II and III diarrhea on Postoperative Days 5 and 7, respectively. Grade III hyperbilirubinemia and thrombocytopenia occurred in one patient on Postoperative Days 3 and 7. Acute respiratory distress syndrome, postoperative ileus, and grade II mucositis occurred in one patient each. All patients had delays and dose reductions on their subsequent chemotherapy treatments secondary to toxicity. Two patients had disease progression, one had stable disease. and one is "disease free." Combining the tumoricidal effects of chemotherapy and cryosurgery is in theory a good concept. However, the toxicity of 5-FU and leucovorin is enhanced by this approach.

Aged↗

PubMed1996

Phase II trial of ZD1694 (Tomudex) in patients with advanced pancreatic cancer.

BACKGROUND: Currently available therapies for advanced pancreatic cancer offer only palliative benefits, and patients with this disease have a poor prognosis. We undertook a phase II trial of ZD1694 (Tomudex), a quinazoline folate analogue that is a potent and selective thymidylate synthase inhibitor, to determine this analogue's efficacy and safety in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: ZD1694, 3.0 mg/m2, was administered to 42 adult patients with pancreatic adenocarcinoma as a 15-minute intravenous infusion every 3 weeks for up to 6 doses. Objective tumor response was assessed every 6 weeks; clinical examinations, adverse event assessments, and clinical laboratory tests were performed every 3 weeks. RESULTS: ZD1694 produced an overall response rate of 5% (95% confidence limits [CI], 1% to 16%) in the study group. Of 42 patients, 2 (5%) had a partial response, 12 (29%) had stable disease, 21 (50%) had disease progression, and 5 (11%) could not be evaluated for response. Grade 3 vomiting, grades 3 and 4 fever, grade 3 leukopenia, grade 4 thrombocytopenia, and grades 3 and 4 liver function elevations were reported. Toxic effects with ZD1694 were reversible and manageable. CONCLUSIONS: ZD1694 has an acceptable safety profile but limited activity in patients with advanced pancreatic cancer.

Adult↗