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Disease Stabilization (disease + stabilization)
Selected AbstractsA phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2008Peter Gimsing Abstract Purpose:, To determine the safety, dose-limiting toxicity and maximum tolerated dose (MTD) of the novel hydroxamate histone deacetylase inhibitor belinostat (PXD101) in patients with advanced hematological neoplasms. Patients and methods:, Sequential dose-escalating cohorts of three to six patients with hematological malignancies received belinostat administered as a 30-min i.v. infusion on days 1,5 of a 21-d cycle. Experience from a parallel dose-finding study in patients with solid tumors influenced the selection of the final dose. Results:, Sixteen patients received belinostat at one of three dose levels: 600 mg/m2/d (three patients), 900 mg/m2/d (three patients) and 1000 mg/m2/d (10 patients), the dose determined to be the MTD in a phase I solid tumor study [Steele et al. (2008) Clin Cancer Res, 14, 804,10]. The most common treatment-related adverse events (all grades) were nausea (50%), vomiting (31%), fatigue (31%) and flushing (31%). No grade 3 or 4 hematological toxicity compared with baseline occurred except one case of grade 3 lymphopenia. There were two related grade 4 adverse events of renal failure observed. Both events occurred in patients with multiple myeloma and had similar characteristics, i.e. an acute episode of decrease in renal function (pre-existing nephropathy in one patient), with a metabolic profile and decrease in tumor burden consistent with tumor lysis syndrome. No other related grade 4 events were noted. The only related grade 3 events noticed in more than one patient were fatigue and neurological symptoms (one patient had status epilepticus in association with uremia and one patient had paresthesia), all other related grade 3 events occurred in single patients. No cardiac events were noted. No complete or partial remissions were noted in these heavily pre-treated (median of four prior regimens) patients. However, five patients, including two patients with diffuse large-cell lymphoma [including one patient with transformed chronic myelomcytic leukaemia (CLL)], two patients with CLL and one patient with multiple myeloma, achieved disease stabilization in of two to nine treatment cycles. Conclusions:, Intravenous belinostat at 600, 900 and 1000 mg/m2/d is well tolerated by patients with hematological malignancies. The study was carried out in parallel to a similar dose-finding study in patients with solid tumors, in which the MTD was determined to be 1000 mg/m2/d days 1,5 in a 21-d cycle. This dose can also be recommended for phase II studies in patients with hematological neoplasms. [source] Long-term results of patients with malignant carcinoid syndrome receiving octreotide LARALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2009C. TOUMPANAKIS Summary Background, Octreotide LAR is an established treatment for malignant carcinoid syndrome. However, studies with large number of patients and long follow-up are lacking. Aim, To present long-terms results with octreotide LAR, assessing duration of clinical and objective response and treatment tolerance, in a large, homogeneous cohort of patients with malignant carcinoid syndrome. Methods, A total of 108 patients with metastatic midgut neuroendocrine tumours were included in this 8-year study. Clinical evaluation was based on a symptom score. Radiological assessment was based on RECIST (Response Evaluation Criteria In Solid Tumours) criteria. Results, Of the 108 patients, 24% had a sustained symptomatic response. In the remaining patients, loss of symptomatic response with the initial dose was noted within 3-60 months. In 17% of them, symptoms were controlled by just an increase of octreotide LAR dose, whilst the other patients required additional treatment. Overall, in 45.3% of patients, symptoms were well controlled during the study period with only octreotide LAR, and no additional treatment was required. No significant adverse effects were noted. Conclusions, Octreotide LAR treatment provides a sustained symptomatic response in about half of the patients with malignant carcinoid syndrome and contributes to disease stabilization for a longer period than previously described. [source] Diabetes mellitus and the peripheral nervous system: Manifestations and mechanisms,MUSCLE AND NERVE, Issue 2 2007Douglas W. Zochodne MD Abstract Diabetes targets the peripheral nervous system with several different patterns of damage and several mechanisms of disease. Diabetic polyneuropathy (DPN) is a common disorder involving a large proportion of diabetic patients, yet its pathophysiology is controversial. Mechanisms considered have included polyol flux, microangiopathy, oxidative stress, abnormal signaling from advanced glycation endproducts and growth factor deficiency. Although some clinical trials have demonstrated modest benefits in disease stabilization or pain therapy in DPN, robust therapy capable of reversing the disease is unavailable. In this review, general aspects of DPN and other diabetic neuropathies are examined, including a summary of recent therapeutic trials. A particular emphasis