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PubMed2004

Opportunities and challenges in the development of targeted therapies.

Expanding knowledge about basic biology and a detailed understanding of the signaling pathways that participate in the growth and metastasis of breast cancer have identified opportunities for diagnostic and therapeutic intervention. Endocrine therapy represents the first and most successful example of targeted therapy in breast cancer. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) is now part of the management of metastatic disease and is under evaluation as adjuvant therapy. Other pathways have been targeted, and several candidate drugs are being developed. While these developments represent opportunities for better therapies, they have also identified limitations in identification of targets and development of targeted therapies. Validation of targets is critical, and it is also critical to determine whether the putative target can be identified in a consistent, practical, and inexpensive manner. Finally, it is imperative that targeted therapies are devoid of toxicities secondary to the ubiquitous nature of the target, and we must improve our understanding of interactions that provide specificity of signaling under physiologic conditions.

Antibodies, Monoclonal↗
PubMed2004

Mammalian target of rapamycin.

Targeted molecular therapeutics are tailored toward the genetic abnormalities that cause tumor progression. Modulation of certain signaling pathways that are aberrant in cancer cells has the potential to provide an effective, nontoxic approach to therapy in a broad range of cancers. Agents targeting BCR-ABL (imatinib mesylate [formerly known as STI-571], Gleevec; Novartis Pharmaceuticals Corp, East Hanover, NJ), retinoid receptor fusion proteins (all-trans retinoic acid), ErbB-2 or HER2/neu (trastuzumab, Herceptin; Genentech, Inc, South San Francisco, CA), epidermal growth factor receptor (IMC-C225 and ZD1839), and the phosphatidylinositol 3-kinase pathway (CCI-779) have all induced remarkable, nontoxic responses in a subset of patients with cancer and abnormalities in the corresponding signal transduction cascades. To achieve successful individualized therapy, the specific components within the aberrant signaling pathways that are driving the pathophysiology of the tumors must be identified in each patient. Molecular diagnostics can identify patients in whom the target is aberrant; linking molecular diagnostics with effective molecular therapeutics will be necessary to translate these concepts into approaches that will alter the outcome for patients with cancer. In addition, intermediary markers and/or molecular imaging techniques must be used to identify the biologically relevant dose that is sufficient to inhibit the target of interest. This review focuses on the P13K pathway, and novel molecules targeting this pathway, to illustrate the questions and challenges underlying the implementation of molecular therapeutics in breast and ovarian cancer.

Animals↗
PubMed2004

Angiogenesis inhibitors in the treatment of colorectal cancer.

Angiogenesis is critical for normal and pathologic processes in new blood vessel formation. A recent significant advance in the treatment of metastatic colorectal cancer has occurred by the development of agents targeting key regulatory molecules involved in this process, specifically vascular endothelial growth factor (VEGF). These angiogenesis inhibitors, include bevacizumab (Avastin, Genentech, Inc, South San Francisco, CA), which binds free VEGF. Recently, a phase III, multicenter, double-blind, randomized, placebo-controlled trial was designed to determine whether or not the addition of bevacizumab to first-line irinotecan, 5-fluorouracil, and leucovorin chemotherapy was completed in patients with metastatic colorectal cancer. The trial showed a higher response rate, longer time to tumor progression, and prolonged overall survival in patients with metastatic colorectal cancer. Of note, this was the first large, randomized, phase III study to show the importance of targeting VEGF and tumor angiogenesis for the treatment of human cancer. Other potential targets of angiogenesis, such as the VEGF receptor and multi-targeted agents, are undergoing evaluation in clinical trials.

Angiogenesis Inhibitors↗
PubMed2001

Targeting HER2: recent developments and future directions for breast cancer patients.

