Clinical Trials In Cancer Patients Research Articles

Antiphosphatidylserine Antibody Combined with Irradiation Damages Tumor Blood Vessels and Induces Tumor Immunity in a Rat Model of Glioblastoma

The vascular targeting antibody bavituximab is being combined with chemotherapy in clinical trials in cancer patients. Bavituximab targets the membrane phospholipid, phosphatidylserine, complexed with beta2-glycoprotein I. Phosphatidylserine is normally intracellular but becomes exposed on the luminal surface of vascular endothelium in tumors. Phosphatidylserine exposure on tumor vessels is increased by chemotherapy and irradiation. Here, we determined whether treatment with the murine equivalent of bavituximab, 2aG4, combined with irradiation can suppress tumor growth in a rat model of glioblastoma. F98 glioma cells were injected into the brains of syngeneic rats where they grow initially as a solid tumor and then infiltrate throughout the brain. Rats with established tumors were treated with 10 Gy whole brain irradiation and 2aG4. Combination treatment doubled the median survival time of the rats, and 13% of animals were rendered disease free. Neither treatment given individually was as effective. We identified two mechanisms. First, irradiation induced phosphatidylserine exposure on tumor blood vessels and enhanced antibody-mediated destruction of tumor vasculature by monocytes/macrophages. Second, the antibody treatment induced immunity to F98 tumor cells, which are normally weakly immunogenic. Surviving rats were immune to rechallenge with F98 tumor cells. In vitro, 2aG4 enhanced the ability of dendritic cells (DCs) to generate F98-specific cytotoxic T cells. Phosphatidylserine exposure, which is induced on tumor cells by irradiation, likely suppresses tumor antigen presentation, and 2aG4 blocks this tolerogenic effect. Bavituximab combined with radiotherapy holds promise as a vascular targeting and immune enhancement strategy for the treatment of human glioblastoma.

4203 Informed participation in randomized clinical trials for cancer patients; perspectives from a research nurse

4203 Informed participation in randomized clinical trials for cancer patients; perspectives from a research nurse

“Antimyeloangiogenic” Therapy for Cancer by Inhibiting PlGF

Inhibition of tumor angiogenesis emerged as valuable strategy to treat cancer and has revolutionized the face of clinical oncology by prolonging the life of numerous cancer patients. However, the duration of this response is rather short and tumors rapidly evade treatment, leaving antiangiogenic treatment thus far unable to cure cancer. Hence, novel targets are needed to diversify antiangiogenic treatments and to overcome resistance. Recent data support the concept that tumor infiltration by bone marrow-derived myeloid cells confers resistance to current antiangiogenic drugs targeting primarily vascular endothelial growth factor (VEGF). In this review, we will summarize (pre)clinical data on the role of PlGF and its receptor VEGFR-1 in promoting angiogenesis and inflammation, and the "antimyeloangiogenic" activity of an antibody against PlGF (alphaPlGF), which may help to overcome resistance against VEGF(R)Is. Because of these promising results, a humanized alphaPlGF antibody (TB403) is currently evaluated in different phase I clinical trials in cancer patients.

Variation in enrollment of colorectal cancer patients in clinical trials

e15094 Background: Correct estimation of patient enrollment is an important success factor for planning clinical studies including studies for metastatic colorectal cancer (CRC). Methods: We reviewed all CRC studies published in the Journal of Clinical Oncology and Annals of Oncology between 01/2007 and 10/01/2008. 43 studies were found and the following data were collected from 39 studies: indication, phase, number of sites, number of patients enrolled, mean patient age, recruitment time, sponsor (Industry, NIH, Organization, University), region, line of treatment and type of drug (6 categories). 4 studies were omitted from analysis as recruitment data were largely missing. Our analysis is based on a literature review as information from unpublished trials is unavailable. This implies some limitations regarding the data interpretation. Results: An average enrollment of 0.92 Patient/Site/Month (range 0.10–7.38) was observed for these trials. The highest recruitment efficacy with a median of 4.11 Pt/S/M (range 1.81–7.38) was found in 5 single institution phase II trials. For multi-center phase II and III studies the median enrollment was 1.82 and 0.32 Pt/S/M respectively, with significant higher recruitment in phase II studies. The highest enrollment rate was observed for studies located in Europe or in USA (0.77 and 2.21 Pt/S/M respectively, p=0.03). No correlation was seen with the mechanism of action (targeted drug vs. chemotherapy), sponsor (NIH vs. Industry vs. IIT), line of treatment (first line vs. 2nd and subsequent line). For phase I recruitment analysis we retrieved 2 studies that investigated novel agents in solid tumor patients including advanced or metastatic colorectal cancer patients with a median recruitment of 0.46 Pt/S/M. For phase Ib and I/II recruitment analysis 5 studies were found with a median recruitment of 0.78 Pt/S/M. Conclusions: Single institution phase II clinical trials on novel agents with high potential to change future treatment standard demonstrate almost a tenfold higher than average recruitment rate for multi-center trials (0.45 Pt/S/M). Despite some limitations in the interpretation of results our analysis provides important information to support estimation of patient recruitment in future clinical trials for colorectal cancer. No significant financial relationships to disclose.

