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Future trends in patient-reported outcomes assessment for patients with advanced-stage lung cancer receiving targeted therapy.

Recent advances in cancer cell biology have led to the development of therapeutic agents that target pathways critical to the development and progression of disease. These so-called "targeted therapies" might offer patients a more tolerable alternative to traditional systemic chemotherapy that often achieves therapeutic benefit at the cost of debilitating side effects. Several targeted agents have been recently tested in clinical trials of advanced-stage lung cancer. As interest in these therapies grows, an understanding of their impact on the patient's well-being will be important. Patient-reported outcome measures such as formal assessments of health-related quality of life and disease symptoms provide a useful means for addressing the impact of therapy from the perspective of the patient. We summarize the most commonly used measures of health-related quality of life in clinical trials of advanced-stage lung cancer. Although existing measurement systems do provide adequate coverage of many important patient-related outcome issues, the advent of targeted therapies in advanced-stage lung cancer does expose several measurement gaps. We highlight some of these gaps by reviewing a representative sample of recently conducted clinical trials of targeted lung cancer therapy and offer insight as to how these gaps can be filled. We also briefly discuss a set of issues unique to patients receiving targeted therapy (eg, perceptions of treatment efficacy, treatment compliance, patient satisfaction, and treatment convenience) and consider a few methodologic concerns unique to patients with advanced cancer.

Clinical Trials as Topic↗

Cell-cycle dysregulation in breast cancer: breast cancer therapies targeting the cell cycle.

Breast cancer is the most commonly diagnosed cancer in American women. The underlying mechanisms that cause aberrant cell proliferation and tumor growth involve conserved pathways, which include components of the cell cycle machinery. Proto-oncogenes, growth factors, and steroids have been implicated in the pathogenesis of breast cancer. Surgery, local irradiation, and chemotherapy have been the mainstay of treatment for early and advanced stage disease. Potential targets for selective breast cancer therapy are herein reviewed. Improved understanding of the biology of breast cancer has led to more specific "targeted therapies" directed at biological processes that are selectively deregulated in the cancerous cells. Examples include tamoxifen for estrogen receptor positive tumors and imunoneutralizing antibodies such as trastuzumab for Her2/neu overexpressing tumors. Other novel anticancer agents such as paclitaxel, a microtubule binding molecule, and flavopiridol, a cyclin dependent kinase inhibitor, exert their anticancer effects by inhibiting cell cycle progression.

Adenocarcinoma↗

Targeted therapy for hematologic malignancies.

BACKGROUND: The introduction of monoclonal antibodies, either as native molecules or conjugated to radioisotopes or other toxins, has led to new therapeutic options for patients with hematologic malignancies. In addition, the use of small molecules against specific cell surface receptors, enzymes, and proteins has become an important strategy in the treatment of such disorders. METHODS: The author reviewed the published clinical trials of monoclonal antibody and other targeted therapies in hematologic malignancies. RESULTS: Results from several trials demonstrate a therapeutic benefit for the use of monoclonal antibodies (either native or conjugated) and other targeted therapies, used alone or in combination with standard cytotoxic chemotherapy. CONCLUSIONS: Targeted therapy of hematologic malignancies seems to be an effective and less toxic approach to the treatment of such disorders. Nevertheless, additional studies are needed to determine where and when such management fits into a therapeutic regimen for any given disorder, whether upfront or as salvage therapy, alone or in combination with chemotherapy (concurrent or sequential).

Antibodies, Monoclonal↗

Radiation binary targeted therapy for HER-2 positive breast cancers: assumptions, theoretical assessment and future directions.

A novel radiation targeted therapy is investigated for HER-2 positive breast cancers. The proposed concept combines two known approaches, but never used together for the treatment of advanced, relapsed or metastasized HER-2 positive breast cancers. The proposed radiation binary targeted concept is based on the anti HER-2 monoclonal antibodies (MABs) that would be used as vehicles to transport the nontoxic agent to cancer cells. The anti HER-2 MABs have been successful in targeting HER-2 positive breast cancers with high affinity. The proposed concept would utilize a neutral nontoxic boron-10 predicting that anti HER-2 MABs would assure its selective delivery to cancer cells. MABs against HER-2 have been a widely researched strategy in the clinical setting. The most promising antibody is Trastuzumab (Herceptin). Targeting HER-2 with the MAB Trastuzumab has been proven to be a successful strategy in inducing tumour regression and improving patient survival. Unfortunately, these tumours become resistant and afflicted women succumb to breast cancer. In the proposed concept, when the tumour region is loaded with boron-10 it is irradiated with neutrons (treatment used for head and neck cancers, melanoma and glioblastoma for over 40 years in Japan and Europe). The irradiation process takes less than an hour producing minimal side effects. This paper summarizes our recent theoretical assessments of radiation binary targeted therapy for HER-2 positive breast cancers on: the effective drug delivery mechanism, the numerical model to evaluate the targeted radiation delivery and the survey study to find the neutron facility in the world that might be capable of producing the radiation effect as needed. A novel method of drug delivery utilizing Trastuzumab is described, followed by the description of a computational Monte Carlo based breast model used to determine radiation dose distributions. The total flux and neutron energy spectra of five currently available neutron irradiation treatment facilities are examined for this application. The tumour boron concentrations and tumour to healthy tissue concentration ratios required to deliver 50 Gy-Eq to the tumour without exceeding 18 Gy-Eq in the skin are determined, as well as the associated therapeutic ratios. Discussion is provided to address the future research direction for assessing the feasibility of the proposed concept.