is placed on the evidence that the neurobiology of DPN reflects a unique yet common and disabling neurodegenerative disorder. Muscle Nerve, 2007 [source] Raloxifene, an oestrogen-receptor-,-targeted therapy, inhibits androgen-independent prostate cancer growth: results from preclinical studies and a pilot phase II clinical trialBJU INTERNATIONAL, Issue 4 2006RONALD L. SHAZER OBJECTIVES To determine, in preclinical in vivo animal and in clinical studies, whether raloxifene (a selective oestrogen-receptor (ER) modulator that targets ER-, and induces apoptosis in vitro in androgen-independent prostate cancer, AIPC cells) affects prostate cell differentiation, proliferation and carcinogenesis, and in the pilot phase II clinical trial, the response rate and duration of patients with AIPC treated with a daily oral dose of raloxifene. PATIENTS, MATERIALS AND METHODS Tumour proliferation rate in response to raloxifene treatment, and molecular markers of cell cycle and apoptosis, were evaluated in established ER-,-positive androgen-dependent (AD) CWR22 and AI CWRSA9 human xenograft prostate cancer models. Twenty-one patients with AIPC and evidence of disease progression were enrolled into the clinical trial and given daily oral raloxifene. RESULTS There was significant growth inhibition by raloxifene in the ADPC and AIPC xenograft models (CWR22 68%, P < 0.010; CWRSA9 64%, P < 0.001), with no tumour regression. There was evidence of G1 arrest by increased p27kip1 expression in the raloxifene-treated group. Eighteen patients comprised the efficacy analysis, as three withdrew before the first evaluation. At the first evaluation, five men had stable disease and continued on the study for a median of five cycles. The longest response was 17 cycles. Drug related toxicity was minimal. CONCLUSION Raloxifene has activity in xenograft models, slowing disease progression. This translated to possible disease stabilization in patients with AIPC. Further studies are warranted. [source] A phase 2 pilot trial of low-dose, continuous infusion, or "metronomic" paclitaxel and oral celecoxib in patients with metastatic melanomaCANCER, Issue 7 2010Rupal S. Bhatt MD Abstract BACKGROUND: Tumor angiogenesis has been associated with a poor prognosis in patients with metastatic melanoma (MM). Microtubule stabilizers and cyclooxygenase 2 (COX-2) inhibitors, alone and in combination, have produced inhibitory effects on endothelial cells and tumor angiogenesis. Angiogenesis, which is the growth of new blood vessels, is necessary for tumor growth and progression. Thus, the authors tested the safety and efficacy of a low dose of paclitaxel and celecoxib in patients with MM. METHODS: Patients received paclitaxel 10 mg/m2 for 96 hours weekly as a continuous intravenous infusion and oral celecoxib 400 mg twice daily. Systemic tumor response was assessed at 6-week intervals. Tumor measurements at the end of Cycle 1 were used as the baseline for assessment of tumor progression. Patients with unacceptable toxicity or disease progression after Cycle 2 relative to the end of Cycle 1 were taken off study. RESULTS: Twenty patients were enrolled. Twelve of 20 patients (60%) had received ,2 previous systemic therapies. Three patients did not receive treatment because of rapid disease progression. Treatment-related grade 3/4 toxicities were limited to catheter-related complications. One patient achieved a partial response, and 3 of 20 patients (15%) had stable disease for >6 months. The median time to progression was 57 days (95% confidence interval, 43-151 days), and the median overall survival was 212 days (95% confidence interval, 147-811 days). CONCLUSIONS: Low-dose, continuous intravenous infusion paclitaxel and oral celecoxib produced disease stabilization in a significant proportion of heavily pretreated patients with MM. These findings support a role for metronomic therapy in patients with this disease. Cancer 2010. © 2010 American Cancer Society. [source] Radioembolization of colorectal hepatic metastases using yttrium-90 microspheresCANCER, Issue 9 2009Mary F. Mulcahy MD Abstract BACKGROUND: The objective of the current study was to determine the safety and efficacy of Yttrium-90 (Y90) microsphere treatment in patients with liver-dominant colorectal metastases. METHODS: Seventy-two patients with unresectable hepatic colorectal metastases were treated at a targeted absorbed dose of 120 Gray (Gy). Safety and toxicity were assessed using version 3 of the National Cancer Institute Common Terminology Criteria. Response was assessed by anatomic imaging and positron emission tomography (PET). Survival from the diagnosis of hepatic metastases and first treatment were estimated using the Kaplan-Meier method. Substratification analyses were performed. RESULTS: The median dose delivered was 118 Gy. Treatment-related toxicities included fatigue (61%), nausea (21%), and abdominal pain (25%). Grade 3 and 4 bilirubin toxicities were observed in 9 of 72 patients (12.6%). The tumor response rate was 40.3%. The median time to hepatic progression was 15.4 months, and the median response duration was 15 months. The PET response rate was 77%. Overall survival from the first Y90 treatment was 14.5 months. Tumor replacement (,25% vs >25%) was associated with significantly greater median survival (18.7 months vs 5.2 months). The presence of extrahepatic disease was associated negatively with overall survival (7.9 months vs 21 months). Overall survival from the date of initial hepatic metastases was 34.6 months. A subset analysis of patients who had an Eastern Cooperative Oncology Group performance status of 0 demonstrated a median survival of 42.8 months and 23.5 months from the time of hepatic metastases and Y90 treatment, respectively. CONCLUSIONS: Y90 liver therapy appears to provide sustained disease stabilization with acceptable toxicity. Asymptomatic patients with preserved liver function at the time of Y90 appeared to benefit most from treatment. Cancer 2009. © 2009 American Cancer Society. [source] Hepatic artery chemoembolization for 110 gastrointestinal stromal tumorsCANCER, Issue 12 2006Response, prognostic factors, survival Abstract BACKGROUND. The efficacy of hepatic artery chemoembolization (HACE) was evaluated for gastrointestinal stromal tumors (GISTs) metastatic to the liver. METHODS. Records for patients with metastatic GIST who underwent HACE between January 1993 and March 2005 were reviewed and cross-sectional images were used to determine objective tumor response. Progression-free survival in the liver (PFS-liver) and overall survival (OS) were calculated with the Kaplan,Meier method. Patient, tumor, and treatment variables were analyzed to identify factors influencing survival. RESULTS. Of the 110 patients identified, the radiologic response to HACE could be evaluated in 85 patients, 12 of whom (14%) demonstrated partial responses, 63 of whom (74%) demonstrated stable disease, and 10 of whom (12%) demonstrated progressive disease. PFS-liver rates were 31.2%, 8.2%, and 5.4% at 1, 2, and 3 years, respectively; the median PFS time was 8.2 months. OS rates were 62% at 1 year, 32% at 2 years, and 20% at 3 years; the median OS time was 17.2 months. Patients who had >5 liver metastases and received only 1 HACE treatment were found to have a shorter PFS compared with patients with fewer metastases or those who received ,2 HACE sessions. Extensive liver involvement, the presence of extrahepatic metastases, and progression of liver disease after HACE were associated with poor OS. Use of imatinib prolonged OS time. CONCLUSIONS. HACE produced a durable tumor response or disease stabilization in the majority of patients with GISTs metastatic to liver. Extent of liver disease, presence of extrahepatic disease, number of embolization treatments, and use of imatinib were found to have prognostic influence on PFS, OS, or both. Cancer 2006. © 2006 American Cancer Society. [source] A phase II trial of arsenic trioxide in patients with metastatic melanomaCANCER, Issue 8 2005Kevin B. Kim M.D. Abstract BACKGROUND Arsenic trioxide induces growth inhibition and apoptosis in human melanoma cell lines. Therefore, a Phase II trial was conducted to evaluate the efficacy and toxicity of single-agent arsenic trioxide in patients with Stage IV melanoma. METHODS Twenty patients, 10 with metastatic melanoma of cutaneous origin and 10 with metastatic melanoma of choroidal origin, received arsenic trioxide 0.25 mg/kg/day for 5 days, followed by a maintenance dose of 0.35 mg/kg/day twice a week. All patients with melanoma of cutaneous origin and four patients with melanoma of choroidal origin had received prior therapy. RESULTS Single-agent arsenic trioxide did not induce clinical response in this patient population. Eight patients (five with melanoma of cutaneous origin, and three with melanoma of choroidal origin) had disease stabilization for at least six weeks. The median overall survival duration for patients with melanoma of cutaneous origin was 7.9 months, and that of patients with melanoma of choroidal origin has not been reached at a median follow-up duration of 11.8 months. Grade 3 toxicity included neutropenia, fatigue, abdominal pain, and arthralgia. Grade 4 toxicity did not occur. CONCLUSIONS Single-agent arsenic trioxide was generally well tolerated; however, no tumor regression was observed in this patient population. Future clinical trials should evaluate arsenic trioxide in combination with other anticancer drugs that may improve its clinical activity in melanoma. Cancer 2005. © 2005 American Cancer Society. [source] Pegylated liposomal doxorubicin-efficacy in patients with recurrent high-grade gliomaCANCER, Issue 6 2004Peter Hau M.D. Abstract BACKGROUND Doxorubicin exhibits high efficacy in malignant glioma cell cultures. Nonetheless, as a standard formulation, doxorubicin has not been used clinically, due to poor penetration of the blood-brain barrier. Furthermore, doxorubicin is known to induce tumor resistance genes. To address both of these issues, the authors investigated the use of pegylated liposomal doxorubicin (CaelyxÔ; Essex Pharma, Munich, Germany) alone (Trial 1) and in combination with tamoxifen (Trial 2) in two sequentially performed nonrandomized prospective Phase II trials involving patients with recurrent high-grade glioma. METHODS Twenty patients were included in each trial. Progression-free survival at 6 months (PFS-6) and toxicity were the primary