Evaluation of factors associated with recruitment in hematological clinical trials: A retrospective study

6567 Background: Recruitment of patients in cancer clinical trials has been reported to be between 3%–5%. Very few data come from Canada. Methods: The objective was to measure the recruitment and its associated characteristics in hematology clinical trials for malignant diseases. This was a retrospective cohort study using charts review in a tertiary hematology centre in Québec City, Canada. Clinical trials opened between 2002 and 2008 were selected. For each protocol, main criteria were used to define the population under study (e.g., stage IV Hodgkin lymphomas first-line). If the patient filled the main criteria, all eligibility criteria (inclusion and exclusion criteria) of the protocol were assessed. Results: Among all charts reviewed, 697 patients were identified in 17 protocols. However, as a patient could be assessed for more than one protocol if applicable, this population reached 1,394 observations. The study population filling the main criteria of a protocol included 195 observations in 17 protocols (186 different patients). Only 9.7% (8.2–11.4) filled all the eligibility criteria and 3.3% (2.5–4.4) were recruited among all charts reviewed (1394 observations). However, theses rates reached 68.2 % (61.2–75.1) and 23.1 % (17.9–29.8), respectively, among patients meeting the main criteria of a protocol (195 observations). Recruitment in the population who filled all eligibility criteria (inclusion and exclusion criteria) was 33.8% (26.7–42.5). Patient's sex, age, comorbidities, doctor's sex, doctor's age and protocol characteristics were not associated with recruitment in the population filling the main criteria, but having a note in the chart about the protocol appears to be associated with higher recruitment (p < 0.0001). The most common reasons for not being recruited were as follow (could have more than one reason): 40.7% not fulfilling all eligibility criteria, 31.3% protocol not being proposed and 22.7% patients’ refusal. Patients reasons for refusals were (could have more than one reason): 50% unknown, 26.5% fear of side effects, 20.6% too many visits, 14.7 % already enough anxious about disease, other. Conclusions: The largest barriers about recruitment were protocol ineligibility and protocol not being proposed by the medical team. No significant financial relationships to disclose.

