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Toxicity Profile (toxicity + profile)
Kinds of Toxicity Profile Selected AbstractsToxicity Profile of Lisdexamfetamine Dimesylate in Three Independent Rat Toxicology StudiesBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2007Suma Krishnan The toxicity profile of orally administered LDX has been evaluated in rats. In an acute study, LDX doses of 60 mg/kg and higher caused increased motor activity. At 1000 mg/kg, one rat died and another was euthanized. In a 7-day repeat-dose study, all rats dosed with LDX (14 per dose group for each sex) showed increased activity; 10 male rats and 11 female rats at 300 mg/kg/day and 3 female rats at 100 mg/kg/day were euthanized because of self-mutilation and 1 male rat at 300 mg/kg/day was found dead. In a 28-day study, only rats at 80 mg/kg showed signs of self-mutilation and thin body condition. In both the 7- and 28-day studies, LDX caused significant changes in some blood chemistry parameters (e.g. blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase) and organ weights (e.g. particularly heart, liver, brain, and spleen). Overall, no apparent treatment-related histopathologic changes were observed. Toxicokinetic assessments indicated that as the dose of LDX was increased, rats were exposed to increasing levels of LDX and d -amphetamine. The extent of exposure to LDX and d -amphetamine increased after repeated-dose in the 28-day study. The findings of the repeat-dose studies indicate that the toxicity profile in rats administered LDX orally is comparable to that for d -amphetamine; however, the apparent lethal dose of LDX in rats is more than five times higher than the LD50 of orally administered d -amphetamine, supporting a putative protective effect of conjugating amphetamine with lysine. [source] Toxicity profile of delayed high dose sodium thiosulfate in children treated with carboplatin in conjunction with blood-brain-barrier disruption,PEDIATRIC BLOOD & CANCER, Issue 2 2006Edward A. Neuwelt MD Abstract Purpose To assess the safety of delayed high dose intravenous (i.v.) sodium thiosulfate (STS) in a case series of 12 children with malignant brain tumors who were treated with intraarterial (i.a.) carboplatin in conjunction with blood-brain-barrier disruption (BBBD). Methods Twelve children ages 17 months,12 years underwent a total of 132 BBBD chemotherapy treatments and also received delayed high dose STS (i.v.). Dose 1 of STS (10,16 g/m2) was administered 2 or 4 hr after carboplatin, and a second STS dose was administered 4 hr after dose 1 if the child had impaired baseline hearing. Toxicity data were graded in accordance with the National Cancer Institute Common Toxicity Criteria (Version 2). Audiologic monitoring to evaluate the otoprotective potential of STS was performed on 11 children. Ototoxicity was defined in accordance with the American Speech-Language-Hearing Association (ASHA) criteria. Baseline and end of treatment hearing status were graded using Brock's criteria. Results Nausea and vomiting were well controlled with anti-emetics administered approximately 30 min prior to STS infusion. Analogous to results in adult patients, there was mild transient hypernatremia and a trend for improved protection from ototoxicity in children who received STS delayed to 4 hr post-treatment versus 2 hr. Tumor responses were seen in heavily pre-treated patients with relatively chemo-resistant tumors, suggesting that STS did not protect the tumor from platinum cytotoxicity. Conclusion High dose STS is well tolerated in children under 12 years of age. Further studies of STS in children are warranted to assess otoprotection and the impact of STS on platinum mediated efficacy. © 2005 Wiley-Liss, Inc. [source] From Adjuvant Therapy to Breast Cancer Prevention: BCPT and STARTHE BREAST JOURNAL, Issue 3 2001Barbara K. Dunn MD Abstract: The continued widespread prevalence of breast cancer supports placing a high priority on research aimed at its primary prevention, particularly among women who are at increased risk for developing this disease. The suggestion of potential agents for the primary chemoprevention of breast cancer evolved out of the treatment setting. Extensive experience with tamoxifen, a first-generation selective estrogen receptor modulator (SERM) showing efficacy, first, in the treatment of advanced breast cancer and, subsequently, as adjuvant therapy for early stage disease established the safety of this agent. Cumulative data from multiple adjuvant studies documented the efficacy of tamoxifen in reducing second primary breast cancers in the contralateral breast, supporting its potential as a chemopreventive agent for breast cancer. The safety and second primary data on tamoxifen, together with extensive information on its pharmacokinetics, metabolism, and antitumor effects, as well as its potentially beneficial effects on lipid metabolism and osteoporosis, led the National Surgical Adjuvant Breast and Bowel Project (NSABP) to select tamoxifen for testing in the first prospective randomized phase III trial of the efficacy of a chemopreventive agent for preventing breast cancer in women at increased risk of the disease. Accordingly, in 1992 the NSABP started the Breast Cancer Prevention Trial (P-1) in which 13,388 women 35 years of age who were at increased risk of breast cancer according to Gail model risk factors [family history, age, and personal history (i.e., age at first birth, age at menarche, previous breast biopsies)] were randomized to tamoxifen 20 mg/day or placebo for 5 years. Through 69 months of follow-up tamoxifen reduced the risk of invasive breast cancer, primarily estrogen receptor-positive tumors, by 49% (two-sided p < 0.00001). Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided p < 0.002). In addition, tamoxifen reduced fractures of the hip, radius, and spine, but it had no effect on the rate of ischemic heart disease. As previously shown, the rates of endometrial cancer and vascular events increased with tamoxifen. With the P-1 results establishing tamoxifen as the standard of care for the primary chemoprevention of breast cancer in high-risk women, concern over the side effects of tamoxifen has prompted a continuing search for an agent that displays a more desirable efficacy/toxicity profile. Raloxifene, a second-generation SERM approved for the prevention of osteoporosis in postmenopausal women, displays antiestrogenic properties in the breast and possibly the endometrium, and estrogenic effects in the bone and on the lipid profile, suggesting it as a candidate for comparison with the chemopreventive standard, tamoxifen. Raloxifene will be compared to tamoxifen in an equivalency trial, the Study of Tamoxifen and Raloxifene (STAR) NSABP P-2, which began in July 1999 at almost 500 centers