Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We hypothesized that hand-foot syndrome is an inflammatory phenomenon mediated by the overexpression of cyclooxygenase 2 (COX-2). Therefore, a specific COX-2 inhibitor such as celecoxib (Celebrex) could attenuate both the incidence and severity of hand-foot syndrome. We undertook a retrospective study comparing the incidences of hand-foot syndrome in 67 patients with metastatic colorectal cancer who took capecitabine (Xeloda) with or without celecoxib. Surprisingly, celecoxib seemed to attenuate capecitabine-induced diarrhea as well. Capecitabine/celecoxib was also associated with increased tumor response, proportion of stable disease (62.5% vs 22.8%, P = .001), and increase in median time to tumor progression (6 vs 3 months, P = .002) compared with capecitabine alone, despite the fact that patients on capecitabine/celecoxib had less favorable disease characteristics (age, performance status, and prior chemotherapies). Overexpression of COX-2, implicated in promoting angiogenesis, enhanced tumor invasiveness, evasion of apoptosis, and immune suppression, is a bona fide molecular target for many solid tumors, including colorectal cancer. Combining capecitabine with celecoxib in the treatment of colorectal cancer has strong preclinical rationales. A prospective study is being designed to evaluate capecitabine and celecoxib with or without epidermal growth factor receptor antagonist ZD1839 in the frontline treatment of metastatic colorectal cancer. These regimens under study are orally based and may significantly impact quality of life in the frontline treatment of metastatic colorectal cancer.
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PMID:Effect of celecoxib on capecitabine-induced hand-foot syndrome and antitumor activity. 1252 Jun 38

Although 5-fluorouracil (5-FU) is still the mainstay of systemic treatment for patients with metastatic gastric cancer, many patients do not show satisfactory response to this drug. We treated patients with metastatic gastric cancer resistant to 5-FU with a combination of irinotecan hydrochloride (I) and low-dose cisplatin (P). Twenty-one consecutive patients with advanced metastatic gastric cancer and performance status of 0-2, who had received prior chemotherapy with S-1, but had nonetheless shown unrelenting tumor progression, were treated with 60 mg/m(2) of I combined with 6 mg/m(2) of P, administered by intravenous infusion over 90 min following premedication with azasetron (I/low-P). I/low-P was repeated weekly for 3 weeks with the patient admitted to hospital, and thereafter, fortnightly on an outpatient basis. Seven, eight and six of the total of 21 patients had liver metastases, lymph node metastases and peritoneal dissemination, respectively. Objective response was observed in 11 of the 21 patients (52%; 95% confidence interval: 31-78%). Two (18%) and nine (82%) of these 11 patients exhibited complete and partial response, respectively. The median duration of the response was 7.9 months. The treatment regimen under study was tolerated very well by the patients. Thirteen of the 21 patients (62%) developed grade 1 or 2 leucopenia, which was the most common adverse reaction recorded. Diarrhea and nausea, grade I in all of the cases, occurred in five (22%) and nine (43%) patients, respectively. Based on its remarkable effectiveness, marked improvement in the quality of life of the patients, and the convenience of its administration, the I/low-P regimen is recommended as a promising second-line chemotherapeutic regimen for patients with metastatic gastric cancer resistant to 5-FU.
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PMID:Second-line chemotherapy with combined irinotecan and low-dose cisplatin for patients with metastatic gastric carcinoma resistant to 5-fluorouracil. 1268 44

A 61-year-old man received reduced intensity stem cell transplantation (RIST) for the treatment of metastatic gastric cancer. The cytoreductive course of RIST was uneventful until day 0, when fever suddenly developed and his performance status deteriorated. Edema developed in the bilateral lower extremities by day 7, which was diagnosed by Doppler ultrasonography as deep vein thrombosis (DVT) involving the femoral veins to the inferior vena cava. While the edema improved with anticoagulation treatment, gastrointestinal graft-versus-host disease (GVHD) followed on day 13. Diarrhea subsided spontaneously, but hypoalbuminemia persisted, with the subsequent development of oliguria and jaundice on day 18. He died of sepsis on day 30, without any evidence of cancer progression. This case demonstrates that DVT is a potentially significant problem following RIST for solid tumors.
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PMID:Fatal deep vein thrombosis after allogeneic reduced intensity hematopoietic stem cell transplantation for the treatment of metastatic gastric cancer. 1468 33