Mechanisms of costimulation

The immune system has the remarkable ability to defend against a diversity of microbial pathogens, yet not respond to self. The discovery of the T-cell antigen receptor (TCR) provided an explanation for the specificity and diversity of T-cell responses. Yet, functional studies of Lafferty and colleagues (1) suggested that antigen alone was not sufficient to drive the activation of naive T cells and led to the two signal concept of T-cell activation. According to this model, productive T-cell activation requires a first signal provided by the interaction of antigenic peptide/major histocompatibility complex (MHC) with the TCR and a second, antigen-independent co-signal, the ‘costimulatory signal’. In addition, seminal studies of Jenkins and Schwartz (2, 3) demonstrated that TCR-mediated activation of T cells in the absence of costimulation resulted in antigen-specific unresponsiveness (termed T-cell anergy), rendering the T cells unable to respond to subsequent exposure to antigen. Thus, costimulation was postulated to have a pivotal role in determining whether the outcome of T-cell encounter with antigen would be activation or anergy. The critical role of costimulation in regulating the immune response has given impetus to the study of costimulation and resulted in incredible growth of this field, since an understanding of costimulation is of fundamental and therapeutic interest. Early studies defined the function of the CD28 receptor as a stimulatory receptor for the activation of naive T cells (2), and identified the B7 family members, B7-1 (CD80) and B7-2 (CD86) as its ligands (5–7). The interaction between CD28 and B7-1/B7-2 fulfilled many of the requirements for the costimulatory signal postulated by Lafferty, Schwarz, and colleagues (1). The CD28 homolog cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) (3) was found to be a higher affinity binding partner for B7-1 and B7-2, as compared to CD28 (4). It was presumed that CTLA-4 would also be a stimulatory receptor; however, the dramatic fatal inflammatory phenotype of CTLA-4 deficient (−/−) mice revealed the critical inhibitory function of CTLA-4 (10, 11). Furthermore, the phenotype of CTLA-4−/− mice demonstrated that T-cell costimulatory receptors could deliver inhibitory, as well as stimulatory, second signals for T-cell responses, and provided the first indication that inhibitory second signals (co-inhibitory) could regulate T-cell tolerance. While the B7-1/B7-2:CD28/CTLA-4 pathway is the best characterized T-cell costimulatory pathway, there are now many additional costimulatory pathways. These pathways fall into two major families: the immunoglobulin (Ig) superfamily, which includes the B7/CD28, CD2, and T-cell Ig and mucin domain (TIM) families, and the tumor necrosis family (TNF)/TNF receptor (TNFR) family. Reviews in this issue of Immunol Rev discuss the functions of pathways within all of these families. These articles not only review the current understanding of costimulation on the fundamental level, but also the therapeutic opportunities and challenges of targeting costimulatory pathways for treating autoimmunity, graft rejection, cancer and infectious diseases. In this introduction, I provide perspectives on key functions of costimulatory pathways, highlighting recent advances, and discuss how this progress is changing our view of the functions of T-cell costimulation.

Melan-A–specific Cytotoxic T Cells Are Associated with Tumor Regression and Autoimmunity Following Treatment with Anti-CTLA-4

Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Often, tumor regressions in these patients are correlated with immune-related side effects such as dermatitis, enterocolitis, and hypophysitis. Although these reactions are believed to be immune-mediated, the antigenic targets for the cellular or humoral immune response are not known. We enrolled patients with advanced melanoma in a phase II study with ipilimumab. One of these patients experienced a complete remission of his tumor. The specificity and functional properties of CD8-positive T cells in his peripheral blood, in regressing tumor tissue, and at the site of an immune-mediated skin rash were investigated. Regressing tumor tissue was infiltrated with CD8-positive T cells, a high proportion of which were specific for Melan-A. The skin rash was similarly infiltrated with Melan-A-specific CD8-positive T cells, and a dramatic (>30-fold) increase in Melan-A-specific CD8-positive T cells was apparent in peripheral blood. These cells had an effector phenotype and lysed Melan-A-expressing tumor cells. Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody. These findings may allow a better integration of ipilimumab into other forms of immunotherapy.

How matrix metalloproteinases regulate signaling in cancer

Matrix metalloproteinases (MMPs) have many functions in the cellular microenvironment through cleavage of proteins leading to their activation, inactivation or removal. As a result broad‐spectrum inhibitors of these enzymes were unsuccessful in clinical trials in cancer patients. We have examined the nature of protumorigenic and antitumorigenic targets and functions of MMPs. Our data indicate that MMP9, MMP13 and MMP14 dependent remodeling of the collagen scaffold regulates angiogenesis, tumor cell invasion and migration and inflammatory cell infiltration. The outcomes vary with oncogenes, tumor type and location. MMPs increase VEGF bioavailability and also increase production of antiangiogenic extracellular matrix fragments.

Over-expression of clusterin is a resistance factor to the anti-cancer effect of histone deacetylase inhibitors

Histone deacetylase inhibitors (HDACIs) modulate gene transcription and are among the most promising new classes of anticancer drugs. OGX-011, an anti-sense oligonucleotide targeting clusterin, sensitises cancer cells to chemo- and radiotherapies. By reviewing microarray gene profiling data reported in the literature, we identified clusterin as one of only two genes commonly up-regulated by most HDACIs in cancer cell lines of different organ origins. Suppression of clusterin gene expression synergistically enhanced high-dosage HDACI-induced cell death through cytochrome C-mediated mitochondrial apoptosis in HDACI-resistant cancer cells, and synergistically enhanced low-dosage HDACI-induced growth arrest in both HDACI-sensitive and HDACI-resistant tumour cells, but not in normal cells. In mice xenografted with neuroblastoma cells, combination of OGX-011 and the HDACI, valproate, synergistically repressed tumour growth. Our data indicate that HDACI-induced clusterin over-expression renders cancer cells resistant to HDACI-induced growth arrest and apoptosis, and suggests the addition of OGX-011 to HDACIs in future clinical trials in cancer patients.