Antibodies, Monoclonal↗

Epidermal growth factor receptor-targeted therapy and symptom improvement in non-small cell lung cancer.

Epidermal growth factor receptor-targeted therapy and symptom improvement in non-small cell lung cancer are discussed. Non-small cell lung cancer (NSCLC) is a common and frequently incurable disease. Patients with advanced stage IIIB/IV disease, although not candidates for curative resection, can benefit from treatment that prolongs survival, alleviates symptoms, and reduces complications. While incremental advances have occurred with the use of chemotherapy and radiation therapy, the benefits have been largely palliative. Moreover, the adverse events associated with these therapies may undermine the treatment goal by replacing disease-related symptoms with treatment-related adverse events. Thus, novel, more targeted approaches are needed. Increased understanding of cellular and molecular biology has resulted in the development of treatments that selectively target key regulatory pathways and molecules involved in cell growth and metastasis. Gefitinib is one member of a new class of targeted anticancer agents known as tyrosine kinase inhibitors with activity against NSCLC. In clinical trials, gefitinib has produced responses in patients with relapsed or refractory NSCLC, reduced disease-related symptoms, and has been associated with improvements in quality of life. Such targeted therapy may have a significant impact on the treatment of patients with NSCLC.

Antineoplastic Agents↗

[A research of endothelial cell-targeted therapy for cure of hypertrophic scar].

OBJECTIVE: To investigate the feasibility of endothelial cell-targeted therapy to cure post-burn hypertrophic scar. METHODS: A hypertrophic scar animal model was made. Intralesional injecting of VEGF monoclonal antibody was performed for three weeks. The changes of scar in volume and morphology were observed. RESULTS: 1. The volume of scar decreased. 2. The number of the capillary, the amount of collagen I and collagen III decreased. 3. Transmission electron microscope examinations demonstrated many dead or apoptotic fibroblasts and endothelial cells. Fibrocytes were seen relatively common. CONCLUSION: VEGF induces the growth and development of hypertrophic scar in that it induces excessive and uncontrollable angiogenesis, which favors excessive collagen synthesis. Endothelial cell-targeted therapy may be a promising method to cure post-burn hypertrophic scar.

Animals↗

Study on the possibility of insulin as a carrier of IUdR for hepatocellular carcinoma-targeted therapy.

AIM: To evaluate the possibility of using insulin as a carrier for carcinoma-targeted therapy mediated by receptor, and to investigate the expression of insulin receptor in human hepatocellular carcinoma and the receptor binding characteristics of insulin-IUdR (iododeoxyuridine). METHODS: IUdR was covalently conjugated to insulin. Receptor binding assays of (125)I-insulin to human hepatocellular carcinoma and its adjacent tissue were performed. Competitive displacements of (125)I-insulin by insulin and insulin-IUdR to bind to insulin receptor were respectively carried out. Statistical comparisons between the means were made with paired t-test at a confidence level of 95 %. RESULTS: The data indicated that there were high- and low- affinity binding sites for (125)I-insulin on both hepatocellular carcinoma and its adjacent tissue. Hepatocellular carcinoma had a significantly higher Bmax for high affinity binding site than its adjacent liver tissue (P<0.05, t=2.275). Insulin-IUdR competed as effectively as insulin with (125)I-insulin for binding to insulin receptor. Values of IC(50)1, C(50)2, KI1 and KI2 for insulin-IUdR were 11.50+/-2.83 nmol x L(-1), 19.35+/-5.11 nmol x L(-1), 11.26+/-2.65 nmol x L(-1) and 19.30+/-5.02 nmol x L(-1) respectively, and for insulin were 5.01+/-1.24 nmol x L(-1),17.75+/-4.86 nmol x L(-1), 4.85+/-1.12 nmol x L(-1) and 17.69+/-4.81 nmol x L(-1), respectively. Values of IC(50)1 and KI1 for insulin-IUdR were significantly higher than that for insulin (P<0.01, t=4.537 and 4.813). CONCLUSION: It is possible to use insulin as a carrier for carcinoma-targeted therapy mediated by receptor.