The objectives of this phase I/II trial were to determine the maximum tolerated dose, toxicities, and the dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non small-cell lung cancer (NSCLC). Seventy-three patients with stage IIIB/IV NSCLC were enrolled in this multicenter, phase I/II study. The initial regimen was paclitaxel 225 mg/m2 over 3 hours, followed by carboplatin at an area under the curve (AUC) of 6 over 30 minutes on day 1 and CPT-11 starting at 40 mg/m2 over 90 minutes on days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of the original seven patients. The regimen was amended with doses reduced to paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 at 40 mg/m2, all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m2 and 125 mg/m2 before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m2. Doses suitable for phase II study were determined to be paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 100 mg/m2. The pri-mary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia. On the phase I portion of the study, objective tumor response was observed in 39% (12 of 31, 95% confidence interval: 22%-58%). The median time to tumor progression was 6.8 months, median survival was 11.0 months, and 1-year survival probability was 0.46. These data were confirmed in the phase II portion with a 30% objective response rate, median time to progression of 5.6 months, median survival of 12.5 months, and a 1-year survival probability of 0.50. In conclusion, CPT-11 100 mg/m2, paclitaxel 175 mg/m2, and carboplatin AUC = 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable, warranting further study of this regimen. A review of other irinotecan-containing triplet combinations is presented.
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PMID:Irinotecan (CPT-11) in triplet combinations in patients with advanced non small-cell lung cancer: a review and report of a phase I/II trial. 1472 27

The purpose of this report is to summarize information on oxaliplatin, a drug recently approved by the U.S. Food and Drug Administration. Information provided includes regulatory history, study design, efficacy and safety results, and pertinent literature references. A single, multicenter, randomized trial, enrolling 463 patients with metastatic colorectal carcinoma whose disease had recurred or progressed during or within 6 months of completion of therapy with the combination of bolus 5-fluorouracil (FU)/leucovorin (LV) and irinotecan, was submitted. Study arms included infusional 5-FU/LV alone (arm A), oxaliplatin alone (arm B), and the combination of oxaliplatin and infusional 5-FU/LV(arm C). Oxaliplatin, at a dose of 85 mg/m2, was administered to patients in arms B and C intravenously over 2 hours in 250-500 ml of dextrose 5% in water (D5W) on day 1 only. A 200-mg/m2 dose of LV was administered simultaneously to arm C patients, in a separate bag using a Y-line, or alone to arm A patients, by i.v. infusion, over 2 hours. 5-FU was then administered to arms A and C patients, first as a bolus injection over 2-4 minutes at a dose of 400 mg/m2, then as a continuous infusion in 500 ml of D5W over 22 hours at a dose of 600 mg/m2. LV was repeated on day 2 of the cycle (arms A and C) followed by a 400-mg/m2 5-FU bolus and a 600-mg/m2 22-hour infusion. Treatment was repeated every 2 weeks. Response rate was the prespecified end point for accelerated approval. Time to progression (TTP) was a secondary end point. The prespecified primary comparison was between the 5-FU/LV regimen and the 5-FU/LV/ oxaliplatin combination regimen. The three arms were well balanced for patient prognostic factors. There were no complete responders. The partial response rates were 0%, 1%, and 9% for the 5-FU/LV, oxaliplatin, and oxaliplatin plus 5-FU/LV treatments, respectively (p = 0.0002, arm C versus arm A). The median times to radiographic tumor progression, based on available radiographs, were 2.7 months, 1.6 months, and 4.6 months, respectively (p < 0.0001, arm C versus arm A). Common adverse events associated with the combination treatment included peripheral neuropathy, fatigue, diarrhea, nausea, vomiting, stomatitis, and abdominal pain. Neutropenia was the major hematologic toxicity. Adverse events were similar in men and women and in patients <65 and > or =65 years of age, but older patients may have been more susceptible to dehydration, diarrhea, hypokalemia, and fatigue. Oxaliplatin in combination with infusional 5-FU/LV was approved for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed during or within 6 months of completion of first-line therapy with the combination of bolus 5-FU/LV and irinotecan. Approval was based on response rate and on an interim analysis of TTP. No results are available, at this time, that demonstrate a clinical benefit, such as improvement in disease-related symptoms or survival.
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PMID:FDA drug approval summaries: oxaliplatin. 1475 10

Although 5-fluorouracil (5-FU)-based chemotherapy is commonly used in patients with advanced colorectal cancer (CRC), little data exist on the tolerability and benefit of therapy in elderly patients. To compare toxicity, dose intensity, response rate, time to tumor progression, and overall survival for older and younger patients, we conducted a pooled analysis of 1748 patients, divided into 4 quartile-based age groups, from 4 North Central Cancer Treatment Group trials testing 5-FU with or without leucovorin for advanced CRC. Patients aged > 65 years had modestly higher rates of severe toxicity (grade >/= 3) overall (53% vs. 46%) and higher rates of diarrhea (21% vs. 16%), stomatitis (17% vs. 13%), and infection (4% vs. 2%). Toxicity rates were similar between patients aged 66-70 years and patients aged > 70 years. The response rate did not differ by age group (2-sided; P = 0.90); it was significantly lower for patients with higher performance status scores (30% for score of 0/1; 17% for 2/3; 2-sided; P = 0.001). Performance status, not age, was predictive of time to tumor progression and overall survival. The older patients with CRC treated with 5-FU have modestly higher rates of severe toxicity, mainly diarrhea and stomatitis. Supportive measures to control diarrhea and stomatitis may be particularly important in elderly patients. Age alone should not be used to determine whether older patients are treated, because performance status is predictive of dose intensity, response rate, time to tumor progression, and overall survival.
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PMID:5-Fluorouracil-based chemotherapy for advanced colorectal cancer in elderly patients: a north central cancer treatment group study. 1566 36

