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)

The drug discovery programs of the National Cancer Institute and the pharmaceutical industry recently have provided oncologists with a wide array of new chemotherapeutic agents that have considerable potential for breast cancer treatment. Foremost among these new agents are the taxanes, of which paclitaxel and docetaxel, the only members of this class currently in clinical use, have been associated with impressive response rates in patients with metastatic disease. Importantly, they display some evidence clinically of not being cross-resistant with the anthracyclines. Efforts now are being directed toward optimizing dose and schedule in the metastatic setting while integrating these agents into standard adjuvant regimens. Other agents that have undergone Phase II testing in breast cancer include vinorelbine, edatrexate, and losoxantrone. It remains to be determined, however, whether these drugs possess substantial advantages over other members of their class. Newer compounds, such as pyrazoloacridine, ICI D1694, topoisomerase-I inhibitors, temozolomide, penclomidine, fumagillin (TNP-470), and differentiators like the retinoids, hold substantial promise because of their unique mechanisms of action; however, Phase II testing of these agents is just beginning. Although alternative approaches to treatment, such as gene therapies, monoclonal antibodies, and growth factor inhibitors, are likely to have a positive impact, it is probable that progress will best be made by combining these strategies with chemotherapy. Therefore, continuation of the search for more effective chemotherapeutic agents should remain a high priority.
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PMID:New chemotherapeutic agents for breast cancer. 791 62

'Tomudex' (ZD1694), a direct and specific thymidylate synthase (TS) inhibitor entered phase III studies in November 1993. We present here the first analysis of a randomised multicentre, international phase III study. 439 patients with previously untreated advanced colorectal cancer were randomised to Tomudex 3.0 mg/m2 given once every 3 weeks or 5-fluorouracil (5-FU) 425 mg/m2 and leucovorin (LV) 20 mg/m2 for 5 days (the Mayo regimen), given every 4-5 weeks. Patients were evaluated weekly for toxicity and every 12 weeks for objective response. The two groups were well matched in terms of demographic characteristics. The mean age of the patients was 61 years and most had either liver (78%) or lung (25-29%) metastases. Ninety seven per cent of patients allocated to Tomudex and 94% of those allocated to 5-FU plus LV had measurable disease. Response was assessed using WHO/UICC criteria; all response data were source validated; 19.8% of patients who received Tomudex and 12.7% of patients who received 5-FU plus LV had complete or partial responses (P = 0.059, odds ratio 1.7, 95% confidence limits 0.98-2.81). There were no statistically significant differences in time to progression or survival between the two groups. Patients who received Tomudex spent a substantially shorter time in hospital for dosing and had significantly lower rates of grade 3 and 4 toxicities such as leucopenia and mucositis. Patients who received Tomudex had a significantly higher incidence of reversible grade 3 or 4 increase in transaminases, which appear to be of limited clinical significance. Improvement in quality of life, weight gain and performance status was seen in both groups. Tomudex has benefits in terms of higher response rates, reduced toxicity and more frequent palliative benefits when compared with 5-FU plus LV in the management of advanced colorectal cancer, and has a more convenient administration schedule.
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PMID:'Tomudex' (ZD1694): results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. The 'Tomudex' Colorectal Cancer Study Group. 856 46

Each year about 26,000 people in Britain develop colorectal cancer. Roughly half of these patients die from locally advanced or metastatic disease. Systemic chemotherapy, usually with regimens including fluorouracil, can prolong survival in patients with advanced or recurrent disease and may improve their quality of life. [symbol: see text] Raltitrexed (Tomudex-Zeneca), a new class of cytotoxic drug introduced last year, is claimed to simplify treatment and be as effective as one established fluorouracil regimen while causing less toxicity. We review raltitrexed and assess its place in the treatment of patients in whom colorectal cancer is advanced.
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PMID:Raltitrexed in colorectal cancer. 893 2