Overexpression of the HER2/neu oncogene (also known as c-erbB2) is a frequent molecular event in multiple human cancers, including breast and ovarian cancer. Patients with cancer that overexpress HER2/neu are associated with unfavorable prognosis, shorter relapse time, and low survival rate. Treatments that target HER2/neu expression in cancer cells have been shown to be useful strategies to significantly reverse the malignancy induced by HER2/neu overexpression. The humanized anti-HER2/neu antibody, trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) has proven to be effective in clinical trials in patients with metastatic breast cancer. In addition, tyrosine kinase inhibitors such as emodin can also target the HER2/neu oncogenic activity. Emodin treatment inhibits HER2/neu tyrosine kinase activity and preferentially suppresses the transformation of HER2/neu-overexpressing breast cancer cells. Emodin also sensitizes HER2/neu-overexpressing cancer cells to chemotherapeutic agents, including cisplatin, doxorubicin, etoposide, and paclitaxel. Alternatively, HER2/neu overexpression can be repressed by attenuating the promoter activity of the HER2/neu gene. We have identified a number of potent transcriptional regulators, including the ets family member PEA3 and the adenovirus type 5 E1A, which are able to repress HER2/neu gene expression. Expression of these transcriptional regulators resulted in downregulation of HER2/neu promoter activity and reversed the transformed phenotype of the cancer cells in vitro. In vivo studies show that these HER2/neu repressors can act therapeutically as tumor suppressor genes for tumors that overexpress HER2/neu. These preclinical studies clearly indicate that transcriptional repressors that downregulate HER2/neu can be effective regimens for cancer treatment in a gene therapy format. More importantly, the tumor-free survival rate of treated animals is dramatically increased under nontoxic doses compared with untreated animals. A phase I clinical trial using E1A-liposome in breast and ovarian patients has recently been completed. Following treatment, we observed downregulation of the HER2/neu protein accompanied by E1A expression in both cancer and noncancer cells. Numbers of tumor cells in the pleural effusion or ascites were found to be dramatically reduced after treatment. Furthermore, apoptosis was strongly induced in the tumor cells. A phase II study has been started to further evaluate therapeutic efficacy and tumor suppression mechanisms of E1A. These studies show the clinical potential of targeting HER2/neu in cancer therapy.

Adenovirus E1A Proteins↗
PubMed1983

Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity.

Human blood mononuclear leukocytes stimulated with toxoplasma antigen, concanavalin A, mezerein plus lentil lectin, or staphylococcal enterotoxin A secreted a factor (macrophage-activating factor, or MAF) that enhanced the capacity of human macrophages to release H2O2 and to kill toxoplasmas. The same lymphoid supernatants contained IFN gamma but not IFN alpha or IFN beta. The MAF activity of six of seven unfractionated supernatants was completely eliminated by a monoclonal antibody that neutralizes IFN gamma, and MAF in the remaining supernatant was almost completely neutralized. Native IFN gamma partially purified by two independent protocols to specific activities of 1 X 10(6) and 10(7) U/mg protein was enriched in MAF activity at least as much as in antiviral activity. The capacity of macrophages to secrete H2O2 after incubation in partially purified native IFN gamma (mean peak stimulation, 8.8-fold) was greater than with unpurified lymphokines (3.8-fold) and sometimes equaled or exceeded the capacity of freshly harvested monocytes. The MAF activity of the partially purified native IFN gamma preparations was abolished by monoclonal anti-IFN gamma. Finally, IFN gamma of greater than 99% estimated purity was isolated (at Genentech, Inc.) from bacteria transformed with the cloned human gene for this lymphokine. Recombinant IFN gamma had potent MAF activity, stimulating the peroxide-releasing capacity of macrophages an average of 19.8-fold at peak response and enhancing their ability to kill toxoplasmas from 2.6 +/- 1.3% for untreated cells to 54 +/- 0.4% for treated cells. Attainment of 50% of the maximal elevation in peroxide-releasing capacity required a geometric mean concentration of 0.1 antiviral U/ml of recombinant IFN gamma, which is estimated to be approximately 6 picomolar for this preparation. Peroxide secretory capacity and toxoplasmacidal activity of macrophages peaked 2-4 d after exposure to IFN gamma. Peroxide-secretory capacity remained elevated during at least 6 d of continuous exposure, but the effect of IFN gamma was reversed within about 3 d of its removal. Activation was usually but not invariably accompanied by characteristic changes in cell morphology. Thus, IFN gamma activates human macrophage oxidative metabolism and antimicrobial activity, and appeared to be the only factor consistently capable of doing so in the diverse LK preparations tested.

Adult↗
PubMed1997

Safety profile of phase I and II preventive HIV type 1 envelope vaccination: experience of the NIAID AIDS Vaccine Evaluation Group.

