Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemotherapeutic agents may damage gastrointestinal epithelium and thereby impair the mucosal barrier to bacteria and their products. In order to obtain an objective measurement of gastrointestinal permeability to large molecules, we measured urinary excretion of [14C]polyvinylpyrrolidone administered p.o. (mean molecular weight 11,000) and tobramycin (molecular weight 467) in ten patients receiving 5-fluorouracil therapy for metastatic cancer of the colon. Base-line absorption of [14C]polyvinylpyrrolidone was 0.013 to 0.048% of the administered dose. Dose-related increases in absorption (range, two to 20 fold) occurred after 5-fluorouracil administration, but the dose response differed markedly between individuals. Absorption was maximal 8 to 15 days after the start of therapy, was correlated in time but not necessarily in severity with the presence of gastrointestinal symptoms, and was unaffected by oral nonabsorbable antibiotics. Tobramycin excretion was 8.5 times greater than [14C]polyvinylpyrrolidone excretion, but the two were highly correlated in simultaneous determinations (r, 0.93; p, < 0.001). With the exception of an episode of Escherichia coli bacteremia, infections coincided not with maximal [14C]polyvinylpyrrolidone absorption but with maximal granulocytopenia 17 to 24 days after the start of therapy. The gastrointestinal absorption of polyvinylpyrrolidone provides an objective measurement of mucosal integrity which may have applications in assessing the gastrointestinal toxicity of other cytotoxic agents.
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PMID:Increased gastrointestinal absorption of large molecules in patients after 5-fluorouracil therapy for metastatic colon carcinoma. 743 30

The delivery of high-dose epirubicin in patients with advanced breast cancer usually entails serious myelotoxicity and frequent treatment delays. Concurrent administration of G-CSF probably allows the administration of epirubicin on schedule with minimal morbidity. From August 1990 to February 1992, 42 women with advanced breast cancer were treated with six cycles of epirubicin 110 mg/m2 every 4 weeks. Filgrastim 5 micrograms/kg per day for 14 days was administered subcutaneously starting 24 hours after chemotherapy. All patients had multiple metastatic sites, and 39 had visceral metastases. All cases were evaluable for response, toxicity, and survival. Treatment was delayed in only two cases. The actually administered average dose per unit time per patient amounted to 99.6% of the dose prescribed by the protocol. Two (4.5%; 95% confidence interval [C.I.] 0-16%) patients demonstrated a complete response and 14 (33%; 95% C.I. 19-49%) a partial response. Median time to progression was 31 weeks and median survival was 60 weeks. Severe granulocytopenia was seen in six patients; stomatitis and diarrhea in one patient each. Myoskeletal pain was noticed in 23 (55%) patients, while cardiac problems were reported in 3 cases. The present study shows that the prophylactic use of r-met-hu G-CSF allows the administration of high-dose epirubicin every 4 weeks with minimal morbidity and an improved quality of life.
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PMID:High-dose epirubicin and r-met-hu G-CSF (filgrastim) in the treatment of patients with advanced breast cancer: A Hellenic Cooperative Oncology Group study. 752 43

Phase II trials of the novel biologic combination isotretinoin (13-cis-retinoic aid) plus recombinant interferon alfa-2a have demonstrated this combination's major activity against advanced squamous cell carcinoma of the skin and cervix. Because this combination has had limited study in other tumors, we initiated a phase II trial of this regimen in patients with metastatic colorectal adenocarcinoma. Sixteen patients with measurable metastatic colon carcinoma who had received no previous chemotherapy were entered on the trial. Patients received recombinant interferon alfa-2a, 6 million units a day subcutaneously, and isotretinoin, 1 mg/kg per day orally in two divided doses. Patients were evaluated for response after 8 weeks of treatment and then continued on therapy until progressive disease was documented. We did not observe complete or partial responses. Two patients experienced minor responses in measurable pulmonary metastases lasting 12 and 8 weeks. Grade 3-4 toxic reactions included fatigue (5 patients), granulocytopenia (6 patients), neurotoxicity (2 patients), and elevated serum triglyceride levels (2 patients). Although this combination has demonstrated significant activity in squamous cell carcinomas of the skin and cervix, our results suggest that it has little therapeutic activity against advanced colorectal adenocarcinomas.
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PMID:Phase II trial of isotretinoin and recombinant interferon alfa-2a in metastatic colorectal carcinoma. 757 63