Over the past year, several new anticancer agents have entered the clinic and are undergoing further phase II clinical development at the time of this writing. There has been a sudden influx of rationally designed drugs with novel therapeutic effects ranging from direct cellular toxicity to inhibition of blood vessel formation and of metastases. This review focuses only on cytotoxic drugs that have been in clinical development for the past 5 years; however, only recently have these drugs found a "niche" in the clinic. These drugs include novel taxanes (eg, docetaxel), the camptothecin analogues (eg, irinotecan [CPT-11]), the newer generation of thymidylate synthase inhibitors (eg, raltitrexed [ZD 1694, Tomudex]), nucleoside analogues (eg, gemcitabine), and oral alternatives to intravenous 5-fluorouracil. Most of these agents have completed or have entered phase II or III testing, and the results of these trials will be available to us over the next few years.
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PMID:Promising new agents in oncologic treatment. 897 73

Colorectal cancer is one of the most frequent cancers in western countries. Five years after curative surgery and adjuvant chemotherapy, about 10% more patients with Dukes C colon cancer are free of disease compared to the control group. Several regimens using 5-fluorouracil with folinic acid (5FU/FA) or levamisole are available. For patients with disseminated disease. 5FU/FA based treatments allows a doubling in survival as compared to best supportive care. Moreover, quality of life is significantly improved. New agents are upcoming. Tomudex seems to be equivalent to 5FU/FA but easier to administer. CPT-11 or oxaliplatin have been investigated in second line after failure of 5FU/FA. The available data suggest that median survival is prolonged by ten months, in addition to what was already obtained in first line with 5FU/FA. Colorectal cancer must be revisited. An active approach of our patients should allow to reduce the incidence of the disease, to increase the number of disease free patients 5 years after surgery, to prolong survival and improve the quality of life of those who will develop metastatic disease.
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PMID:[Colorectal cancer: a controllable disease]. 941 44

The current phase III studies of chemotherapy in advanced colorectal cancer include 60% to 85% of patients with the liver as a site of metastatic disease. Within the past 10 years, various modulatory combinations of 5-fluorouracil (5-FU) with agents such as leucovorin, interferon, N-(phosphonacetyl)-L-aspartate (PALA), and methotrexate have produced higher response rates than 5-FU alone. A major seven-arm study, conducted by the Southwestern Oncology Group and reported in 1995, suggested that single-agent, continuous-infusion 5-FU demonstrated the most encouraging results. Nine of 12 reported randomized studies comparing the combination of 5-FU and leucovorin with 5-FU alone report significant increases in response rates; two studies reported significant increases in survival. The meta-analysis project involving 1381 patients confirmed the increase in response rate with the combination (23%) vs. 5-FU alone (11%) but did not demonstrate any significant difference in median survival. The current issues involving 5-FU administration largely concentrate on the best approach (modulation vs. scheduling) and comprehensive evaluation of end points (quality of life, survival, and pharmacoeconomics). The current literature examining quality-of-life issues suggests that 5-FU and low-dose leucovorin produce the best overall improvement in symptoms. Others argue that continuous-infusion scheduling is also associated with a very good quality of life (although the increased cost and morbidity of continuous-infusion administration has to be factored into this consideration). An important phase III study is currently being conducted by the National Cancer Institute of Canada comparing immediate vs. delayed (until symptomatic) chemotherapy in patients with advanced colorectal cancer. Of the new approaches to therapy, perhaps the most immediately applicable are the new thymidylate synthase inhibitors (in particular, Tomudex, which produces a response rate equivalent to that of 5-FU plus leucovorin with less toxicity and a more convenient schedule).
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PMID:Management of hepatic metastases from colorectal cancer: systemic chemotherapy. 983 94

Colorectal carcinoma is one of the most common malignancies in the western world, and although fluorouracil (5-FU) has been used in its treatment for almost 40 years, new agents with significant activity have been introduced recently. Irinotecan (CPT-11, Camptosar), a topoisomerase I inhibitor, administered at 300 to 350 mg/m2 every 3 weeks is significantly more active than continuous-infusion 5-FU in patients who have experienced disease progression after conventional therapy with 5-FU. In comparison to best supportive care, irinotecan improves survival and preserves quality of life despite treatment-related toxicity. Moreover, the combination of irinotecan and 5-FU has been explored in a number of different schedules. In previously untreated patients, overall response rates are high. Irinotecan can also be combined with mitomycin (mitomycin-C [Mutamycin]), oxaliplatin, or raltitrexed (Tomudex). Oxaliplatin is a new-generation platinum compound that has demonstrated activity against colorectal carcinoma in preclinical trials. It has been evaluated as a single agent against advanced colorectal carcinoma in the salvage setting and also in combination with 5-FU as initial therapy for metastatic disease (where it shows significant activity). The toxicity profile of oxaliplatin (chiefly characterized by neurotoxicity) differs from that of irinotecan (primarily producing diarrhea) and the potential, therefore, exists for combining these agents or for exploiting their possible synergy with 5-FU. The introduction of these two new active agents of different pharmacologic classes promises to enable significant improvements in the treatment of patients with colorectal carcinoma.
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PMID:The role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer. 1134 31

