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)

Useful palliation can often be achieved when standard treatment approaches of external beam irradiation and chemotherapy with or without resection are used for locally advanced primary rectal malignancies. Local control and long-term survival are achieved in only 10% to 50% of patients, however, due to the limited irradiation tolerance of surrounding organs and tissues. Encouraging trends exist in separate intra-operative irradiation analyses from Massachusetts General Hospital and Mayo Clinic with regard to improvement in local control and possibly survival of locally advanced rectal lesions, warranting continued evaluation of such approaches. Disease control within the intra-operative and external irradiation field is decreased, however, when the surgeon is unable to accomplish gross total resection. Therefore it seems reasonable to consistently add 5-Fluorouracil with or without Leucovorin during external irradiation and to evaluate the use of dose modifiers, such as sensitizers or hyperthermia, in conjunction with intra-operative irradiation. Since high systemic failure rates exist with both locally advanced primary and recurrent lesions, more effective chemotherapy needs to be evaluated during external irradiation as well as after completion of such. In view of survival advantages with 5-Fluorouracil plus Leucovorin versus 5-Fluorouracil alone for metastatic disease, this regimen is currently being employed. Even with locally recurrent lesions, the aggressive multimodality approaches including intra-operative irradiation have resulted in improved local control, and long-term survival rates of 20% to 25% versus an expected 5% with conventional techniques in historical series.
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PMID:The role of intra-operative irradiation in locally advanced primary and recurrent rectal adenocarcinoma. 158 87

Sixteen patients with metastatic carcinoma of the colon were treated with a regimen of leucovorin 200 mg/m2, given as a 10-min infusion followed by a median dose of 833 mg/m2 (range 500-1000 mg/m2) 5-fluorouracil every two weeks. For the 16 patients with proven metastatic disease, two-year survival exceeds 50%. Responses were: 2 complete; 4 partial; 4 minor; 3 progression; and 3 not evaluable but without progression to date. Toxicities include: 8 (50%) leukopenia; 9 (56%), 1 severe thrombocytopenia; 9 (56%), 2 severe, diarrhea; 9 (56%), 3 severe, nausea/vomiting; 8 (50%), 1 severe, stomatitis; 7 (44%) conjunctivitis; 6 (38%) alopecia; and 13 (81%), 3 severe, neurotoxicity. Leucovorin appears to exert a dose-dependent beneficial effect on both the response and survival produced by the intermittent high-dose 5-fluorouracil schedule. This benefit first appears to increase substantially when the leucovorin dose is increased from 120 to 200 mg/m2. Findings identify a testable candidate regimen for selected good risk patients. Full selection criteria remain to be identified.
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PMID:Dose-dependent leucovorin efficacy with an intermittent high-dose 5-fluorouracil schedule. 220 56

Thymidylate synthase (TS) is the enzyme target of 5-fluorouracil (FUra) that recent laboratory and clinical studies with folinic acid (calcium leucovorin) suggest may mediate important antitumor cytotoxicity. Measurement in carcinoma tissue of parameters related to TS inhibition by 5-fluorodeoxyuridylate (FdUMP), by analogy to hormone receptor analysis, should be useful to determine which patients should receive fluoropyrimidine drug therapy and to evaluate folinic acid requirements. Folinic acid is metabolized to 5,10-methylenetetrahydropteroylglutamine (CH2FH4), which must be present in large excess to effect desired levels of maximal inhibition of TS, by promoting formation and stabilization of TS-FdUMP-CH2FH4 ternary complexes. In patients with metastatic disease, serial biopsies of tumor and normal tissues for studies of pharmacodynamic responses to test-dose FUra or folinic acid are shown to be easily added to routine intraoperative management. A suitable methodologic approach is described and examples given of assays of free TS, FdUMP, dUMP, and CH2FH4 levels after FUra or folinic acid, that may be useful in future studies aimed at improving the cost-effectiveness of FUra-folinic acid combinations.
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PMID:Folinic acid modulation of fluorouracil: tissue kinetics of bolus administration. 250 Apr 6