Aminofurazans as potent inhibitors of AKT kinase

AKT inhibitors containing an imidazopyridine aminofurazan scaffold have been optimized. We have previously disclosed identification of the AKT inhibitor GSK690693, which has been evaluated in clinical trials in cancer patients. Herein we describe recent efforts focusing on investigating a distinct region of this scaffold that have afforded compounds ( 30 and 32) with comparable activity profiles to that of GSK690693.

Combination of active specific immunotherapy or adoptive antibody or lymphocyte immunotherapy with chemotherapy in the treatment of cancer

Successful treatment of cancer patients with a combination of monoclonal antibodies (mAb) and chemotherapeutic drugs has spawned various other forms of additional combination therapies, including vaccines or adoptive lymphocyte transfer combined with chemotherapeutics. These therapies were effective against established tumors in animal models and showed promising results in initial clinical trials in cancer patients, awaiting testing in larger randomized controlled studies. Although combination between immunotherapy and chemotherapy has long been viewed as incompatible as chemotherapy, especially in high doses meant to increase anti-tumor efficacy, has induced immunosuppression, various mechanisms may explain the reported synergistic effects of the two types of therapies. Thus direct effects of chemotherapy on tumor or host environment, such as induction of tumor cell death, elimination of regulatory T cells, and/or enhancement of tumor cell sensitivity to lysis by CTL may account for enhancement of immunotherapy by chemotherapy. Furthermore, induction of lymphopenia by chemotherapy has increased the efficacy of adoptive lymphocyte transfer in cancer patients. On the other hand, immunotherapy may directly modulate the tumor's sensitivity to chemotherapy. Thus, anti-tumor mAb can increase the sensitivity of tumor cells to chemotherapeutic drugs and patients treated first with immunotherapy followed by chemotherapy showed higher clinical response rates than patients that had received chemotherapy alone. In conclusion, combination of active specific immunotherapy or adoptive mAb or lymphocyte immunotherapy with chemotherapy has great potential for the treatment of cancer patients which needs to be confirmed in larger controlled and randomized Phase III trials.

How Should Oncologists Face Complementary and Alternative Medicine?

There are many inconsistent usages of complementary and alternative medicine (CAM) in modern medicine. Once a kind of CAM is evaluated on the basis of scientific method and is revealed to have the substantial effects and acceptable downsides against some malignancies, it would be integrated into standard oncology care as major or supportive medicine. CAM is outside the evidence-based medicine. In other words, modern medical practitioners named the experiencebased or traditional medicine that has not been assessed scientifically yet as CAM, as a tentative and generic term. Humankind have profited greatly from the development of medicine. However, this benefit is mainly limited to those living in the developed countries, and traditional medicine is still a mainstream in many other countries. Many people throughout Africa, Asia and Latin America use traditional medicine to meet their primary health-care needs. It is easily accessible and affordable for them. Traditional medicine is also often part of a wider belief system and is considered integral to everyday life and well-being. In Western countries, CAM is increasingly being used in parallel to allopathic medicine, particularly for treating and managing chronic disease. Concerns about the adverse drug effects, a desire for more personalized health care, and greater public access to health information fuel the increasing use of CAM in many developed countries. Recent surveys demonstrate that .50% of US cancer patients use CAM therapies at some point after their diagnosis. Despite extensive use, there is a paucity of data available to indicate whether these therapies are efficacious and safe. An enormous amount of unreliable information on cancer CAM is released into the Internet and other media sources. CAM products (herbs and other natural products, such as shark cartilage, mushrooms etc.) in cancer medicine are widely available in Japan and the Western countries (1). Internet and its marketing have accelerated it. The providers emphasize their effects on boosting the immune system based on the pre-clinical experimental findings and advertise using anecdotal reports of users. No reliable and well-designed clinical trials in cancer patients have been performed with this kind of products. Nonetheless, many cancer patients use such products hoping for tumor growth suppression and cure rather than complementary effects. These natural products are generally expensive. It is often the case that the cancer patients and their relatives are at a loss about how to deal with such information and have a difficult time choosing what kind of CAM they should adopt. Oncologist cannot advice them appropriately due to the lack of evidence and even information. A great need for public and professional education regarding this subject is evident. Munshi et al. (2) have reviewed the prominent modalities in CAM for cancer treatment in this issue of JJCO. They see CAM in oncology practice as a complicated issue like a Pandora box in a medical labyrinth. Many oncologists can share this thought. They tried to search evidence on CAM in the literatures and could not find many well-designed trials. A few kinds of CAMs (yoga, acupuncture, some herbal medicine, homeopathy etc.) have been studied in clinical trials. However, the evidence from randomized controlled trials is fragmentary and inconclusive. Therefore, many kinds of CAMs could not be evaluated properly for both efficacy and safety. Many previous reports on CAM indicate that more reliable evidence-based information on CAM is needed for better patient–physician communication (3). The lack of useful information on CAM makes oncologists tend to neglect CAM and avoid communication with patients on its usage. To resolve this problem, a study team consisted of oncologists, pharmacists, psychologists, nurses and CAM providers was organized by the research grant from the Ministry of Health, Labor and Welfare. They are now aggressively educating cancer patients on CAM and evaluating natural products used for cancer treatment in the prospective comparative studies. Another remaining issue is the high prevalence of the concurrent use of anticancer drugs and CAM. Our present knowledge of interactions is incomplete, and further study is urgently needed.