Estramustine phosphate is a unique antimitotic agent that binds to tubulin and microtubule-associated proteins. Preclinically, estramustine combined with other microtubule inhibitors, like vinblastine or paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), produced additive or greater antimitotic and cytotoxic effects. Clinically, the estramustine/vinblastine combination has significant activity in hormone-refractory prostate cancer. We have begun a phase I study of paclitaxel by 96-hour continuous infusion every 3 weeks combined with daily oral estramustine (600 mg/m2). Eighteen patients with refractory solid tumors have received paclitaxel doses ranging from 80 to 140 mg/m2. Grade 3 or 4 granulocytopenia occurred in one of seven and two of four patients treated at the 120- and 140-mg/m2 dose levels, respectively. The latter two patients experienced grade 3 mucositis and had mean plasma paclitaxel levels exceeding 0.1 mumol/L. Other toxicities, principally nausea and hepatic function abnormalities, have been mild. The apparent steady-state concentrations of paclitaxel 100 and 120 mg/m2 administered with estramustine are similar to those reported for single-agent paclitaxel administered as a 96-hour infusion at doses of 100 and 120 mg/m2. In contrast, at the 140 mg/m2 dose level, paclitaxel concentrations increased throughout the infusion, and steady state was not reached in three of the four patients treated. Objective responses have been observed in two of three patients with adenocarcinoma of the esophagus and in two patients with hormone-resistant prostate cancer and measurable soft tissue metastases. Two additional patients with prostate cancer have been treated with the estramustine/paclitaxel combination, one achieving a major response and the other stable disease. The recommended phase II dose for 96-hour infusional paclitaxel with daily oral estramustine is at least 120 mg/m2. Studies to determine the effect of estramustine on paclitaxel pharmacokinetics are continuing. The antitumor activity observed merits phase II studies of this combination in hormone-resistant prostate cancer and other malignancies.
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PMID:Phase I study of paclitaxel and estramustine: preliminary activity in hormone-refractory prostate cancer. 759 35

Methoxymorpholinyldoxorubicin (FCE 23762) is a novel, highly lipophilic doxorubicin analogue. It possesses potent in vitro and in vivo antitumor activity including efficacy in multidrug-resistant tumor cell lines. It is also metabolically activated in vivo resulting in an 80-fold increase in potency over the parent drug. In this phase I study the drug was administered by i.v. bolus injection at 3-week intervals. Fifty-three patients with refractory solid tumors were treated; 133 courses of FCE 23762 were administered at doses ranging from 30 to 2250 micrograms/m2. The dose limiting toxicity was reversible myelo-suppression (granulocytopenia and thrombocytopenia), demonstrating a delayed nadir and recovery in comparison to doxorubicin. Other toxicities included transient elevation of hepatic transaminases, delayed and prolonged nausea and vomiting, mucositis, anorexia, fatigue, and diarrhea. Heavily pretreated patients demonstrated more myelosuppression than previously untreated patients at 1250 micrograms/m2. No cardiotoxicity was observed. Four objective tumor responses were seen: one complete response in a patient with pelvic recurrence of cervical cancer; one partial response in a patient with cutaneous and lymph gland metastases from head and neck cancer; and two minor responses in patients with liver metastases from colorectal cancer. Plasma concentrations of FCE 23762 and its 13-dihydro metabolite, FCE 26176, were measured in 20 patients at doses > or = 675 micrograms/m2, using HPLC with fluorescence detection. The area under the plasma concentration-time curve ranged from 30 to 80 ng/h/ml; plasma data suggested linear kinetics in the range of tested doses (although there was considerable interpatient variability). The maximum tolerated dose defined in this study using this schedule is 1500 micrograms/m2. A safe phase II dose for previously untreated patients using this schedule is 1250 micrograms/m2; however, this may actually be below the optimal dose for this patient population.
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PMID:Phase I clinical and pharmacokinetic study of 3'-deamino-3'-(2-methoxy-4-morpholinyl)doxorubicin (FCE 23762). 774 8