in North America. The plan is to randomize 22,000 postmenopausal women 35 years of age at increased risk of breast cancer by Gail criteria to tamoxifen 20 mg/day or raloxifene 60 mg/day for 5 years. Study endpoints include invasive and noninvasive breast cancer, cardiovascular disease, endometrial cancer, bone fractures, and vascular events. [source] Tumoral and tissue-specific expression of the major human ,-tubulin isotypes,CYTOSKELETON, Issue 4 2010Luis J. Leandro-García Abstract The ,-tubulins are microtubule components encoded by a multigene family, which produces slightly different proteins with complex expression patterns. Several widely used anticancer drugs base their activity on ,-tubulin binding, microtubule dynamics alteration, and cell division blockage. The expression of these drug targets in tumoral and normal cells could be of crucial importance for therapy outcome, unfortunately, the complex ,-tubulin expression patterns have been poorly characterized in human. In this study, we developed a quantitative RT-PCR technique that accurately determines the mRNA expression of the eight human ,-tubulin isotypes, encoding class I, IIa, IIb, III, IVa, IVb, V, and VI and applied it to 21 nontumoral tissues and 79 tumor samples belonging to seven cancer types. In the nontumoral tissues, we found that, overall, TUBB (I), TUBB2C (IVb), and TUBB6 (V) were ubiquitous, TUBB1(VI) was hematopoietic cell-specific, and TUBB2A (IIa), TUBB2B (IIb), TUBB3 (III), and TUBB4 (IVa) had high expression in brain; however, the contribution of the different isotypes to the total ,-tubulin content varied for each tissue and had a complex pattern. In tumoral tissues, most isotypes exhibited an altered expression in specific tumor types or related to tumoral characteristics. In general, TUBB3 showed a great increase in expression while TUBB6 expression was largely decreased in most tumors. Thus, normal tissues showed a complex ,-tubulin isotype distribution, which could contribute to the toxicity profile of the microtubule-binding drugs. In addition, the specific isotypes significantly altered in tumors might represent markers for drug response. © 2010 Wiley-Liss, Inc. [source] Chronic toxicity of five structurally diverse demethylase-inhibiting fungicides to the crustacean Daphnia magna: A comparative assessmentENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 6 2009Enken Hassold Abstract Demethylase inhibitors (DMIs) are broad-spectrum fungicides that are ubiquitously used in agriculture and medicine. They comprise chemically heterogeneous substances that share a common biochemical target in fungi, the inhibition of a specific step in sterol biosynthesis. Several DMIs are suspected to disrupt endocrine-mediated processes in a range of organisms and to inhibit ecdysteroid biosynthesis in arthropods. It is unclear, however, whether and, if so, to what extent different DMI fungicides have a similar mode of action in nontarget organisms, which in turn would lead to a common chronic toxicity profile. Therefore, we selected a representative of each of the major DMI classes,-the piperazine triforine, the pyrimidine fenarimol, the pyridine pyrifenox, the imidazole prochloraz, and the triazole triadimefon,-and comparatively investigated their chronic toxicity to Daphnia magna. No toxicity was detectable up to the limit of solubility of triforine (61 ,mol/L). All other DMIs reduced reproductive success by delaying molting and development and by causing severe developmental abnormalities among offspring. Prochloraz was most toxic (median effective concentration [EC50] for fecundity reduction, 0.76 ,mol/L), followed by fenarimol (EC50, 1.14 ,mol/L), pyrifenox (EC50, 3.15 ,mol/L), and triadimefon (EC50, 5.13 ,mol/L). Mean effect concentrations for fecundity reduction were related to lipophilicity and followed baseline toxicity. However, triadimefon and fenarimol (but none of the other tested DMIs) caused severe eye malformations among exposed offspring. Affected neonates did survive, but a reduced ecological fitness can be assumed. Offspring exposed to fenarimol in mater matured earlier. The investigated different life-history parameters were affected in a substance-specific manner. These qualitatively different toxicity profiles suggest additional, substance-specific mechanisms of action in D. magna that probably are related to an antiecdysteroid action. [source] Effects of a MAPK p38 inhibitor on lung function and airway inflammation in equine recurrent airway obstructionEQUINE VETERINARY JOURNAL, Issue 6 2008J.-P. LAVOIE Summary Reasons for performing study: It has been suggested that many of the beneficial effects of corticosteroids are mediated through mitogen-activated protein kinase (MAPK) p38 inhibition. Objective: To investigate the efficacy of the MAPK p38 inhibitor compound MRL-EQ1 to either prevent (Phase 1) or treat (Phase 2) recurrent airway obstruction (RAO) in horses. Methods: MRL-EQ1 was administered i.v. at a dosage of 0.75-1.5 mg/kg bwt q. 12 h. In Phase 1, susceptible horses in clinical remission were divided into 2 groups (n = 5/group), based on historical values of respiratory mechanics. All horses were entered in the study in pairs (one control, one treated horse) and exposed to the same environmental challenge (stabling, mouldy hay and dusty conditions). The treatment group received MRL-EQ1 for 14 days while the control horses were untreated during the same period. In Phase 2, affected horses were ranked by severity of respiratory dysfunction and split randomly into either dexamethasone or MRL-EQ1 treatment groups (n = 5/group). Bronchoalveolar lavage fluid, respiratory mechanic measurements, MRL-EQ1 plasma concentration and tumour necrosis factor (TNF) whole blood activity were evaluated sequentially. Results: In Phase 1, MRL-EQ1 did not prevent the occurrence of clinical signs and pulmonary inflammation. However, treatment was associated with a reduction in severity and a delay in the onset of signs and a reduction in pulmonary neutrophilia. In Phase 2, plasma concentrations achieved resulted in ex vivo suppression of lipopolysaccharide-induced TNF production in equine blood. MRL-EQ1 did not improve airway inflammation or lung function and was associated in a dose dependent manner with behavioural (depression, excitability) and blood changes (neutrophilia, increased serum muscle enzyme concentrations). Conclusions: Inhibition of p38 in the horse was partially effective in reducing clinical signs and airway inflammation when administered prior to, but not during clinical exacerbation in RAO. Potential relevance: Inhibitors of p38 MAPK with a better toxicity profile may be effective in the prevention or treatment of RAO. [source] Human immunodeficiency virus-associated diffuse non-Hodgkin's lymphoma in Venezuelan