Binding Sites↗

Targeted therapy in rheumatoid arthritis.

The approach of targeting cytokines has dramatically improved the success in the treatment of rheumatoid arthritis (RA). The blocking of tumor necrosis factor (TNF)-alpha or interleukin (IL)-1 is well established in clinical practice, but a lack or loss of clinical response still occurs in up to 30% of RA patients. Therefore, enhanced efforts must be made to develop new strategies to disrupt the inflammatory process and to inhibit synovitis and joint destruction. In this respect, the blocking of IL-6 receptor with tocilizumab, the prevention of costimulatory T cell signals by abatacept, or targeting B cells with rituximab look promising in clinical trials. Furthermore, blocking intracellular signal transduction broadens the spectrum of targeted therapy. This article reviews recent clinical aspects of established anti-cytokine therapies and gives an insight into the experimental and clinical development of new specifically acting drugs.

Abatacept↗

[Application of radiolabeled anti-HBx monoclonal antibody for HCC targeting therapy].

OBJECTIVE: To explore the possibility of anti-HBx McAb as a carrier of HCC targeting therapy after we prepared successfully the anti-HBx monoclonal antibody by immunizing BALB/C mice with 17KD hepatitis B virus X protein. METHODS: The antibody was prepared, purified, identified, radiolabled and used in nude mice bearing human HCC and two HCC patients respectively for experimental and clinical trials. In the experimental study, 0.5mCi 131I-anti-HBx was injected peritoneally. In the clinical trial, the patients were treated with 131I-anti-HBx by injecting into the hepatic artery. After the treatment for one course, a total dose of 37.5 mCi was administered. RESULTS: The survival periods of the mice were prolonged and the tumors were suppressed significantly. The symptoms of the patients were improved significantly with decreased titre of AFP. The B-ultrasonic and CT scanning showed that the tumors became smaller. For these reasons, one of the two patients was reoperated. The tumor was removed and necrosis of the whole tumor was noted except few living tumor cells on the edge of tumor specimen. CONCLUSIONS: It is possible to use the anti-HBx monoclonal antibody as a carrier for human HCC targeting therapy.

Adult↗

Emerging efficacy endpoints for targeted therapies in advanced renal cell carcinoma.

Several novel targeted agents are being tested for the treatment of advanced renal cell carcinoma (RCC), and results of phase I and II trials have been encouraging. A recently completed phase III, placebo-controlled study showed that median progression-free survival doubled from 12 weeks to 24 weeks in patients treated with the multi-kinase inhibitor sorafenib (Nexavar) (hazard ratio [HR], 0.44; P < .00001), and approximately three-quarters of patients had some degree of tumor regression. Furthermore, interim analysis showed an estimated 39% improvement in overall survival in sorafenib-treated patients (HR, 0.72; P = .018) and an investigator-assessed response rate of 10%, indicating that many more patients had clinical benefit than had tumor regression qualifying as response by traditional criteria. These data and others have added to the evidence of lack of correlation between response rate and clinical benefit in RCC patients (as well as in other tumor types) treated with targeted therapies. Issues surrounding study endpoints and biologic efficacy markers for molecular targeted agents in RCC are discussed in this article, with a focus on results of the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs).

Antimetabolites, Antineoplastic↗

Combination antigene therapy targeting c-myc and c-erbB(2) in the ovarian cancer COC(1) cell line.

OBJECTIVE: Antigene therapy targeting only one oncogene in ovarian cancer has made much progress, although it still has some limitations. To explore the potential for combination antigene therapy in ovarian cancer, we examined the in vitro effects of liposmal antisense phosphorothioate oligodeoxynucleotides targeting c-erbB(2) and c-myc (LF-c-erbB(2)/c-myc AS-ODNs) in the human ovarian cancer COC(1) cell line. METHODS: COC(1) cells were treated differently as follows: group A with single LF-c-erbB(2) AS-ODNs; group B with single LF-c-myc AS-ODNs; group C with combination LF-c-erbB(2)/c-myc AS-ODNs; and group D as untreated control. Cell proliferation was studied by MTT assay and clonal cultures. RT-PCR was used to measure gene expression of c-erbB(2) and c-myc before and after transfection. Morphologic changes in the COC(1) cells were observed with the electron microscope. RESULTS: Single antigene therapy targeting c-erbB(2) or c-myc could reduce target gene expression and inhibit COC(1) cell growth by 61.9 +/- 9.3 and 64.5 +/- 11.2%, respectively. However, combination antigene therapy could not only suppress expression of c-erbB(2) and c-myc simultaneously, but also inhibit COC(1) cell proliferation with a higher inhibitory rate of 82.6 +/- 12.1%. Apart from that, the combination agents could induce COC(1) cell apoptosis. CONCLUSIONS: Our study suggests that combination antigene therapy targeting c-erbB(2) and c-myc can inhibit COC(1) cell proliferation and gene expression of c-erbB(2) and c-myc. Furthermore, its effectiveness is much higher than that of individual antigene therapy.