Valproic acid activity in androgen-sensitive and -insensitive human prostate cancer cells

Histone deacetylase (HDAC) inhibitors are currently undergoing clinical trials in cancer patients on the basis of their effect on proliferation, differentiation and apoptosis demonstrated in vitro. The goal of this study was to assess the effects of an HDAC inhibitor, valproic acid (VA), on proliferation, androgen-sensitivity, androgen receptor levels and E-cadherin (E-cad) expression in human prostate cancer cells. The effects of VA were evaluated in androgen-sensitive, LNCaP and -insensitive PC-3 human prostate cancer cell lines. Proliferation was assayed by cell counts and protein expression by Western blot analysis. Morphological changes were analysed under an inverted phase contrast microscope. High VA concentrations (1-25 mM) induced a very strong reduction in cell numbers (≈90% with respect to control) of the two cell lines due to drug cytotoxicity. A low concentration (0.45 mM VA) slightly reduced (14%) LNCaP cell proliferation and abolished the response to androgen. In the PC-3 cells, the same concentration of VA had a more pronounced (40%) inhibitory effect and induced a response to dihydrotestosterone in terms of an enhancement in cell growth. These events were associated with morphological changes, an absence of cytotoxicity, an increase in androgen receptor levels, and, in PC-3 cells, an enhancement in E-cad expression which may be ascribed to VA differentiative action. Our findings, obtained with a VA dose (0.45 mM), which is consistent with plasma concentrations reached under oral administration of therapeutical doses in patients treated for different diseases, suggest that VA might have clinical value in prostate cancer therapy in androgen-sensitive and -insensitive tumors.