Both cisplatin and leucovorin may increase the activity of 5-fluorouracil (5-FU) by increasing the intracellular concentration of reduced folates. Therefore, a Phase I study was conducted in patients with recurrent or metastatic head and neck cancer in which high doses of oral leucovorin were added to the combination of cisplatin and 5-FU. Patients received intravenous cisplatin 100 mg/m2 on day 1, followed by a continuous intravenous infusion of 5-FU at 600 mg/m2/day for 5 days. Leucovorin 50 mg/m2 orally was administered from the start of the cisplatin infusion and then every 6 hours throughout the 5-FU infusion. The dose of 5-FU was increased to 800 mg/m2/day and 1 g/m2/day according to observed toxicity. In a second phase of the study, the dose of leucovorin was increased to 50 mg/m2 orally every 4 hours. Twenty-five patients were registered: 23 had recurrent head and neck cancer after extensive treatment; two had newly diagnosed metastatic disease. The maximum tolerated dose of 5-FU was 800 mg/m2/day with leucovorin administered every 6 hours. Toxicities at that level included mild-to-moderate myelosuppression. Mucositis in the previously irradiated field prevented the further increase of the 5-FU dose to 1 g/m2/day. Identical toxicities were observed when administering 5-FU at 800 mg/m2/day with 50 mg/m2 of leucovorin every 4 hours. Eighteen patients were evaluated for response: one had a pathologic complete response; nine had a partial response (including four who had previously received cisplatin and 5-FU as induction chemotherapy). Eight patients did not respond. The median survival for all 25 patients was 6.5 months. It was concluded that the combination of cisplatin, 5-FU, and leucovorin is active in the treatment of recurrent head and neck cancer. The maximum tolerated dose of 5-FU in previously treated patients is 800 mg/m2/day, with mucositis being the dose-limiting toxicity. Further investigation of this regimen as neoadjuvant chemotherapy in previously untreated patients with locally advanced head and neck cancer is in progress.
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PMID:Cisplatin, 5-fluorouracil, and high-dose oral leucovorin for advanced head and neck cancer. 278 81

Isolated liver metastases of colorectal carcinomas principally can be treated by surgical intervention or cytostatic chemotherapy. Unquestionable indications for resection therapy are either solitary metastases or metastases limited to one liver lobe, since resection provides the best long-time results. In multilocular metastases or non-resectable liver metastases systemic monochemotherapy with 5-Fluorouracil (5-FU) presents respondance rates of about 20 percent with remissions lasting 3 to 6 months. Thereby a prolongation of life could not be proven statistically. Initial studies with a combination therapy of 5-FU/Folinic acid promise higher remission rates due to an increased cytotoxicity caused by a synergistic effect. Because of the mainly arterial supply of liver metastases the different procedures of regional chemotherapy-intraarterial infusion, isolated liver perfusion, chemoembolisation-provide the tumor with high drug concentrations without provoking systemic side effects. This advantage of a regional application of cytostatic drugs is reduced by the high percentage (2 to 87 percent) of extrahepatic tumor manifestations occurring after an average of 6 to 8 months.
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PMID:[Therapy concepts in colorectal liver metastases. What is proven, what is open to discussion?]. 297 48