The NIAID-sponsored AIDS Vaccine Evaluation Group was established in 1988 to perform phase I/II clinical trials with candidate preventive HIV-1 vaccines. This report includes safety data from 1398 HIV-negative, healthy volunteers who were enrolled into 25 phase I and 1 phase H multicentered, randomized, double-blind studies evaluating seven recombinant HIV-1 envelope vaccines, two V3 loop synthetic peptide vaccines, and two live poxvirus-vectored recombinant envelope vaccines. All studies but three were placebo controlled; the placebo was either the adjuvant alone or, in studies of recombinant poxvirus vaccines, it was the vector with no gene insert or a non-HIV gene insert. All candidate vaccines were generally well tolerated. The only adverse effects that were clearly related to vaccination were occasional acute local and systemic reactions that were associated with the adjuvants. Three adjuvants in particular were associated with moderate to severe local reactions: alum plus deoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), and QS21 (Genentech, Inc.). MTP-PE was also associated with self-limited severe systemic reactions. There were no serious adverse laboratory toxicities and no evidence of significant immunosuppressive events after receipt of the candidate vaccines. A few volunteers experienced symptoms that might relate to an underlying immunopathologic mechanism (rash, hemolytic anemia, arthralgia), but their presentations were mild and their incidence was low. Eleven volunteers were diagnosed with malignancies during or after their participation, which was within the 95% confidence interval of the number of cases predicted by the National Cancer Institute SEER (Program for cancer surveillance, epidemiology, and end result reporting) database. In conclusion, the envelope-based recombinant or synthetic candidate HIV-1 vaccines appear to be safe and this work has prepared the way for the testing of increasingly complex candidate HIV-1 vaccines.

AIDS Vaccines↗
PubMed1994

Enhancement of protein synthesis efficiency in parenterally fed trauma victims by adjuvant recombinant human growth hormone.

In the early catabolic phase of severe injury, conventional nutritional support is inadequate to reverse negative nitrogen balance and an anabolic stimulus may be beneficial. The utilization efficiency of body energy sources after injury could be improved by adjuvant recombinant human growth hormone (rhGH) therapy. We measured the protein kinetic response to exogenous rhGH in trauma patients fed parenterally (TPN). Severely injured (mean ISS, 31 +/- 2), highly catabolic (mean nitrogen loss, 19 +/- 2 g/day), and hypermetabolic (mean BEE/REE, 1.41 +/- 0.05), adult (mean age, 46 +/- 5 years), multiple trauma victims (n = 20, 17 men/3 women) were investigated. Rates of whole-body protein kinetics (turnover [WBPT], synthesis [WBPS], breakdown [WBPB], and protein synthesis efficiency [PSE]--the fraction of nitrogen turnover utilized for protein synthesis) were measured using a primed-constant infusion of 18N glycine 48 to 60 hours after injury when the patients were receiving only maintenance fluids without calories or nitrogen. The patients were then fed glucose-based TPN (1.1 x REE; 250 mg N/kg/day) and randomized to receive or not to receive rhGH. Group H (n = 10) received daily rhGH (0.15 mg/kg/day, Somatropin, Genentech, Inc.) intramuscularly at 8 am and group C (n = 10) received only the vehicle of infusion. Protein kinetic measurements were repeated at the end of 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2006

Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab (Avastin).

PURPOSE: Intravitreal bevacizumab (Avastin; Genentech Inc., San Francisco, CA) is a new treatment for age-related macular degeneration. The aim of this study was to evaluate retinal penetration and toxicity of bevacizumab. METHODS: Ten albino rabbits were injected intravitreally with 0.1 mL (2.5 mg) of Avastin into one eye and 0.1 mL saline into the fellow eye. The electroretinogram (ERG) was recorded after 3 hours, 3 days, and 1, 2, and 4 weeks. The visual evoked potential (VEP) was recorded after 4 weeks. Confocal immunohistochemistry was used to assess retinal penetration. RESULTS: The ERG responses of the control and experimental eyes were similar in amplitude and pattern throughout the follow-up period. The flash VEP responses of the experimental eyes were of normal pattern and amplitude and did not differ from those recorded by stimulation of the control eye alone. Full thickness retinal penetration was present at 24 hours and was essentially absent at 4 weeks. CONCLUSIONS: Bevacizumab was found to be nontoxic to the retina of rabbits based on electrophysiologic studies. Full thickness retinal penetration may explain observed clinical effects of intravitreal bevacizumab. Although it is difficult to directly extrapolate to humans, our study supports the safe use of intravitreal bevacizumab injection.