Thirty-five patients with bulky (designated as > or = 4 cm size) International Federation of Gynaecology and Obstetrics (FIGO) Stage IB cervical cancer were treated with cisplatin, 50 mg/m2, and vincristine, 1 mg/m2, administered intravenously at 10-day intervals for a total of three courses before planned radical hysterectomy. One patient died of unrelated cause following one course of chemotherapy and was not evaluated for response. Of the 34 evaluable patients who completed chemotherapy, a complete clinical response was noted in two patients (6%) and a partial response in 26 patients (76%). Five patients (15%) had stable disease and one patient (3%) had disease progression. All chemotherapy was completed within 4 weeks (range 17-28 days). There was no grade 4 toxicity noted. Only one case each of reversible grade 3 granulocytopenia and stomatitis and two cases of reversible grade 3 peripheral neuropathy were noted. Of the 34 patients who received chemotherapy, the only patient with disease progression received standard pelvic radiation therapy in lieu of radical surgery. A second patient with stable disease had unresectable pelvic lymph node metastases and underwent confirmatory lymph node biopsy only and received standard radiation therapy postoperatively. The remaining 32 patients underwent radical hysterectomy and pelvic lymphadenectomy from 12 to 49 days following chemotherapy. Surgery was performed without significant difficulty. Eight of these patients (25%) had pelvic node metastases and received postoperative pelvic radiation therapy. Twenty-four months following initiation of treatment, 25 (74%) were alive and presumed free of disease, 4 had died of cancer (12%), 1 was alive with recurrence (3%), and 4 patients (12%) were lost to follow-up. A prospective randomized study is needed to assess the value of this approach compared with standard management.
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PMID:Neoadjuvant chemotherapy with vincristine and cisplatin followed by radical hysterectomy and pelvic lymphadenectomy for FIGO stage IB bulky cervical cancer: a Gynecologic Oncology Group pilot study. 777 47

Thirty-two eligible patients with advanced metastatic breast cancer who had received no more than 1 prior chemotherapy regimen for metastatic disease (16 had received prior doxorubicin) were treated with piroxantrone at a dose of 120 mg/m2 intravenously every 21 days. In the twenty-seven patients evaluable for response, two partial responses were seen. Toxicities observed were primarily hematologic with grade 3 or greater granulocytopenia occurring in 34% of the patients. One patient developed symptomatic congestive heart failure at a total cumulative dose of 960 mg/m2. We conclude that piroxantrone given at this dose and schedule has minimal activity in patients with metastatic breast cancer.
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PMID:Phase II trial of piroxantrone in metastatic breast cancer. A Southwest Oncology Group study. 777 36

The purpose of this study was to determine whether methotrexate, vinblastine, doxorubicin, and cisplatin, each individually active in metastatic breast cancer (MBC), could, in combination, produce an overall response rate, median survival, and long-term survival sufficiently promising to merit its consideration for phase III trials in MBC and as induction therapy prior to autologous bone marrow transplant. From July 1986 through February 1990, 30 patients with stage IV, measurable breast carcinoma received M-VAC: methotrexate--30 mg/m2 days 1, 15, 22; vinblastine--3 mg/m2 days 2, 15, 22; doxorubicin--30 mg/m2 day 2; cisplatin--70 mg/m2 day 2. Cycles were repeated at 4-week intervals for up to six courses. Median age was 53 years (range 34-64 years). Prior treatment included adjuvant cyclophosphamide, methotrexate, and 5-Fluorouracil in 12 patients, radiotherapy in 13 patients, and hormonal therapy in 14 patients. Eleven patients were ER (+) at the time of initial diagnosis. Five patients had disease restricted to bone and/or nodes; the other 25 had visceral-dominant sites of metastases, with or without bone involvement, or evidence of rapid, inflammatory chest wall relapse. Twenty-nine of 30 patients were evaluable for toxicity and response; all were evaluable for survival. The major overall response rate was 83%, with a 21% complete remission rate. The chief toxicity was bone marrow suppression, with grade 4 granulocytopenia in 20 patients, grade 3 in 7 patients, and grade 3 and 4 thrombocytopenia in 5 patients. Grade 3 stomatitis occurred in 9 patients. Renal insufficiency was clinically insignificant, and neurotoxicity mild, with 7 patients sustaining grade 1 or 2 paresthesias. Median time to progression was 9 months and median survival 19 months (range, 5-84+ months) with 4 patients still alive at least 45+ months or more from the start of treatment and 2 presently free of progressive disease. Although highly toxic, M-VAC produces a response rate and survival duration in visceral-dominant MBC competitive with, if not superior to, conventional regimens such as CAF (Cytoxan, doxorubicin, 5-fluorouracil); it therefore merits further investigation in conjunction with hematopoietic growth factors and as cytoreductive therapy prior to autologous bone marrow transplantation.
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PMID:Phase II evaluation of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) in advanced, measurable breast carcinoma. 787 68