patients: treatment with full-dose cyclophosphamide-doxorubicin-vincristine-prednisone without routine use of granulocyte-colony stimulating factorEUROPEAN JOURNAL OF CANCER CARE, Issue 5 2006D.E. HERNÀNDEZ md, phd The routine use of granulocyte-colony stimulating factor (G-CSF) for 10 days during full-dose cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) chemotherapy in HIV-associated diffuse non-Hodgkin's lymphoma (NHL) patients is very expensive in developing countries. We treated 22 HIV-associated diffuse NHL patients with standard-dose CHOP and used G-CSF after an episode of febrile neutropenia until neutrophil count reached 1000/mm3. The clinical response was: complete response (36%), partial response (32%), stable disease (14%) and progression (18%). There were no toxicity-related deaths. Grade 3 or 4 neutropenia was observed in 16% of cycles, but only 8% were complicated with febrile neutropenia. Seventeen patients died (median survival 15 months; range 2,70). There are five patients alive (median survival 24+ months; range 17,36+). Our experience showed that we can treat HIV-related NHL patients with full-dose CHOP, achieve good responses and have an acceptable toxicity profile, with the use of G-CSF as needed. [source] Rituximab therapy in adult patients with relapsed or refractory immune thrombocytopenic purpura: long-term follow-up resultsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2008Marta Medeot Abstract Objective:, To evaluate the long-term activity and toxicity profile of rituximab in adult patients with idiopathic immune thrombocytopenic purpura (ITP). Patients and methods:, Twenty-six patients with active and symptomatic ITP relapsed or refractory received weekly infusions of rituximab 375 mg/m2 for 4 wk. Median time from diagnosis to rituximab was 34.5 months. The following parameters of efficacy and toxicity were considered: complete response (CR) and partial response (PR), relapse rate, relapse-free survival (RFS), therapy-free survival (TFS), short- and long-term toxicity. Results:, CR and PR were 14/26 (54%) and 4/26 (15%), respectively. Median time of observation was 56.5 months (range 39,77). Nine of the 18 responding patients relapsed after a median of 21 months (range 8,66); 9/26 patients (35%) maintained the response, with a median follow-up of 57 months (range 39,69), and 11/26 (42%) did not necessitate further therapy; estimated 5 yr RFS and TFS were 61% and 72%, respectively. Younger age and shorter interval from diagnosis to rituximab appeared indicators of better outcome. Rituximab administration was associated with two episodes of short-term toxicity, with one case of serum sickness syndrome; no infectious or other significant long-term complications were documented. Conclusion:, Rituximab therapy may achieve long-lasting remission in nearly one-third of patients with relapsed or refractory ITP, with a good safety profile. [source] Safety and efficacy of docetaxel, estramustine phosphate and hydrocortisone in hormone-refractory prostate cancer patientsINTERNATIONAL JOURNAL OF UROLOGY, Issue 7 2010Yoshihiro Nakagami Objective: To assess the combination of docetaxel (DTX), estramustine phosphate (EMP) and hydrocortisone for patients with hormone-refractory prostate cancer (HRPC). Methods: A total of 63 patients with HRPC were treated with a chemotherapeutic regimen including DTX, EMP, and hydrocortisone. Clinical and pathological features were correlated to serum prostate-specific antigen (PSA) recurrence and survival rates. Incidence and degree of toxicities were also retrospectively reviewed. Results: A median of 11 courses of chemotherapy was administered per patient. PSA levels decreased by >50% in 32 (51%) patients and >90% in 18 (29%) patients. Median time to PSA progression was 6 months (range from 1 to 41 months) and median time of overall survival was 14 months (range from 1 to 56 months). In a univariate analysis to predict overall survival, PSA, hemoglobin, alkaliphosphatase, and performance status prior to the chemotherapy were significant factors. Despite grade 3,4 neutropenia in 87% of patients, grade 5 interstitial pneumonia in one patient and grade 4,5 myocardial infarction in two patients were recognized, the regimen seemed to be relatively safe. Conclusions: Combination chemotherapy with DTX, EMP and hydrocortisone provides survival benefits for patients with HRPC with an acceptable toxicity profile. We need to further evaluate who might benefit most from this regimen. [source] Phase I,II trial of weekly gemcitabine plus high-dose 5-fluorouracil and leucovorin in advanced pancreatic cancerJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 3 2006HER-SHYONG SHIAH Abstract Background:, Pancreatic cancer is a dismal disease. Few drugs, including gemcitabine and 5-fluorouracil (5-FU), have notable antitumor effects against advanced pancreatic cancer. The purpose of the present study was to determine the maximum tolerated dose (MTD) of 5-FU and the efficacy and toxicity profile of weekly gemcitabine plus infusional 5-FU/leucovorin in advanced pancreatic cancer. Methods:, Patients with histo-/cytologically confirmed, advanced pancreatic cancer were eligible. Treatment consisted of a 30-min infusion of gemcitabine (800 mg/m2), followed by a 24-h infusion of 5-FU and leucovorin (300 mg/m2) at day 1, day 8 and day 15 every 28 days, and was termed the GemFL24 regimen. The dose of 5-FU was escalated from 1600, 2000, to 2600 mg/m2 in the phase I study, and fixed MTD for subsequent enrolled patients. Results:, Eighteen patients were enrolled in the phase I study, and 24 in phase II. The MTD of 5-FU was 2000 mg/m2, with major dose-limiting toxicities being febrile neutropenia and delayed recovery from neutropenia. The dose intensity of gemcitabine of the 35 patients with 5-FU dosage set at MTD was 593 mg/m2 per week. In the entire series of 42 patients, myelosuppression was the main toxicity, with grade 3 neutropenia in eight patients, and grade 3/4 thrombocytopenia in six. On an intention-to-treat analysis, the overall and clinical benefit response rates were 22% and 46%, respectively; with median progression-free and overall survival of 4.1 and 6.9 months, respectively. Conclusions:, The GemFL24 regimen is a feasible and moderately active treatment with manageable toxicities for advanced pancreatic cancer, and could be a basis for further combination with other anticancer drugs. [source] Assessing the antifungal activity and toxicity profile of amphotericin B lipid complex (ABLC; Abelcet®) in combination with caspofungin in experimental systemic aspergillosisJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2004Olena Sivak Abstract The purpose of this study was to assess the antifungal activity and renal and hepatic toxicity of amphotericin B lipid complex (ABLC; Abelcet®) following co-administration of Caspofungin to rats infected with Aspergillus fumigatus. Aspergillus fumigatus inoculum (1.3,2.3,×,107 colony forming units [CFU]) was injected via the jugular vein; 48 h later male albino Sprague,Dawley rats (350,400 g) were administered either a single intravenous (IV) dose of Fungizone® (1 mg AmpB/kg), ABLC (1 or 5 mg AmpB/kg), or an equivalent volume of normal saline (NS) (vehicle control) once daily for 4 days. Rats were further randomized into groups to receive 3 mg/kg Caspofungin or physiologic saline IV once daily for 4 days. To assess antifungal activity, brain, lung, heart, liver, spleen, and kidney sections were homogenized with NS (2 mL; 1 g of each tissue/mL) and a 0.1-mL aliquot was spread plated onto a Sabouraud dextrose agar plate. The plates were incubated for 48 h at 37°C, at which time the numbers of CFU were determined and corrected for tissue weight. To assess renal and hepatic toxicity, serum creatinine and aspartate aminotransferase levels were determined. Fungizone and ABLC at a dosing regimen of 1 mg/kg i.v. once daily for four consecutive days and Caspofungin at a dosing regimen of 3 mg/kg i.v. once daily for four consecutive days had similar effectiveness in decreasing the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to non-treated controls. A combination of ABLC (1 mg/kg i.v.,×,4 days) and Caspofungin (3 mg/kg i.v.,×,4 days) significantly decreased the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to Caspofungin alone and non-treated controls. ABLC at a dosing regiment of 5 mg/kg i.v. once daily for four consecutive days was more effective in decreasing the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to Fungizone or ABLC alone at 1 mg/kg and Caspofungin alone at 3 mg/kg. However, a combination of ABLC (5 mg/kg i.v.,×,4 days) and Caspofungin (3 mg/kg i.v.,×,4 days) was not more effective than ABLC at 5 mg/kg or the combination of ABLC at 1 mg/kg and Caspofungin 3 mg/kg in reducing the total number of Aspergillus fumigatus CFUs compared to controls. Except for non-treated infected control rats, none of the treatment groups tested displayed a greater than 50% increase in serum creatinine concentrations from baseline. In addition, only ABLC at a dosing regimen of 1 mg/kg i.v. once daily for four consecutive days displayed a greater than 50% increase in AST concentration from baseline. Taken together, these findings suggest that ABLC at 5 mg/kg once daily,×,4 days appears to be the best therapeutic choice in this animal model. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1382,1389, 2004 [source] Evaluation of serum cystatin C levels and 99mTechnetium-mercaptoacetyltriglycine-3 renal scintigraphy for the early detection of cisplatin-induced renal toxicity in cancer patientsNEPHROLOGY, Issue 2 2002Nazan GÜNEL SUMMARY: Cisplatin has a broad-spectrum antineoplastic activity. Nephrotoxicity is a prominent component of the toxicity profile of cisplatin-based chemotherapy. In recent years, several reports have confirmed that cystatin C (cys-C) demonstrates a better correlation with the glomerular filtration rate than with serum creatinine. Scintigraphic techniques are also widely used in evaluating renal function. In the present study, serum cys-C, serum creatinine concentrations and 99mTechnetium-mercaptoacetyltriglycine-3 (99mTc-MAG-3) scintigraphy were studied in 22 cisplatin-naive cancer patients, 3 days before and 24 h after the first cycle of cisplatin-based chemotherapy. Serum cystatin C and creatinine levels increased in cancer patients after chemotherapy (creatinine: from 68 ± 12 to 72 ± 17 nmol/L; cystatin-C: from 0.064 ± 0.025 to 0.072 ± 0.033 jimol/L), but these differences were not statistically significant (P>0.05). Semiquantitative variables of 99mTc-MAG-S scintigraphy significantly elevated after chemotherapy (T½*: from 10.27 ± 5.00to 16.17 ± 9.40 min, R20/max*: from 0.40 ± 0.12 to 0.67+0.45, Tmax**: from 5.40 ± 4.01 to 7.59 ± 5.30 min; *P<0.001, **P<0.01, respectively). These results suggest that MAG-3 scintigraphy is a highly sensitive method in the early detection of cisplatin-induced nephrotoxicity. Serum cystatin C doesn't seem to play a role in the early detection of cisplatin-induced nephrotoxicity. As a result, MAG-3 scintigraphy may be used in selected patients who have a predisposition for renal toxicity. [source] Retrospective review of mitomycin C use as third-line chemotherapy in metastatic colorectal cancerASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 3 2008Wei CHUA Abstract The aim of this review was to determine the therapeutic value of the combination of mitomycin C with either infusional 5-fluorouracil or oral capecitabine in metastatic colorectal cancer when used as third-line treatment or beyond in the setting of routine clinical practice. We retrospectively reviewed 18 patients with advanced colorectal cancer who received this combination at our institution after the failure of two lines of prior treatment. All the patients were assessable for toxicity and survival and 14 for tumor response. The median age of the patients was 61 (range 39,78). Of these, 72% were male and 78% had Eastern Cooperative Oncology Group performance status 0 or 1. Eighty nine percent of the patients had metastatic involvement of the liver and five patients had at least three sites of metastatic involvement. All patients had received at least two lines of chemotherapy and had progressed on an oxaliplatin-containing regimen. Most of the patients had previously received an irinotecan-containing regimen, and a third had received prior biological agents. Overall, none of the patients achieved either complete or partial responses. Two patients (11%) achieved stable disease and 12 patients (67%) had progressive disease. The median progression-free survival was 2.7 months (range 0.5,8.8) and the median overall survival was 5.4 months (range 1.3,31.2). This chemotherapy regimen was well tolerated with an acceptable toxicity profile. The results of our review confirm the low efficacy of combination mitomycin C in heavily pretreated Australian patients with advanced colorectal cancer. This review confirms that it has no role after two lines of modern combination chemotherapy regimens and recommends that focus should be placed on investigating newer agents for good performance status patients progressing after these treatments. [source] Toxicity Profile of Lisdexamfetamine Dimesylate in Three Independent Rat Toxicology StudiesBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2007Suma Krishnan The toxicity profile of orally administered LDX has been evaluated in rats. In an acute study, LDX doses of 60 mg/kg and higher caused increased motor activity. At 1000 mg/kg, one rat died and another was euthanized. In a 7-day