Combined modality therapy is an effective adjuvant therapy for many patients with clinically resectable rectal cancer. The indications for adjuvant therapy for rectal cancer are based on the pattern of failure after surgery. Despite radical surgery, local-regional failure frequently occurs in patients with transmural or node-positive rectal cancers. The incidence of treatment failure in the pelvis is directly correlated with the extent of transmural penetration (microscopic vs gross) and the additional risk of lymph node metastases. In the post-operative setting its use is dictated by pathologic stage and the type of operation (i.e. conventional surgery or a local excision). The choice of which post-operative adjuvant regimen to recommend in the non-protocol setting remains controversial. If 5-FU alone is used, then it is best administered by continuous infusion. In the preoperative setting, the use of adjuvant therapy depends on the clinical stage and the need for sphincter preservation. Phase I/II trials examining the use of newer chemotherapeutic agents such as Tomudex, UFT/leucovorin, CPT-11, oxaliplatin, eniluracil and capecitabine with preoperative radiation therapy are in progress. This review examines both the selection criteria and results of adjuvant combined modality therapy for patients with clinically resectable rectal cancer.
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PMID:Present indications for adjuvant therapy in resectable rectal cancer. 1197 5

Raltitrexed (Tomudex; TOM) hepatotoxicity is usually characterized by a transient and self-limiting increase in transaminase levels. How this may condition daily clinical practice is still unclear. The aim of this study was to investigate predictive factors of TOM hepatotoxicity. In total, 130 patients were treated at two medical oncology institutions with TOM (3 mg/m2) (52 patients) or TOM plus oxaliplatin (TOMOX) (100 mg/m2 day 1 or 70 mg/m2 day 1, 8) (78 patients). A multinomial logistic regression (adjusted for multilevel data) was performed (on all administered chemotherapy courses) to assess the dependence of hepatic toxicity on a set of clinical factors correlated with patient, disease and treatment characteristics. Creatinine clearance was calculated by the Cockcroft formula before each chemotherapy course. Most of the patients presented colorectal cancer (95%) and metastatic disease (93%). Out of the 130 patients, 41 were aged 70 or more, while 119 (91.5%) had a good performance status (PS) (ECOG 0 or 1). Before chemotherapy, liver metastases were present in 78 (60%) patients and elevated transaminase in 25 (19%). A total of 584 courses were administered (252 TOM and 332 TOMOX). National Cancer Institute Common Toxicity Criteria grade 1/2 and 3/4 transaminase toxicity was observed in 62 and 20% of patients, respectively. To control transaminase increase, glutathione (GSH) or ademethionine (SAMe) was administered in 96 and 129 cycles, respectively. Hepatotoxicity conditioned delays (a week or more) in 60 (10%) chemotherapy cycles and was the reason for the discontinuation of chemotherapy in eight (6%) patients. Among the factors evaluated with multivariate analysis, sex, age, PS, creatinine clearance, previous chemotherapy treatment, presence of liver metastases and oncology centre were not significantly associated with TOM hepatotoxicity. Elevated baseline transaminase levels (p=0.001), number of chemotherapy cycles (p<0.001), TOM cumulative dose (p=0.018), unprolonged intervals between courses (p<0.001) and TOMOX regimen (p<0.001) emerged as factors predictive of hepatotoxicity. In the same analysis, GSH (p<0.001) and SAMe (p<0.001) were hepatoprotective agents. This study confirmed TOM-based hepatotoxicity as a clinical relevant side-effect and a major factor for treatment delays or discontinuation. Predictive and protective factors listed above could assist the management of this toxicity that has probably been underestimated until now.
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PMID:Raltitrexed-induced hepatotoxicity: multivariate analysis of predictive factors. 1296 Jul 37