Animals↗
PubMedDate not supplied

Six-month stability of bevacizumab (Avastin) binding to vascular endothelial growth factor after withdrawal into a syringe and refrigeration or freezing.

PURPOSE: To determine the change in anti-vascular endothelial growth factor (VEGF) activity of bevacizumab (Avastin, Genentech, Inc., San Francisco, CA) after refrigeration or freezing. METHODS: Samples of bevacizumab were drawn up from new vials into plastic tuberculin syringes and refrigerated at 4 degrees C for 1 week, 3 weeks, 1 month, 3 months, and 6 months. The vials and syringes were stored at 4 degrees C, and the syringes were capped with a needle. One syringe was frozen at -10 degrees C. The bevacizumab concentration was measured, via its binding to VEGF-165. RESULTS: The percentage of degradation of bevacizumab in the previously pierced vials stored at 4 degrees C compared with that in the unpierced vial was 9.6% at 3 months and 12.7% at 6 months. The bevacizumab drawn into the syringe and stored at 4 degrees C was degraded by 1.6% at 1 week, 0% at 3 weeks, 8.8% at 3 months, and 15.9% at 6 months. The bevacizumab frozen in a syringe at -10 degrees C was degraded by 12.0% at 6 months. CONCLUSION: The anti-VEGF activity of bevacizumab may degrade minimally over time, with storage.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.

PURPOSE: To evaluate the safety and efficacy of intravitreal bevacizumab (Avastin, Genentech Inc.) for the treatment of neovascular age-related macular degeneration (ARMD). METHODS: A retrospective review was performed on consented patients with neovascular ARMD receiving intravitreal bevacizumab therapy. All patients received intravitreal bevacizumab at baseline with additional monthly injections given at the discretion of the treating physician. At each visit, a routine Snellen visual acuity assessment was performed followed by an ophthalmic examination and optical coherence tomography (OCT) imaging. RESULTS: Fifty-three eyes of 50 patients received an intravitreal bevacizumab injection between May and August 2005. Including the month 3 visit, the average number of injections was 2.3 out of a maximum of 4 injections. No serious drug-related ocular or systemic adverse events were identified. Improvements in visual acuity and central retinal thickness measurements were evident by week 1 and continued through month 3. At month 3, the mean visual acuity improved from 20/160 to 20/125 (P < 0.001) and the mean central retinal thickness decreased by 99.6 microm (P < 0.001). CONCLUSION: Off-label intravitreal bevacizumab therapy for neovascular ARMD was well tolerated over 3 months with improvements in visual acuity and OCT central retinal thickness measurements. While the long-term safety and efficacy of intravitreal bevacizumab remain unknown, these short-term results suggest that intravitreal bevacizumab may be the most cost effective therapy for the treatment of neovascular ARMD.

Aged↗
PubMedDate not supplied

Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema.