Farnesyltransferase 억제제인 Ionafarnib의 인슐린 작용에 대한 영향

구강 섭취형 비펩타이드성 삼환구조의 franesyltransferase 억제인 lonafarnib는 Ras단백질의 prenylation을 억제하며 현재 암환자의 임상실험 중인 약물이다. 본 연구에서 인슐린 반응성의 HIRc-B 세포와 3T3-L1 지방세포에서 인슐린에 의한 DNA 합성, c-Jun 발현, membrane ruffling과 당수송에 대한 lonafarnib의 영향을 조사하였다. Pan-Ras 항체와 isoform 특이 Ras 항체를 이용하여 HIRc-B 세포에서 lonafarnib가 농도 의존적으로 H-Ras의 prenylation을 억제하였으나, K-와 N-Ras의 prenylation은 억제하지 않았다. 또한 인슐린에 의한 일부 DNA 합성 유도를 농도 의존적으로 억제하였으나 혈청 유도성 정상적인 세포 증식에는 영향이 없었다. HIRc-B 세포에서 c-Jun 발현과 membrane ruffling 및 3T3-LI 지방세포의 당수송과 같은 인슐린 작용에는 영향이 없었다. 이러한 결과는 lonafarnib가 인슐린 작용에 일부억제 효과가 있음을 제시하고 있다. Lonafarnib, a orally bioavailable nonpeptide tricyclic farnesyltransferase inhibitor, inhibits the prenylation of Ras and is currently under clinical trials in cancer patients. In the present studies, we examined the effects of lonafarnib on insulin actions including DNA synthesis, c-Jun expression, membrane ruffling and glucose uptake in insulin-responsive <TEX>$HIRc{\sim}B$</TEX> cells and 3T3-L1 adipocytes. Using pan-Ras and isoform-specific anti-Ras antibodies, lonafarnib treatment specifically inhibited the prenylation of endogenous H-Ras in HIRc-B cells in dose-dependent manner, but not those of K- and N-Ras. Lonafarnib partially inhibited insulin-stimulated DNA synthesis in a dose-dependent manner, while it did not affect normal serum-mediated HIRc-B cell proliferation. Other insulin actions including c-jun expression and membrane ruffling in HIRc-B cells and glucose uptake in 3T3-L1 adipocytes were not affected. These results suggest that lonafarnib has a partial adverse effect on insulin actions.

Barriers to recruitment of rural patients in cancer clinical trials

17502 Background: With advancement in research, it is imperative for clinical trials to be accurate and generalizable. This is best achieved through improving patient participation in clinical trials. However, according to the National Cancer Institute, only 3% of adult cancer patients participate in clinical trials. Although, several studies have looked into the barriers to accrual in clinical trials amongst various patient subgroups, there is lack of data regarding factors that influence enrollment of rural patient population. Our study aims to identify these barriers in an attempt to improve future participation. Methods: Amongst patients with a known cancer diagnosis who followed with the Mary Babb Randolph Cancer Center at West Virginia University, we randomly selected 1000 patients. Questionnaires were mailed to the patients. Data obtained in the questionnaire consisted of demographics, clinical information, awareness about clinical trials, willingness to participate in and factors influencing participation in clinical trials. Patients had six weeks to respond. The data was tabulated and analyzed using SPSS. Results: 241 patients responded to the survey. Most respondents (68.4%) had heard about clinical trials prior to the survey. 20.3% reported of their healthcare team discussing about clinical trials. 9.2% reported having participated in clinical trials. Most respondents reported that they (87.3%) and their families (70.9%) participated in healthcare decisions. Respondents were more likely to be at least somewhat willing to participate in a cancer screening trial compared to a new cancer drug trial. With regards to their decision to participate in cancer clinical trials, patients cited discouragement from oncologist (62.5%), monetary burden (53.4%), discouragement from family physician (49.5%) and lack of information (35%) as strongly/extremely influential factors. Conclusions: Our findings specify the need for patient education through community outreach programs and through educating physicians about cancer clinical trials. Physicians should be trained to discuss clinical trial protocols and to address patient concerns regarding availability, utility and accessibility of clinical trials. Financial counseling can play an important role in improving accrual rates. No significant financial relationships to disclose.

Prognostic factor analysis of health-related quality of life data in cancer: a statistical methodological evaluation

A significant body of research exists in oncology to identify and evaluate prognostic factors, historically focused on histology, clinical stage and laboratory parameters. Recent evidence suggests that patient self-reported health-related quality-of-life (HRQOL) data provide additional prognostic information. A review by Gotay et al. of published prognostic analyses reports on the usefulness of patient-reported outcomes (PROs), including HRQOL, in predicting survival in cancer patients in clinical trials. An impressive number of studies have found a positive relationship that supports an independent association between HRQOL and survival. However, due to the considerable diversity in, for example, patient groups, types of HRQOL measures used and analytical strategies, current evidence is far from conclusive. This paper examines the statistical research methods employed, discusses key issues for HRQOL prognostic factor-analysis parameters and proposes recommendations for future outcome research.

Invariant natural killer T cells in immune surveillance and tumor immunotherapy: perspectives and potentials.