Female↗

Targeted therapy for multiple myeloma.

Multiple myeloma (MM) remains incurable with conventional treatment approaches, and novel biologically based therapies are therefore urgently needed. Targeted therapies are either under development or already undergoing clinical evaluation predicated upon: identifying genetic abnormalities in myeloma cells to enhance chemoradiosensitivity; interrupting growth or triggering apoptotic signaling cascades in tumor cells; treating both the tumor cell and its microenvironment; enhancing allogeneic and autologous antimyeloma immunity; and characterizing new myeloma antigens for serotherapy. These therapies, alone or in combination with conventional treatments, offer great promise to improve the outcome for patients with MM.

Antigens, Neoplasm↗

[Targeted therapies in thoracic oncology].

INTRODUCTION: Better understanding of the alterations of cellular physiology during carcinogenesis has resulted in the development of new anticancer agents called biological targeted therapies. These therapies will probably complement the traditional treatments (surgery, radiotherapy and chemotherapy). STATE OF THE ART: In thoracic oncology, targeted therapies may interfere with signal transduction by interaction with growth factors receptors. This is the case with monoclonal antibodies directed against the extracellular part of the receptors and with small molecules inhibiting the intracellular part of the receptors (for example, EGF-R). PERSPECTIVES: Other strategies include the use of farnesyl transferase inhibitors or of antisense oligonucleotides; the new therapies may also inhibit angiogenesis by targeting either the VEGF receptor or the matrix metalloproteases. Inhibitors of metalloproteases were the first targeted agents tested. However, all published studies on metalloproteases inhibitors have been negative so far. CONCLUSIONS: Currently, the agents most advanced in clinical development are the EGFR inhibitors (either monoclonal antibodies or small molecules inhibiting tyrosine-kinases) which, in those that have clinical activity, may produce a sustained response at a cost of a degree of toxicity.

Alkyl and Aryl Transferases↗

Potential role of molecularly targeted therapy in the management of advanced nonsmall cell lung carcinoma in the elderly.

BACKGROUND: More than 50% of all lung carcinoma cases are diagnosed in patients age > 65 years, and approximately 30% are diagnosed in patients age > 70 years. Elderly patients do not tolerate chemotherapy as well as their younger counterparts do, primarily because of the increased prevalence of comorbid conditions and organ failure. Thus, at present, the majority of elderly patients with malignant disease do not receive aggressive chemotherapy. For such elderly patients, alternatives to conventional chemotherapy, such as novel molecularly targeted therapy regimens, are of interest. METHODS: The current review summarizes contemporary approaches to and recent advances in the treatment of elderly patients with nonsmall cell lung carcinoma (NSCLC) and offers perspectives on the future of molecularly targeted therapy in this population. Inhibitors of epidermal growth factor receptor, vascular endothelial growth factor, and cyclooxygenase-2 are discussed in the current report, with such inhibitors being, in our opinion, among the best candidates for clinical development in the setting of interest. RESULTS: Novel biologic agents with putative activity against advanced NSCLC are at various stages of clinical development. Some of these agents have yielded benefits in terms of disease-related symptom reduction, quality of life, and survival. For elderly patients, the potential advantages of such agents include improved tolerability compared with conventional chemotherapy. This feature also makes these novel agents attractive alternatives for younger patients who cannot tolerate or are reluctant to receive conventional chemotherapy. CONCLUSIONS: Current studies are investigating the safety and efficacy of these novel biologic agents administered alone, in combination with other noncytotoxic agents, and in combination with conventional chemotherapy. These studies will help elucidate the role of targeted therapy in the management of elderly patients with advanced NSCLC.

Angiogenesis Inhibitors↗

Gene therapy targeted by ionizing radiation.