PURPOSE: To evaluate the efficacy of bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) for the treatment of diabetic macular edema. METHODS: This prospective, consecutive, noncomparative case series included 51 consecutive patients (26 females and 25 males; mean age, 64 years) with diffuse diabetic macular edema. Inclusion criteria were determined independently of the size of edema, retinal thickness, visual acuity, age, metabolic control, type of diabetes, or previous treatments beyond a 6-month period. At each visit, patients underwent complete eye examination, including determination of best-corrected visual acuity, slit-lamp examination, intraocular pressure measurement, stereoscopic biomicroscopy of the macula, retinal thickness measurement by optical coherence tomography, fluorescein angiography, and fundus photography. After written informed consent was obtained, all patients were treated with a 0.05-mL injection containing 1.25 mg of bevacizumab. RESULTS: All patients completed 6 weeks of follow-up; 23 (45%) completed 12 weeks of follow-up. Sixteen patients (70%) had received at least two intravitreal injections. All patients had undergone previous treatments, such as focal laser therapy (35%), full-scatter panretinal laser therapy (37%), vitrectomy (12%), and intravitreal injection of triamcinolone (33%). The mean diameter of the foveal avascular zone was 503 micro m, with 49% with values of >500 micro m. At baseline, mean visual acuity +/- SD was 25.88 +/- 14.43 ETDRS letters (0.86 +/- 0.38 logMAR of Snellen letters). Mean central retinal thickness by optical coherence tomography +/- SD was 501 +/- 163 micro m (range, 252-1,031 micro m). Mean visual acuity +/- SD increased to 0.75 +/- 0.37 logMAR of Snellen letters at 6 weeks after injection (P = 0.001), with some regression to 0.84 +/- 0.41 logMAR of Snellen letters after 12 weeks. Changes in ETDRS letters were not significant throughout follow-up. Mean retinal thickness +/- SD decreased to 425 +/- 180 micro m at 2 weeks (P = 0.002), 416 +/- 180 micro m at 6 weeks (P = 0.001), and 377 +/- 117 micro m at 12 weeks (P = 0.001). Changes of retinal thickness and visual acuity correlated weakly (r = -0.480 and P = 0.03 at 6 weeks; r = -0.462 and P = 0.07 at 12 weeks). The increase of visual acuity after 6 weeks as measured by ETDRS charts could be predicted best by baseline visual acuity. No other factors investigated, such as age, thickness by optical coherence tomography, or previous treatments, were predictive for the increase in visual acuity. CONCLUSION: Even in cases of diffuse diabetic macular edema not responding to previous treatments such as photocoagulation, intravitreal injection of triamcinolone, or vitrectomy, improvement of visual acuity and decrease of retinal thickness could be observed after intravitreal injection of bevacizumab. Although our follow-up period was too short to provide specific treatment recommendations, the short-term results encourage further prospective studies with different treatment groups and longer follow-up.

Adult↗
PubMed1995

Efficacy of growth hormone replacement therapy in children with organic growth hormone deficiency after cranial irradiation.

We evaluated the growth response of 20 childhood cancer survivors who received growth hormone (GH) replacement therapy (0.3 mg/kg/week) for at least 12 months. In all subjects, GH deficiency was associated with cranial irradiation and was documented with growth charts, bone age, and somatomedin C levels; at least one GH stimulation test was available for 14 children. Pretreatment overall growth velocity was 3.3 +/- 0.5 cm/year (mean +/- SE) over a 3-year period. After GH replacement, growth velocity was 8.6 +/- 0.6 cm/year during the first year (n = 20), 7.2 +/- 0.5 cm/year during the second year (n = 17), 5.9 +/- 0.6 cm/year during the third year (n = 11), and (6.1 +/- 0.6 cm/year during the fourth year (n = 7). Growth response, tabulated by age at onset of GH replacement, was compared with the response in GH-naive children with idiopathic GH deficiency (data obtained through the Genentech Inc. National Cooperative Growth Study Summary, September 1991); the growth velocity fell within the range described for idiopathic GH deficiency adjusted for either chronological or bone age. We conclude that children with GH deficiency after cranial irradiation for neoplastic diseases respond to GH replacement therapy as well as children with idiopathic GH deficiency.

Adolescent↗
PubMed2006

Intravitreal bevacizumab for choroidal neovascularization caused by AMD (IBeNA Study): results of a phase 1 dose-escalation study.

PURPOSE: To evaluate the safety of three dose regimens of intravitreal bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) for the management of choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD). METHODS: This was a prospective, nonrandomized open-label study of 45 patients with AMD and subfoveal CNV. A standardized ophthalmic evaluation was performed at baseline and at weeks 1, 6, and 12 (+/-1) after a single intravitreous injection (1.0, 1.5, or 2.0 mg) of bevacizumab. Main outcomes measures include clinical evidence of toxicity and complications. Changes in best corrected visual acuity (BCVA) and lesion characteristics-macular morphology were also evaluated. RESULTS: The most common adverse events were conjunctival hyperemia and subconjunctival hemorrhage at the injection site. Mean BCVA improved from baseline throughout the study (P < 0.001; ANOVA with Geisser-Greenhouse correction). Compared with baseline, BCVA was improved at week 1 (P = 0.001), week 6 (P < 0.001), and week 12 (P = 0.001; Dunnett test). At week 12, the lesion area and CNV area were stable or decreased in 79.1% (34/43) and in 74.4% (32/43) of patients, respectively, with no deterioration of macular architecture observed in 83.7% (36/43). A dose-related change in BCVA (in Early Treatment Diabetic Retinopathy Study [ETDRS] lines) was observed at week 12 (1.0 mg [+0.3 line]; 1.5 mg [+0.6 line]; and 2.0 mg [+1.0 line]; P = 0.02; nonparametric test for ordered groups). CONCLUSIONS: A single intravitreal bevacizumab injection was well tolerated and, except for minor transient local adverse events, no other adverse events were observed. In the short-term, treatment was associated with vision stabilization or improvement and no unfavorable neovascular lesion-macular changes in most patients.