From January 1978 to May 1983, 41 patients with primary high-grade osteogenic osteosarcoma of a limb were treated with a combination of intensive chemotherapy and prophylactic lung irradiation (PLI) intercalated between the first two cycles of chemotherapy. The primary tumor was treated according to its size and location by amputation, resection, high-dose radiotherapy, and salvage amputation for a tumor progressing under radiotherapy. Two weeks after surgery or simultaneously with radiotherapy, a three-drug regimen (cycle A) consisting of mitomycin C on day 1, vincristine followed by a 6-hour infusion of methotrexate on day 2 was given. Folinic acid rescue was started 6 hours after the end of the methotrexate infusion. A PLI of 20 G was given from day 10 to 22. On day 28, a four-drug regimen (cycle B) combining doxorubicin on day 1, vincristine on day 2 and dacarbazine with cyclophosphamide on days 3 to 6 was administered. Thereafter, five additional cycles of A and B were administered provided that the absolute number of polymorphonuclear cells and platelets had recovered. When these values were not attained, treatment was delayed until recovery. After a mean follow-up of 60.6 months, 16 patients have developed distant metastases, associated in four cases with local recurrence. Sixteen patients have died: 15 with metastases, one with no evidence of disease (toxic death). The overall survival of the entire group is 66% and the continuously disease-free survival 58% at 5 years. Alopecia, nausea, vomiting, asthenia, anorexia, and infraclinical and reversible impairment of lung ventilatory function were universal. A noticeable hematologic toxicity also was seen. One toxic death occurred after a pulmonary infection. Two patients developed cardiomyopathy. A multiparametic analysis of prognostic factors shows the very significant influence of age on treatment outcome. The continuous disease-free survival among the 17 patients younger than 15 years is 41% compared to 79% in older patients. The prognostic influence of age was independent of other factors. The delay (for more than two cycles) of methotrexate administration was the second independent prognostic factor. These results raise the question of using different protocols of adjuvant chemotherapy for patients younger or older than 15 years in order to optimize the curability/toxicity ratio.
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PMID:Age and dose of chemotherapy as major prognostic factors in a trial of adjuvant therapy of osteosarcoma combining two alternating drug combinations and early prophylactic lung irradiation. French Bone Tumor Study Group. 312 57

We added high-dose oral leucovorin to the combination of cisplatin and fluorouracil (5-FU) to assess the efficacy of this regimen in the treatment of patients with head and neck cancer. Cisplatin, 100 mg/m2, was followed by a 5-FU continuous infusion at 600 mg/m2/d for five days. Leucovorin, 50 mg/m2, was administered at the start of cisplatin and every six hours throughout the duration of the 5-FU infusion. The dose of 5-FU was escalated to 800 mg/m2 and 1,000 mg/m2 according to observed toxicity. In a second phase of the study, the dose of leucovorin was escalated to 50 mg/m2 every four hours. A total of 25 patients were registered: 23 had recurrent disease after extensive prior treatment; and two had newly diagnosed metastatic disease. The maximally tolerated dose of 5-FU was 800 mg/m2/d with leucovorin administered every six hours. Toxicities at that level included mild to moderate myelosuppression and dose-limiting mucositis in the previously irradiated field. Identical toxicities were observed when administering 800 mg/m2/d of 5-FU with leucovorin every four hours. Eighteen patients were evaluated for response: one had a pathologic complete response; nine had a partial response (including four who received prior cisplatin and 5-FU as induction chemotherapy); and eight patients failed to respond. The mean peak and trough plasma leucovorin concentrations were 2.61 (+/- 1.07) mumol/L and 2.46 (+/- 0.95) mumol/L with administration of the drug every six hours, and 2.75 (+/- 2.15) mumol/L and 2.52 (+/- 1.48) mumol/L with administration every four hours. We conclude that the combination of cisplatin, 5-FU, and leucovorin has activity in the treatment of recurrent head and neck cancer. The maximally tolerated dose of 5-FU in this study was 800 mg/m2/d, with mucositis in previously irradiated sites being dose-limiting. Plasma leucovorin concentrations exceeding 1 mumol/L are achieved following oral administration of this drug.
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PMID:Cisplatin, fluorouracil, and high-dose leucovorin for recurrent or metastatic head and neck cancer. 325 29