Treatment options for advanced hepatocellular carcinoma (HCC) remain limited. Recently, octreotide has been proposed for therapy, although its efficacy remains controversial. Thus, the aim of this open-label pilot study was to evaluate the response of HCC to long-acting octreotide (Sandostatin LAR). Thirty patients were enrolled for this prospective 2-year trial. Initially, patients were given short acting octreotide to ensure drug tolerability. Thereafter, patients received long-acting octreotide 30 mg IM every 4 to 6 weeks. Measurable disease was assessed at 3-month intervals. Five of 30 patients were unable to tolerate the test dose, and 1 patient was reevaluated and underwent hepatic resection. The remaining 24 patients, who received long-acting octreotide, all had advanced stage of disease with multifocal-massive morphology (67%), vascular thrombosis (63%), or extrahepatic spread (17%), but well compensated liver disease. The treatment was well tolerated, except for diarrhea. Median time to tumor progression was 3.6 months, and median survival was 5.1 months. Seven patients (29%) had stable disease (median duration of 8.0 months) with 2 patients demonstrating disease stability for 24 months. In conclusion, although occasional patients appear to have stable disease on long-acting octreotide therapy, overall the beneficial response in terms of time to tumor progression and survival is limited.
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PMID:Octreotide therapy for advanced hepatocellular carcinoma. 1634 Jun 41

Imatinib targets KIT and platelet-derived growth factor receptors (PDGFR) and is highly effective in the treatment of CML and GIST patients. Pancreatic cancers express KIT and PDGFRs. Therefore, 26 patients with unresectable pancreatic cancer were randomized to either gemcitabine (1000 mg/m2 weekly) or imatinib (2x400 mg po) treatment daily. Pancreatic adenocarcinoma was confirmed histologically and expression of KIT and PDGFRbeta was determined immunohistochemically in the biopsy specimens. Quality of life was assessed with two standard questionnaires. No objective responses were seen in either group. Median time to progression was 77 and 29 days (P=0.411) and median survival time was 140 and 60 days (P=0.517) for gemcitabine and imatinib, respectively. Survival and treatment responses were independent of KIT and PDGFRbeta expression in patients treated with imatinib. Grade 3/4 toxicities of imatinib treatment were anemia, elevated liver enzymes, vomiting, and dyspnea. Patients treated with imatinib reported diarrhoea and/or altered bowel function more frequently, which were treatable symptomatically. Quality of life was similar in both groups. In this small series of pancreatic cancer patients, treatment with imatinib was not associated with a significant control of cancer progression.
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PMID:The tyrosine kinase inhibitor imatinib fails to inhibit pancreatic cancer progression. 1589 16

Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. Sorafenib, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for sorafenib and 0% for placebo. Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively. Sorafenib significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated.
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PMID:Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. 1647 53

The purpose of this study was to determine the response to CPT-11 administered every three weeks to adults with progressive malignant glioma, treated with or without enzyme-inducing antiepileptic drug (EIAED) therapy, at the recommended phase 2 dose determined from a previous phase 1 study. Adult patients age 18 or older with a KPS of 60 or higher who had measurable recurrent grade III anaplastic glioma (AG) or grade IV glioblastoma multiforme (GBM) were eligible. No more than one prior chemotherapy was allowed, either as adjuvant therapy or for recurrent disease. The CPT-11 dose was 350 mg/m(2) i.v. every three weeks in patients not on EIAED and 750 mg/m(2) in patients on EIAED therapy. Patients with stable or responding disease could be treated until tumor progression or a total of 12 months of therapy. The primary end point of the study was to determine whether CPT-11 could significantly delay tumor progression, using the rate of six-month progression-free survival (PFS-6). The trial was sized to be able to discriminate between a 15% and 35% rate for the GBM group alone and between a 20% and 40% rate for the entire cohort. There were 51 eligible patients, including 38 GBM and 13 AG patients, enrolled. The median age was 52 and 42 years, respectively. PFS-6 for the entire cohort was 17.6%. PFS-6 was 15.7% (95% confidence interval [CI], 0.07-0.31) for the GBM patients and 23% (95% CI, 0.07-0.52) for AG patients. Toxicity for the group included diarrhea and myelosuppression. We conclude that the recommended phase 2 dose of CPT-11 for patients with or without EIAED was ineffective on this schedule, in this patient population.
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PMID:A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study. 1653 78


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