repeat-dose study, all rats dosed with LDX (14 per dose group for each sex) showed increased activity; 10 male rats and 11 female rats at 300 mg/kg/day and 3 female rats at 100 mg/kg/day were euthanized because of self-mutilation and 1 male rat at 300 mg/kg/day was found dead. In a 28-day study, only rats at 80 mg/kg showed signs of self-mutilation and thin body condition. In both the 7- and 28-day studies, LDX caused significant changes in some blood chemistry parameters (e.g. blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase) and organ weights (e.g. particularly heart, liver, brain, and spleen). Overall, no apparent treatment-related histopathologic changes were observed. Toxicokinetic assessments indicated that as the dose of LDX was increased, rats were exposed to increasing levels of LDX and d -amphetamine. The extent of exposure to LDX and d -amphetamine increased after repeated-dose in the 28-day study. The findings of the repeat-dose studies indicate that the toxicity profile in rats administered LDX orally is comparable to that for d -amphetamine; however, the apparent lethal dose of LDX in rats is more than five times higher than the LD50 of orally administered d -amphetamine, supporting a putative protective effect of conjugating amphetamine with lysine. [source] Microfluidic Tissue Model for Live Cell ScreeningBIOTECHNOLOGY PROGRESS, Issue 4 2007Philip J. Lee We have developed a microfluidic platform modeled after the physiologic microcirculation for multiplexed tissue-like culture and high-throughput analysis. Each microfabricated culture unit consisted of three functional components: a 50 ,m wide cell culture pocket, an artificial endothelial barrier with 2 ,m pores, and a nutrient transport channel. This configuration enabled a high density of cancer cells to be maintained for over 1 week in a solid tumor-like morphology when fed with continuous flow. The microfluidic chip contained 16 parallel units for "flow cell" based experiments where live cells were exposed to a soluble factor and analyzed via fluorescence microscopy or flow-through biochemistry. Each fluidically independent tissue unit contained ,500 cells fed with a continuous flow of 10 nL/min. As a demonstration, the toxicity profile of the anti-cancer drug paclitaxel was collected on HeLa cells cultured in the microfluidic format and compared with a 384-well dish for up to 5 days of continuous drug exposure. [source] Long-term results of a combination of paclitaxel, cisplatin and gemcitabine for salvage therapy in male germ-cell tumoursBJU INTERNATIONAL, Issue 3 2009Nicola Nicolai OBJECTIVE To retrospectively review the long-term activity, efficacy and toxicity of the combination of paclitaxel, cisplatin and gemcitabine (TPG) as third- or further-line chemotherapy in patients with germ-cell tumours (GCTs) who are not cured after at least two courses of standard-dose chemotherapy, high-dose chemotherapy or both. PATIENTS AND METHODS We evaluated 22 consecutive men treated between April 1999 and December 2000. Half of them were classified as absolutely refractory to cisplatin and a further two as refractory. The median (range) number of previous courses of chemotherapy was 8 (5,11). Treatment consisted of paclitaxel 80 mg/m2, cisplatin 50 mg/m2 and gemcitabine 800 mg/m2 on days 1 and 8, every 3 weeks for four courses, followed by surgery of actual residual resectable masses. RESULTS The follow-up was updated at August 2007. There were no deaths from toxicity and only one patient needed suspension of therapy for toxicity. There was both grade 3,4 thrombocytopenia and neutropenia in 15 patients (68%), and anaemia in nine (41%). There were partial remissions in eight (36%) patients. Six (27%) patients were rendered disease-free with surgical removal of a residual mass after chemotherapy (two still containing viable cancer). Four (18%) patients are long-term survivors at more than 80, 81, 94 and 99 months. The median (range) overall survival of the whole series was 13.5 (1,>99) months. CONCLUSION This combination had a toxicity profile that was acceptable and comparable with other third-line regimens. There were eight (36%) major responses. After a 6-year minimum follow-up, four (18%) patients were long-term disease-free survivors. [source] High activity 90Y-ibritumomab tiuxetan (Zevalin®) with peripheral blood progenitor cells support in patients with refractory/resistant B-cell non-Hodgkin lymphomasBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2007Pier F. Ferrucci Summary Radioimmunotherapy (RIT) is an alternative approach in the treatment of resistant/refractory B-cell non-Hodgkin lymphoma (NHL). We performed a feasibility and toxicity pilot study of escalating activity of 90Y-ibritumomab tiuxetan followed by autologous stem cell transplantation (ASCT). Three activity levels were fixed , 30 MBq/kg (0·8 mCi/kg), 45 MBq/kg (1·2 mCi/kg) and 56 MBq/kg (1·5 mCi/kg) , and 13 patients enrolled. One week before treatment all patients underwent dosimetry. ASCT was performed 13 d after Zevalin® administration. Treatment was well tolerated and all patients engrafted promptly. No differences in terms of haematological toxicities were observed among the three levels, apart from a delayed platelet recovery in heavily pretreated patients receiving 56 MBq/kg. Non-haematologic toxicity was mainly related to infections and liver toxicity. One patient died 4 months after treatment because of hepatitis C virus reactivation. One patient developed a myelodysplastic syndrome 2 years after treatment. In conclusion, high-activity Zevalin® with ASCT is feasible and could be safely delivered in elderly and heavily pretreated NHL patients, including those who previously received high-dose chemotherapy and ASCT. Maximum tolerated dose was not clearly defined according to dosimetry and clinical toxicities, and further studies are needed to confirm the toxicity profile and evaluate efficacy. [source] Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL),CANCER, Issue 10 2007Oliver G. Ottmann MD Abstract BACKGROUND Elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) have a poor prognosis, with a low complete remission (CR) rate, high induction mortality, and short remission duration. Imatinib (IM) has a favorable toxicity profile but limited antileukemic activity in advanced Ph+ALL. Imatinib in combination with intensive chemotherapy has yielded promising results as front-line therapy, but its value as monotherapy in newly diagnosed Ph+ALL is not known. METHODS Patients with de novo Ph+ALL were randomly assigned to induction therapy with either imatinib (IndIM) or multiagent, age-adapted chemotherapy (Indchemo). Imatinib was subsequently coadministered with consolidation chemotherapy. RESULTS In all, 55 patients (median age, 68 years) were enrolled. The overall