Taxol was evaluated in metastatic breast cancer in three trials. In the first, a phase II study, 25 patients who had received only one prior regimen of chemotherapy received Taxol (starting dose of 250 mg/m2). The response rates were 12% complete, 44% partial, and 32% minor. The median duration of response was 9 months (range, 3 to 19 months). The median survival was 20 months (range, 5 to 29+ months). Toxic effects were granulocytopenia less than 500/mm3 in 85% of all courses but serious infection in only 6% of courses, myalgias, and cumulative neuropathy. The second trial was a phase I study of Taxol by 24-hour infusion sequenced with doxorubicin by 48-hour infusion as initial chemotherapy for metastatic disease. In arm 1, Taxol preceded doxorubicin. The starting doses were 125 mg/m2 Taxol, 60 mg/m2 doxorubicin. Neupogen (5 micrograms/kg) was given subcutaneously on days 5 through 19. Ten patients received 96 courses. The maximum tolerated dose was defined by mucositis and infection at the starting dose. Cumulative thrombocytopenia occurred in subsequent courses. The unexpectedly severe toxic effects at doses that were low by comparison to other studies suggested schedule-related toxicity. Therefore, in arm 2 the sequence has been reversed: doxorubicin precedes Taxol. Doses have been escalated to 180 mg/m2 Taxol with 60 mg/m2 doxorubicin without dose-limiting toxic effects occurring. The third trial, a phase II study in patients who have received three or more prior chemotherapy regimens, is ongoing. Twenty-one of a planned 35 patients have been entered. Taxol has shown significant antitumor activity in minimally pretreated patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The M. D. Anderson Cancer Center experience with Taxol in metastatic breast cancer. 791 22

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane to enter routine clinical practice, has aroused considerable interest due to its novel mechanism of action and its significant activity in metastatic breast cancer. Given this activity, it seemed logical to attempt to combine paclitaxel with doxorubicin, the other most active single agent in metastatic breast cancer. The Eastern Cooperative Oncology Group performed two trials investigating paclitaxel/doxorubicin combinations in patients with advanced breast cancer in an attempt to identify a tolerable dose and schedule of the combination. In the first trial, paclitaxel and doxorubicin were alternated every 3 weeks in doses of 200 mg/m2 and 75 mg/m2, respectively, for patients who had received no more than one prior chemotherapeutic regimen. Therapy was well tolerated in this setting. At these doses, paclitaxel induced more granulocytopenia and less thrombocytopenia than did doxorubicin. Objective responses (complete and partial responses) were seen in seven of 12 patients; two other patients had improved disease (relief of pain in bony metastases). A second limited-institution Eastern Cooperative Oncology Group trial evaluated paclitaxel and doxorubicin given in combination. In this phase I trial, doxorubicin was given as an intravenous push and paclitaxel as a 24-hour continuous infusion. The sequence of drug administration (D-->P or P-->D) was alternated both between and within patients, so that we might evaluate the effect of administration schedule on toxicity. Therapy was begun at an initial paclitaxel dose of 150 mg/m2 and an initial doxorubicin dose of 50 mg/m2 in six patients, with a subsequent six patients receiving 175 and 60 mg/m2, respectively, of paclitaxel and doxorubicin. In addition, patients received granulocyte colony-stimulating factor 5 micrograms/kg/d. While therapy at the initial dose level was well tolerated, dose-limiting mucositis was seen at the second dose level, although only when paclitaxel preceded doxorubicin. This suggests that sequence of drug administration in paclitaxel-based regimens may play an important role as a determinant of toxicity and (perhaps) efficacy, a finding similar to that seen when paclitaxel and cisplatin were combined in patients with ovarian cancer. Based on this study, we identified the sequence of doxorubicin (50 mg/m2) followed by paclitaxel (150 mg/m2) to be the maximum tolerated dose. This combination is currently being compared with paclitaxel alone and doxorubicin alone in patients with advanced breast cancer in an intergroup trial led by the Eastern Cooperative Oncology Group.
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PMID:Paclitaxel (Taxol)/doxorubicin combinations in advanced breast cancer: the Eastern Cooperative Oncology Group experience. 793 56


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