Aged↗
PubMed1985

Primate mammary development. Effects of hypophysectomy, prolactin inhibition, and growth hormone administration.

The pituitary gland has been found to be an important factor in mammary development in primates. Hypophysectomy in 12 sexually immature monkeys caused significant inhibition of estradiol (E2)-induced mammary growth and development. A histological index of mammary development in sexually immature hypophysectomized animals was lower (0.82) than in intact E2-treated controls (3.4; P less than 0.008). Hypophysectomy also inhibited growth of the mammary gland as judged by a size index. Despite the hypophysectomy, E2 stimulated some, albeit blunted, mammary growth and development, which may have been due to incomplete hypophysectomy. Selective inhibition of prolactin by ergot drugs in intact animals did not prevent full mammary development, suggesting that there may be pituitary mammogens other than prolactin, or that very low or unmeasurable concentrations of prolactin were sufficient to synergize with E2 to cause full acinar development. The mean histological index was 3.08 in E2-treated animals and 3.16 in animals treated with E2 plus pergolide. There was also no difference in the size of the glands. We evaluated the effect of growth hormone on mammary development by treating three hypophysectomized animals with pure 22,000 mol wt human growth hormone (hGH) (Genentech, Inc., South San Francisco, CA). We found that physiological or slightly supraphysiological concentrations of hGH in animals with unmeasurable prolactin were incapable of restoring the capacity of E2 to induce full mammary growth. These findings suggest that, if growth hormone is a mammary mitogen, that physiological concentrations are insufficient to synergize with E2 to induce full mammary growth or that other forms of hGH are mammogenic. Our studies suggest that the role of the pituitary gland in mammary mitogenesis in primates is more complicated than previously thought. They also raise the possibility that heretofore unidentified pituitary substances may be mammogenic.

Animals↗
PubMed2004

Epidermal growth factor receptor tyrosine kinase inhibitors: evolving role in the treatment of solid tumors.

Inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) activity have shown promise as novel anticancer agents in a variety of common solid tumors. In preclinical studies and phase I trials, tumor responses to EGFR-TK inhibitors (EGFR-TKIs), such as gefitinib (Iressa, AstraZeneca Pharmaceuticals LP, Wilmington, DE) and erlotinib (Tarceva, OSI Pharmaceuticals, Melville, NY, and Genentech, Inc., South San Francisco, CA) were observed in heavily pretreated patients with advanced non-small cell lung cancer (NSCLC), head and neck cancer, breast cancer, colorectal cancer, and other solid tumors. Subsequent phase II studies resulted in tumor responses, disease stabilization, symptom improvement, and improved quality of life in patients with advanced NSCLC who had received prior platinum-based chemotherapy or platinum and docetaxel chemotherapies. Side effects related to treatment with EGFR-TKIs were generally mild, reversible, and noncumulative. Severity and frequency of drug-related adverse events were related directly to dose. The potential role of EGFR-TKIs in treating other solid tumors currently is being studied. Furthermore, research is being conducted to explore the potential use of EGFR-TKIs in novel combinations with chemotherapy, radiation therapy, endocrine therapy, and other molecular targeted therapies.

Antibodies, Monoclonal↗
PubMed2005

Antivascular endothelial growth factor monoclonal antibody therapy: a promising paradigm in colorectal cancer.