CR rate was 96.3% in patients randomly assigned to IndIM and 50% in patients allocated to Indchemo (P = .0001). Nine patients (34.6%) were refractory and 2 patients died during Indchemo; none failed imatinib induction. Severe adverse events were significantly more frequent during Indchemo (90% vs 39%; P = .005). The estimated overall survival (OS) of all patients was 42% ± 8% at 24 months, with no significant difference between the 2 cohorts. Median disease-free survival was significantly longer in the 43% of patients (21 of 49 evaluable) in whom BCR-ABL transcripts became undetectable (18.3 months vs 7.2 months; P = .002). CONCLUSIONS In elderly patients with de novo Ph+ALL, imatinib induction results in a significantly higher CR rate and lower toxicity than induction chemotherapy. With subsequent combined imatinib and chemotherapy consolidation, this initial benefit does not translate into improved survival compared with chemotherapy induction. Cancer 2007. © 2007 American Cancer Society. [source] Efficacy and safety of first- or second-line irinotecan, cisplatin, and mitomycin in mesotheliomaCANCER, Issue 1 2007Dean A. Fennell MD Abstract BACKGROUND. Malignant pleural mesothelioma (MPM) is a rapidly progressive lethal tumor. Treatment options remain limited and the outcome in recurrent disease is poor. METHODS. A Phase II open-label noncomparative study was conducted to assess the safety and efficacy of the triplet combination irinotecan, cisplatin, and mitomycin-C (IPM) chemotherapy in untreated patients and in those with previous exposure to chemotherapy. RESULTS. In 62 patients an objective response rate of 25% was observed. In the first-line setting progression-free survival measured 6.4 months (95% confidence interval [CI]: 4.5,7.3) and overall survival was 10.8 months (95% CI: 7.9,13.7). In the second-line setting progression-free survival was 7.3 months (95% CI: 3.4,11.2) and overall survival was also 7.3 months (95% CI: 4.8,9.8). Psychosocial well-being improved during chemotherapy and the main toxicity observed was neutropenia (40%). CONCLUSIONS. IPM appeared to have a reasonable response rate with an acceptable toxicity profile in the first- and second-line treatment of MPM. Cancer 2007. © 2006 American Cancer Society. [source] Phase II study of lenalidomide in patients with metastatic renal cell carcinomaCANCER, Issue 11 2006Toni K. Choueiri MD Abstract BACKGROUND. Lenalidomide (LEN) is a structural and functional analogue of thalidomide that has demonstrated enhanced immunomodulatory properties and a more favorable toxicity profile. A Phase II, open-label study of LEN in patients with metastatic renal cell carcinoma (RCC) was conducted to determine its safety and clinical activity. METHODS. Patients with metastatic RCC received LEN orally at a dose of 25 mg daily for the first 21 days of a 28-day cycle. The primary endpoint was the objective response rate. Time to treatment failure, safety, and survival were secondary endpoints. RESULTS. In total, 28 patients participated in the trial and were included in the current analysis. Three of 28 patients (11%) demonstrated partial responses and continued to be progression-free for >15 months. Eleven patients (39%) had stable disease that lasted >3 months, including 8 patients who had tumor shrinkage. In total, 6 patients (21%) remained on the trial, and 5 additional patients continued to be followed for survival. The median follow-up for those 11 patients was 13.5 months (range, 8.3,17.0 months). The median survival had not been reached at the time of the current report. Serious adverse events included fatigue (11%), skin toxicity (11%), and neutropenia (36%). CONCLUSIONS. LEN demonstrated an antitumor effect in metastatic RCC, as evidenced by durable partial responses. LEN toxicities were manageable. Further studies will be required to assess the overall activity of LEN in patients with metastatic RCC. Cancer 2006. © 2006 American Cancer Society. [source] Novel therapeutics with enhanced biological activity generated by the strategic introduction of silicon isosteres into known drug scaffoldsDRUG DEVELOPMENT RESEARCH, Issue 4 2007Stephen Gately Abstract The strategic replacement of carbon with silicon within biologically prevalidated drug scaffolds can generate focused libraries of pharmaceutically relevant agents with novel, durable and marketable intellectual property. This approach can be cost-effective and of lower developmental risk because known drugs have recognized pharmacology and toxicity profiles, proven safety in humans, and established manufacturing and formulation methods. The change in shape, charge, and lipophilicity that can result from the addition of silicon can favorably alter the biological activity and toxicology of the parent drug. Silicon-containing derivatives of indomethacin are COX-2 selective, suggesting they will not be associated with the classical toxicities associated with nonselective inhibition of the cyclooxygenases. The silicon-indomethacin derivatives also demonstrated superior anti-cancer activity at clinically achievable concentrations when tested in vitro against a human pancreatic cancer cell line, MiaPaCa-2, and a panel of 14 human multiple myeloma cell lines. Bioorganosilicon chemistry represents an attractive approach for emerging biopharmaceutical organizations seeking to rapidly develop a portfolio of novel pharmacological agents that have the potential for enhanced therapeutic and pharmacological benefit. Drug Dev Res 68:156,163, 2007. ©2007 Wiley-Liss, Inc. [source] Chronic toxicity of five structurally diverse demethylase-inhibiting fungicides to the crustacean Daphnia magna: A comparative assessmentENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 6 2009Enken Hassold Abstract Demethylase inhibitors (DMIs) are broad-spectrum fungicides that are ubiquitously used in agriculture and medicine. They comprise chemically heterogeneous substances that share a common biochemical target in fungi, the inhibition of a specific step in sterol biosynthesis. Several DMIs are suspected to disrupt endocrine-mediated processes in a range of organisms and to inhibit ecdysteroid biosynthesis in arthropods. It is unclear, however, whether and, if so, to what extent different DMI fungicides have a similar mode of action in nontarget organisms, which in turn would lead to a common chronic toxicity profile. Therefore, we selected a representative of each of the major DMI classes,-the piperazine triforine, the pyrimidine fenarimol, the pyridine pyrifenox, the imidazole prochloraz, and the triazole triadimefon,-and comparatively investigated their chronic toxicity to Daphnia magna. No toxicity was detectable up to the limit of solubility of triforine (61 ,mol/L). All other DMIs reduced reproductive success by delaying molting and