Gene therapy used for the treatment of neoplastic diseases is not well localized. Ionizing radiation can be used to activate the transcription of exogenous genes that encode cytotoxic proteins. This may be accomplished through the use of radiation responsive elements distal to the transcription start site of such genes. We discuss this concept and describe a technique which can be used to amplify the signal initiated by localized radiation therapy. These techniques may be used to target gene therapy during the treatment of human neoplasms.

Genetic Therapy↗

Targeted therapy for malignant melanoma.

There has been much development in the field of targeted therapy for melanoma stemming from efforts to decrease treatment-related toxicities and enhance specific cytotoxicity. This review focuses on three modalities of targeted melanoma therapy based on the biology of the targeting mechanism. The first of these modalities is immunotherapy, which functions to generate a specific antimelanoma immunity. A second modality utilizes metabolic pathways of melanin synthesis to target melanoma cells specifically. A third modality ensues from recent advances in molecular biology and the identification of genes responsible for the malignant transformation of normal melanocytes to melanomas. This work has furthered our understanding of the basis of malignancy, as well as the development of novel strategies aimed at targeting aberrant growth in melanoma.

Humans↗

Multiple myeloma: an update of developments in targeted therapy.

Multiple myeloma continues to be an incurable illness. Improvement in our understanding of the disease is leading to new therapeutic modalities and the definition of new targeted therapy. Several pathways have been identified as areas for targeted therapy, and this review will discuss key molecules in some detail. New agents and molecules with biologic modulator activity appear to be changing the natural history of the disease. Agents such as thalidomide or its analogs, arsenic trioxide or bortezomib, hold great promise; however, much is yet to be learned on how to integrate these agents into disease management.

Antineoplastic Agents↗

In vitro antigene therapy targeting HPV-16 E6 and E7 in cervical carcinoma.

Human papillomavirus (HPV) infection is believed to play a central role in cervical carcinogenesis. Specifically, two viral oncoproteins, E6 and E7, possess transforming ability and have been shown to interact with the cellular tumor suppressors p53 and p105, the retinoblastoma (Rb) gene product. To test the hypothesis that E6 and E7 play an active role in the maintenance of the malignant phenotype and may be ideal targets for antigene therapy, we tested the antiproliferative effects of phosphorothioate oligodeoxynucleotides (oligos) targeting HPV-16 E6 and E7 in cervical cancer cell lines and primary tumor explants. The ATP cell viability assay was used to measure growth effects of 27-mer antisense oligos targeting the ATG translational start region of HPV-16 E6 and E7 sequences in HPV-16-positive cell lines SiHa and CaSki and four advanced, primary cervical tumor explants. A random oligo sequence, an HPV-18-positive and HPV-negative cell line, one histologically confirmed endometrial and two ovarian tumors were used as negative controls. HPV type was confirmed by hybrid capture techniques. Cell lines and sterile (staging laparotomy) tumor cells were plated at 5000 cells/0.1 ml and 100,000 cells/0.5 ml in 96-well plates or soft agar, respectively, and incubated at 37 degrees C with a single treatment of oligos at 0-16 microM. E6/E7 combinations at a fixed ratio of 1:1 were used at 0-8 microM for each oligo. Cellular ATP was measured by luciferin/luciferase fluorescence on Day 6. HPV-16 E6 and E7 oligos showed antiproliferative effects in all HPV-16-positive cell lines and primary tumor explants (IC50s 6.9-9.5 microM for cell lines, 9.1-12.1 microM primary cervical tumors), while the HPV-negative C33-A cell line and HPV-18-positive cell line HeLa were relatively insensitive to the HPV-16 oligos (IC50s > 30 microM extrapolated). The endometrial and two ovarian primary tumors were also insensitive to the HPV E6 and E7 oligos (IC50s > 25 microM extrapolated). Random oligos had little effect on cell growth at concentrations up to 16 microM (< 25% inhibition), except in CaSki (@50% inhibition at 16 microM). Combinations of E6 and E7 demonstrated mixed synergistic and antagonistic effects as determined by combination indices (CI) derived from median effect parameters. In the HPV-16-positive primary cervical tumors and the cell line SiHa, E6/E7 combinations were synergistic at low doses (< 25% growth inhibitory dose range) and antagonistic at doses above this. For the HPV-16-positive cell line CaSki, however, E6/E7 combinations were antagonistic at all dose ranges. Phosphorothioate oligos directed against the viral oncogenes E6 and E7 were shown to have antiproliferative effects specific to HPV-containing cancer cells. These specific antiproliferative effects suggest that HPV-16 E6 and E7 sequences play an active role in the malignant growth properties of cervical cancer cells and may be ideal targets for antigene therapy.

Antigens, Viral↗