The primary site of metastasis of osteosarcoma is the lung. In the past, even if the primary lesion was completely removed by radical surgery, more than 90% of patients of died pulmonary metastasis with in one to two years. Control of osteosarcoma therefore depends upon the prevention and treatment of its pulmonary metastasis. The introduction of chemotherapy consisting mainly of Adriamycin and high-dose methotrexate with Leucovorin rescue, dramatically improved the prognosis of osteosarcoma. In the past where systemic chemotherapy was not available, the five-year survival rate was around 19%. The majority of patients developed bilateral pulmonary metastasis within one year after onset, and died. These patients exhibited numerous micro-metastases as well. In patients receiving surgical adjuvant chemotherapy with current combination of chemotherapeutic agents (ADM, HD-MTX, VCR, CPM, CDDP), the incidence of pulmonary metastasis was low, and the five-year survival rate increased to 65%. In patients who receive chemotherapy, pulmonary metastasis may be either delayed, a single metastasis appearing after the termination of treatment, or early and multiple, appearing resistant to treatment. Surgery is indicated in the former situation while some therapeutic system must be devised for the latter. Recently, preoperative chemotherapy for limb-saving is given to patients with osteosarcoma of the extremities (NSH-3, 4, 5). The adjuvant of chemotherapy proved to be of great significance for improving the survival rate of osteosarcoma and for achieving limb salvage.
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PMID:[Surgery and adjuvant chemotherapy of osteosarcoma]. 346 May 27

5-Fluorouracil (5-FU), when preceded by methotrexate (MTX), results in synergistic tumor cell kill both in vitro and in vivo in mice. Since MTX concentrations 10 microM or greater maximize the synergy in vitro, we administered sequential MTX-5-FU as follows: MTX 125-250 mg/m2 i.v. followed 1 hr later by 5-FU 600 mg/m2 i.v. Leucovorin (LV) rescue 10 mg/m2 i.v. was given at hr 24, then 10 mg/m2 p.o. every 6 hr for 5 doses. One-hour and 24-hr serum MTX levels were monitored and 24-hr serum creatinine levels obtained. A weekly schedule was adhered to where possible, although most patients had at least one course delayed during the first month of treatment because of toxicity. Maintenance was every 2 wk. Since our initial report (Proc Am Soc Clin Oncol 21:473, 1980), a total of 35 squamous cell head and neck cancer patients, 12 with de novo and 23 with recurrent or metastatic disease, have been treated. Overall response rate is 71%, 65% in recurrent patients, 83% in de novo patients. Complete response rate was 11%. Median response duration for recurrent patients was 3.6 mo. With all deaths scored as disease-related and a minimum follow-up of 18 mo in all patients, a median survival of 11.5 mo for the 23 recurrent and 12 mo for the de novo patients was seen. Pretreatment performance status affected survival with Eastern Cooperative Oncology Group (ECOG) 0-1 patients living significantly longer than bedridden patients (p less than 0.001). Toxicity was either hematologic or gastrointestinal, with diarrhea, the limiting toxicity, accounting for the one drug-related death. The MTX/5-FU combination sequence may provide significant long-lasting palliation in patients with recurrent squamous head and neck cancer.
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PMID:Methotrexate and 5-fluorouracil in sequence in squamous head and neck cancer. 634 97

Fifty-seven patients with transitional cell carcinoma of the bladder, categories pT2, pT3a and pT3b, were treated by transurethral resection of the tumour mass (54 cases) or partial cystectomy (3 cases) followed by 8 doses of methotrexate 2 g i.v. every 3 weeks with appropriate Leucovorin rescue. At completion of chemotherapy 6 months after TUR 33/57 patients were tumour-free; 5/57 had new superficial tumours; 13/57 had persistent tumour invading muscle, 3 showed tumour progression and 3 had died from treatment complications. One-year survival was 45/57 (82%); 2-year survival was 23/39. Although some patients developed metastases and others have grown new superficial tumours, of those surviving, the bladder was free of the original invasive tumour in 38/45 (84%) at 1 year and in 19/24 (79%) at 2 years. It is concluded that transurethral resection plus high dose methotrexate may offer an effective alternative to radiotherapy or cystectomy for a significant proportion of patients with invasive bladder cancer.
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PMID:Treatment of invasive bladder cancer by local resection and high dose methotrexate. 653 87


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