Angiogenesis plays an important role in tumor growth and development. Vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic factors and therefore is an ideal target in colorectal cancer therapy. Bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA) is a humanized monoclonal antibody, designed to directly target VEGF. The agent has shown promising activity in preclinical and phase I and II studies and is well tolerated compared with conventional cytotoxic chemotherapy. The U.S. Food and Drug Administration recently approved bevacizumab in combination with 5-fluorouracil-based chemotherapy as first-line therapy for patients with metastatic colorectal cancer. The approval was based on phase III data demonstrating that patients treated with bevacizumab plus chemotherapy survived approximately five months longer compared with patients treated with chemotherapy alone. This article will focus on the role of VEGF in tumorigenesis and summarize the available data on the use of bevacizumab in the treatment of metastatic colorectal cancer.

Antibodies, Monoclonal↗
PubMed2001

Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma.

PURPOSE: To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody Rituxan (rituximab, IDEC-C2B8; Genentech Inc, South San Francisco, CA) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in patients with aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-three patients with previously untreated advanced aggressive B-cell NHL received six infusions of Rituxan (375 mg/m2 per dose) on day 1 of each cycle in combination with six doses of CHOP chemotherapy given on day 3 of each cycle. RESULTS: The ORR by investigator assessment confirmed by the sponsor was 94% (31 of 33 patients). Twenty patients experienced a complete response (CR) (61%), 11 patients had a partial response (PR) (33%), and two patients were classified as having progressive disease. In the 18 patients with an International Prognostic Index (IPI) score > or = 2, the combination of Rituxan plus CHOP achieved an ORR of 89% and CR of 56%. The median duration of response and time to progression had not been reached after a median observation time of 26 months. Twenty-nine of 31 responding patients remained in remission during this follow-up period, including 15 of 16 patients with an IPI score > or = 2. The most frequent adverse events attributed to Rituxan were fever and chills, primarily during the first infusion. Rituxan did not seem to compromise the ability of patients to tolerate CHOP; all patients completed the entire six courses of the combination. The bcl-2 translocation of blood or bone marrow was positive at baseline in 13 patients; 11 patients had follow-up specimens obtained (eight CR, three PR), and all had a negative bcl-2 status after therapy. Only one patient has reconverted to bcl-2 positivity, and all patients remain in clinical remission. CONCLUSION: This is the first report to demonstrate the safety and efficacy of the Rituxan chimeric anti-CD20 antibody in combination with standard-dose CHOP in the treatment of aggressive B-cell lymphoma. The clinical responses are at least comparable to those achieved with CHOP alone with no significant added toxicity. The presence or absence of the bcl-2 translocation did not affect the ability of patients to achieve a CR with this regimen. The ability to achieve sustained remissions in patients with an IPI score > or = 2 warrants further investigation with a randomized study.

Adult↗
PubMed2002

Effects on quality of life of combined trastuzumab and chemotherapy in women with metastatic breast cancer.

PURPOSE: The study was designed to compare the effects of treatment with a combination of trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) and chemotherapy versus chemotherapy alone on health-related quality of life (HRQL) in patients with HER-2/neu overexpressing, metastatic breast cancer. PATIENTS AND METHODS: A sample of 400 patients, not previously treated for metastatic disease and randomized to receive either trastuzumab plus chemotherapy (208 patients) or chemotherapy alone (192 patients), completed the European Organization for Research and Treatment Care Quality of Life Questionnaire at baseline and on at least one subsequent occasion at 8, 20, 32, 44, and 56 weeks. HRQL improvement or worsening was defined as a >or= 10-point change (range, 0 to 100 points) in the scores of six preselected domains (global quality of life [QOL], physical, role, social, and emotional functioning, and fatigue). Stable HRQL was defined as a change of less than 10. A Bonferroni correction was applied for multiple testing. RESULTS: After completion of chemotherapy, patients treated with trastuzumab and chemotherapy reported significant improvement in fatigue (P <.05) as compared with their baseline scores. Higher proportions of patients receiving the combined therapy achieved improvement in global QOL (P <.05) than did patients treated with chemotherapy alone. Higher proportions of the combined therapy group also achieved improvement in physical and role functioning and in fatigue as compared with the chemotherapy group, but the differences were not statistically significant. There were no differences in the proportions of patients in the two groups that reported worsening. CONCLUSION: Statistically significantly higher proportions of patients treated with a combination of trastuzumab and chemotherapy reported improved global QOL than did patients treated by chemotherapy alone.

Adult↗