endpoints. Expression of the tumor resistance proteins multidrug resistance protein 1 (MDR-1) and multiple resistance protein (MRP) was evaluated by immunohistochemical methods and by sestamibi,single-photon emission computed tomography (SPECT). RESULTS The overall response rate (including cases of disease stabilization) was 40% in both Trial 1 and Trial 2. PFS-6 was 15%, and the median time to disease progression was 17 weeks. It is noteworthy that 40% of patients with Grade III tumors had long-term responses, which lasted for up to 3 years. There was no significant difference between Trial 1 and Trial 2 in terms of efficacy. Both regimens were well tolerated, with the main side effect being palmoplantar erythrodysesthesia. The authors found no correlation between clinical response and expression of tumor resistance genes or between clinical response and SPECT data. CONCLUSIONS Pegylated liposomal doxorubicin administered alone or in combination with tamoxifen is safe and moderately effective in patients with recurrent high-grade glioma. None of the putative predictors for response that were evaluated proved to be significant in this setting. Cancer 2004. © 2004 American Cancer Society. [source] Radioimmunotherapy of small-volume disease of metastatic colorectal cancerCANCER, Issue S4 2002Results of a phase II trial with the iodine-13, carcinoembryonic antigen antibody hMN-1, labeled humanized anti Abstract BACKGROUND Whereas radioimmunotherapy (RIT) has shown disappointing results in bulky, solid tumors, preclinical results in small-volume disease and in an adjuvant setting are promising. In a previous Phase I study, the authors had encouraging results with the iodine-131 (131I),labeled humanized anti,carcinoembryonic antigen (anti-CEA) antibody (MAb) hMN-14 in small-volume disease of colorectal cancer. The aim of this study was to evaluate, in a subsequent Phase II trial, the therapeutic efficacy of this 131I-labeled humanized anti-CEA antibody in colorectal cancer patients with small-volume disease or in an adjuvant setting. METHODS Thirty colorectal cancer patients, with small-volume metastatic disease (n = 21; all lesions , 3.0 cm, and chemorefractory to 5-fluorouracil and folinic acid) or in an adjuvant setting (n = 9), 4,6 weeks after surgical resection of liver metastases with curative intention, were studied. The patients were given a single injection of 131I-hMN-14 immunoglobulin G at a 60 mCi/m2 dose level, which was shown to be the maximum tolerated dose in the previous Phase I study. Follow-up was obtained at 3-month intervals for as long as 36 months. RESULTS At a mean blood-based red marrow dose of 1.8 ± 0.8 Gy, myelotoxicity was the only toxicity observed, but only 1 of 28 assessable patients developed transient Grade 4 thrombocytopenia. Of the 21 patients with radiologically documented lesions, 19 were assessable. Three experienced partial remission and eight showed minor responses up to 15 months in duration (corresponding to an objective response rate of 16% and an overall response rate of 58%; the mean duration of response was 9 months). At the time this article was written, seven of nine patients in the adjuvant setting had remained free of disease for up to 36 months (one patient relapsed after 6 months and another after 30 months), whereas the relapse rate in a historical control group receiving chemotherapy was 67% over the same time period. Five patients with radiologically documented lesions, having experienced at least disease stabilization as a consequence of RIT, were retreated at the same 60-mCi/m2 dose level at 8,16 months after the first therapy. No evidence of increased toxicity was observed (no hematologic toxicity was higher than Grade 3). Two of four assessable retreated patients experienced partial remissions; one of these four again experienced disease stabilization as a consequence of the second radioantibody therapy injection. CONCLUSIONS These data suggest that RIT is a safe and effective form of therapy for small-volume colorectal cancer and has potential as treatment for colorectal cancer in an adjuvant setting. Toxicity is restricted to mild and transient leuko- and thrombocytopenia. Retreatment seems to be a feasible option. A prospective randomized comparison with standard chemotherapy is indicated. Cancer 2002;94:1373,81. © 2002 American Cancer Society. DOI 10.1002/cncr.10308 [source] KP1019, A New Redox-Active Anticancer Agent , Preclinical Development and Results of a Clinical Phase I Study in Tumor PatientsCHEMISTRY & BIODIVERSITY, Issue 10 2008Christian Abstract The promising drug candidate indazolium trans -[tetrachlorobis(1H -indazole)ruthenate(III)] (KP1019) is the second Ru-based anticancer agent to enter clinical trials. In this review, which is an update of a paper from 2006 (Hartinger et,al., J. Inorg. Biochem.2006, 100, 891,904), the experimental evidence for the proposed mode of action of this coordination compound is discussed, including transport into the cell via the transferrin cycle and activation by reduction. The results of the early clinical development of KP1019 are summarized in which five out of six evaluated patients experienced disease stabilization with no severe side effects. [source] | ||||||||||