development and by causing severe developmental abnormalities among offspring. Prochloraz was most toxic (median effective concentration [EC50] for fecundity reduction, 0.76 ,mol/L), followed by fenarimol (EC50, 1.14 ,mol/L), pyrifenox (EC50, 3.15 ,mol/L), and triadimefon (EC50, 5.13 ,mol/L). Mean effect concentrations for fecundity reduction were related to lipophilicity and followed baseline toxicity. However, triadimefon and fenarimol (but none of the other tested DMIs) caused severe eye malformations among exposed offspring. Affected neonates did survive, but a reduced ecological fitness can be assumed. Offspring exposed to fenarimol in mater matured earlier. The investigated different life-history parameters were affected in a substance-specific manner. These qualitatively different toxicity profiles suggest additional, substance-specific mechanisms of action in D. magna that probably are related to an antiecdysteroid action. [source] Arsenic derivatives in hematologic malignancies: a role beyond acute promyelocytic leukemia?HEMATOLOGICAL ONCOLOGY, Issue 4 2006Srdan Verstovsek Abstract The importance of arsenic trioxide (As2O3) has been underscored over the last decade due to its efficacy against acute promyelocytic leukemia (APL), a disease in which this agent has been associated with complete hematologic and molecular remission rates of 87% and 83%, respectively. The different molecular mechanisms of action of As2O3 suggest its applicability in hematologic malignancies other than APL. However, responses obtained thus far have consisted of improvements in signs and symptoms without the elimination of a given disease. Toxicities derived from As2O3 are significant but manageable and reversible. However, the risk/benefit ratio of As2O3 in hematologic malignancies other than APL is still unclear. The development of new generations of orally bioavailable inorganic, as well as new organic, arsenic compounds with improved toxicity profiles may bolster the therapeutic application of arsenic derivatives in hematologic malignancies such as leukemia, multiple myeloma and myelodysplastic syndromes. Copyright © 2006 John Wiley & Sons, Ltd. [source] Controlled application and removal of liposomal therapeutics: Effective elimination of pegylated liposomal doxorubicin by double-filtration plasmapheresis in vitroJOURNAL OF CLINICAL APHERESIS, Issue 2 2010Gerhard Pütz Abstract Introduction: Nanoscale particle-based drug delivery systems like long circulating liposomal doxorubicin show unique pharmacokinetic properties and improved toxicity profiles. Liposomal doxorubicin accumulates in tumor tissue due to the enhanced permeation and retention effect, but only a small fraction of a total dose reaches the tumor site. Accumulation of liposomal doxorubicin is much faster in tumor sites than in certain organs where dose limiting adverse effects occur. Finding a way to detoxify the predominant part of a given dose, circulating in the blood after accumulation is completed, will presumably reduce severe side effects during chemotherapy. Methods: Elimination properties of therapeutic used pegylated liposomal doxorubicin (Doxil®/Caelyx®) and therapeutic used double-filtration plasmapheresis systems were evaluated in vitro and in reconstituted human blood. Results: Liposomes can be filtered by appropriate membranes without leakage of doxorubicin up to a pressure of 1 bar. At higher pressures, liposomes (,85 nm) may squeeze through much smaller pores without significant leakage of doxorubicin, whereas decreasing pore size to ,8 nm leads to increased leakage of doxorubicin. With therapeutic used apheresis systems, liposomal doxorubicin can be efficiently eliminated out of buffer medium and reconstituted human blood. No leakage of doxorubicin was detected, even when liposomes were circulating for 48 h in human plasma before apheresis. Conclusions: Convenient apheresis techniques are capable of a safe and efficient elimination of therapeutic used liposomal doxorubicin in an experimental model system. J. Clin. Apheresis, 2010. © 2010 Wiley-Liss, Inc. [source] Current concepts in the endocrine therapy of breast cancer: tamoxifen and aromatase inhibitorsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2005G. Sing Ranger BSc(Hons) MRCS(Eng) Summary Recent results from randomized controlled trials have indicated that aromatase inhibitors have superior anticancer efficacy and toxicity profiles compared with tamoxifen in the treatment of post-menopausal women with node-negative hormone receptor positive breast cancer. This has led clinicians to question whether adjuvant tamoxifen therapy is still justified. This article discusses the evidence for the superiority of aromatase inhibitors over tamoxifen. There are limitations to the use of these drugs, and they have side effects, which require further clarification. In addition, there are certain niche advantages to the use of tamoxifen, and this drug has undergone rigorous appraisal over the last 20 years. [source] ,Boomerang' technique: An improved method for conformal treatment of locally advanced nasopharyngeal cancerJOURNAL OF MEDICAL IMAGING AND RADIATION ONCOLOGY, Issue 2 2004June Corry Summary The primary aim of the present study was to assess radiation dosimetry and subsequent clinical outcomes in patients with locally advanced nasopharyngeal cancer using a novel radiation technique termed the ,Boomerang'. Dosimetric comparisons were made with both conventional and intensity modulated radiation therapy (IMRT) techniques. This is a study of 22 patients treated with this technique from June 1995 to October 1998. The technique used entailed delivery of 36 Gy in 18 fractions via parallel opposed fields, then 24 Gy in 12 fractions via asymmetric rotating arc fields for a total of 60 Gy in 30 fractions. Patients also received induction and concurrent chemotherapy. The radiation dosimetry was excellent. Dose,volume histograms showed that with the arc fields, 90% of the planning target volume received 94% of the prescribed dose. Relative to other conventional radiation therapy off-cord techniques, the Boomerang technique results in a 27% greater proportion of the prescribed dose being received by 90% of the planning target volume. This translates into an overall 10% greater dose received for the same prescribed dose. At 3 years, the actuarial loco-regional control rate, the failure-free survival rate and the overall survival rate were 91, 75 and 91%, respectively. At 5 years, the actuarial loco-regional control rate, the failure-free survival rate and the overall survival rate were 74, 62 and 71%, respectively. The Boomerang technique provided excellent radiation dosimetry with correspondingly good loco-regional control rates (in conjunction with chemotherapy) and very acceptable acute and late toxicity profiles. Because treatment can be delivered with conventional standard treatment planning and delivery systems, it is a validated treatment option for centres that do not have the capability or capacity for IMRT. A derivative of the Boomerang technique, excluding the parallel opposed component, is now our standard for patients with locally advanced nasopharyngeal cancer when IMRT is not available. [source] Dioxin-like and non-dioxin like effects of polychlorinated biphenyls: Implications for risk assessmentLAKES & RESERVOIRS: RESEARCH AND MANAGEMENT, Issue 3 2002John P. Giesy Abstract Polychlorinated biphenyls (PCBs) are persistent, bioaccumulative and toxic contaminants in the environment. Individual PCB congeners exhibit different physicochemical properties and biological activities that result in different environmental distributions and toxicity profiles. The variable composition of PCB residues in environmental matrices and their different mechanisms of toxicity complicate the development of scientifically based regulations for risk assessment. Various approaches for the assessment of risks of PCBs have been critically examined. Recent developments in the toxic equivalency factor (TEF) approach for the assessment of toxic effects due to dioxin-like PCBs have been examined. The PCB exposure studies that describe non-dioxin-like toxic effects, particularly neurobehavioural effects and their effective doses in animals, were compiled. A comparative assessment of effective doses for dioxin-like and non-dioxin-like effects by PCBs has been made to evaluate the relative significance of non- ortho and ortho -substituted PCBs in risk assessment. Using mink as an example, relative merits and implications of using TEF and total PCB approaches for assessing the potential for toxic effects in wildlife were examined. There are several advantages and limitations associated with each method used for PCB risk assessment. Toxic effects due to coplanar PCBs occur at relatively smaller concentrations than those due to non-dioxin-like PCBs and, therefore, the TEF approach derives the risk assessment of PCBs in the environment. The need for the refinement of the TEF approach for more accurate assessment of risks is discussed. [source] Mitochondrial impacts of insecticidal formate esters in insecticide-resistant and insecticide-susceptible Drosophila melanogasterPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 6 2009Cheol Song Abstract BACKGROUND: Previous research on insecticidal formate esters in flies and mosquitoes has documented toxicity profiles, metabolism characteristics and neurological impacts. The research presented here investigated mitochondrial impacts of insecticidal formate esters and their hydrolyzed metabolite formic acid in the model dipteran insect Drosophila melanogaster Meig. These studies compared two Drosophila strains: an insecticide-susceptible strain (Canton-S) and a strain resistant by cytochrome P450 overexpression (Hikone-R). RESULTS: In initial studies investigating inhibition of mitochondrial cytochrome c oxidase, two proven insecticidal materials (hydramethylnon and sodium cyanide) caused significant inhibition. However, for insecticidal formate esters and formic acid, no significant inhibition was identified in either fly strain. Mitochondrial impacts of formate esters were then investigated further by tracking toxicant-induced cytochrome c release from mitochondria into the cytoplasm, a biomarker of apoptosis and neurological dysfunction. Formic acid and three positive control treatments (rotenone, antimycin A and sodium cyanide) induced cytochrome c release, verifying that formic acid is capable of causing mitochondrial disruption. However, when comparing formate ester hydrolysis and cytochrome c release between Drosophila strains, formic acid liberation was only weakly correlated with cytochrome c release in the susceptible Canton-S strain (r2 = 0.70). The resistant Hikone-R strain showed no correlation (r2 < 0.0001) between formate ester hydrolysis and cytochrome c release. CONCLUSION: The findings of this study provide confirmation of mitochondrial impacts by insecticidal formate esters and suggest links between mitochondrial disruption, respiratory inhibition, apoptosis and formate-ester-induced neurotoxicity. Copyright © 2009 Society of Chemical Industry [source] Hepatic arterial infusion of chemotherapy for advanced hepatocellular carcinomaASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 2 2010Yu-Yun SHAO Abstract Treatment of advanced hepatocellular carcinoma (HCC) remains a significant problem for clinicians. Sorafenib, the only approved agent, improves survival rate, but is associated with a low tumor response rate. Alternative approaches for the treatment of advanced HCC are urgently needed. Hepatic arterial infusion of chemotherapy (HAIC) is a promising modality for the treatment of advanced HCC. Since its introduction, there have been improvements in implantable pumps, in catheter implantation and in the convenience and safety of HAIC in general. Numerous clinical studies have shown that HAIC provides moderate therapeutic efficacy with substantially favorable toxicity profiles in selected patient groups with advanced HCC. However, the lack of large randomized studies means that HAIC is not yet a well-established treatment for advanced HCC. We believe there is an urgent need for the further investigation of HAIC for the treatment of advanced HCC. [source] Role of novel targeted agents in the treatment of metastatic colorectal cancerASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 1 2007Dragan DAMIANOVICH Abstract Modern chemotherapy regimens, combining bolus or infused schedules of 5-fluorouracil (5-FU) with irinotecan or oxaliplatin, have significantly improved the treatment outcomes of patients with metastatic colorectal cancer (CRC). The addition of novel targeted agents to chemotherapy has the potential to increase the median survival of patients with metastatic CRC beyond 2 years. Bevacizumab, a monoclonal antibody (mAb) to vascular endothelial growth factor, has an established role in first-line treatment in combination with either 5-FU/leucovorin or irinotecan/5-FU/leucovorin regimens, while cetuximab, a mAb to epidermal growth factor receptor, in combination with irinotecan is more suitable for the treatment of refractory metastatic CRC. The use of bevacizumab in later stages of the disease and cetuximab in chemotherapy-naive patients as well as concurrent treatment with both agents is still under investigation. The landmark studies leading to the approval of these agents in the treatment of metastatic CRC as well as associated toxicity profiles and detailed treatment recommendations are discussed in this review. [source] | |||||||||||||||||||||||||||||||||||||