Although various elements of the immune system are involved in detection and elimination of neoplastic cells, immune surveillance mechanisms are not always successful in eradicating cancer. Invariant natural killer T cells are potent immunomodulatory lymphocytes that secrete large amounts of Th-1 and/or Th-2 cytokines in response to glycolipid agonists. The observed role of invariant natural killer T cells in antitumor immunity in various animal models and the relatively recent identification and availability of Invariant natural killer T cell glycolipid ligands with anticancer properties such as -galactosylceramide have led to several invariant natural killer T cell-based clinical trials in cancer patients with somewhat promising outcomes. The objective of this article is to provide a short overview on immunobiology of invariant natural killer T cells followed by their potential applications in treatment of cancer.

Carcinoembryonic antigen transgenic mouse models for immunotherapy and development of cancer vaccines.

The goal of cancer therapy remains as the long-term eradication of tumor cells without adverse effects on normal tissue. Conventional approaches utilizing chemotherapy and radiotherapy are limited by both their toxicity and lack of specificity. In recent years, investigators have carried out several studies designed to evaluate whether human tumor-associated antigens (TAAs) can be exploited as targets for immunotherapy, specifically for human cancer vaccine development. A major limitation in immunotherapy studies of human cancer is the general lack of appropriate preclinical models. Clinical studies can be difficult to implement, particularly when a clear understanding of the potential efficacy, limitation, and safety of an immunotherapeutic strategy is not available from relevant animal investigations. However, mice carrying a transgene for a human tumor self-antigen may provide a more acceptable experimental model in which knowledge about immunotherapeutic strategies aiming at the TAA of interest can be enhanced prior to initiating clinical trials. Since the different strategies in experimental immunotherapy of cancer have been directed to activate different immune system components, a variety of transgenic mouse models have been generated expressing either TAA, human leukocyte antigen (HLA), oncogene, or immune effector cell molecules. These models may serve as an excellent platform for the identification of novel targets for immunotherapy as well as to evaluate the efficacy of targeted therapies and will lead to the development of clinical trials for cancer patients. In this unit, a brief overview of the generation and study of different vaccine approaches in carcinoembryonic antigen (CEA) transgenic mouse models and the experimental findings in mouse models that spontaneously develop gastrointestinal tumors and express the CEA transgene is provided.

Early Breast Cancer in the Elderly

Breast cancer is a common tumour in the elderly and management of early disease in particular is a major challenge for oncologists and geriatricians alike. The process should begin with the Comprehensive Geriatric Assessment (CGA), which should be undertaken before any decisions about treatment are made. The important role of co-morbidities and their effect on life expectancy also need to be taken into account when making treatment decisions. The primary treatments for early breast cancer are surgery, adjuvant radiotherapy and adjuvant systemic therapy. Unfortunately, lack of a specific literature relating to early breast cancer in the elderly means formulating an evidence-based approach to treatment in this context is difficult. We have developed a new approach based on the CGA and comprehensive oncological assessment. This approach facilitates the development of an individualized oncogeriatric care plan and follow-up based on several considerations: the average patient's life expectancy at a given age; the patient's co-morbidities, level of dependence, and the impact of these considerations on diagnostic and therapeutic options as well as life expectancy; and the potential benefit-risk balance of treatment. In the elderly patient with breast cancer, the standard primary therapy is surgical resection (mastectomy or breast-conserving therapy). While node dissection is a major component of staging and local control of breast cancer, no data are available to guide decision-making in women aged >70 years. Primary endocrine therapy (tamoxifen) should be offered to elderly women with estrogen receptor (ER)-positive breast cancer only if they are unfit for or refuse surgery. Trials are needed to evaluate the clinical effectiveness of aromatase inhibitors as primary therapy for infirm older patients with ER-positive tumours. Breast irradiation should be recommended to older women with a life expectancy >5 years, particularly those with large tumours, positive lymph nodes or negative hormone receptors. Adjuvant hormone therapy remains a reasonable therapeutic option in elderly women with positive hormone receptor tumours. Aromatase inhibitors have demonstrated a better toxicity profile and effectiveness as adjuvant therapy than tamoxifen in young postmenopausal women but have not been specifically studied in the elderly population. The efficacy of adjuvant chemotherapy for breast cancer has been established by meta-analysis and numerous randomized trials but, again, women aged > or = 70 years have rarely been included in such trials. At present, it is difficult to provide a validated recommendation for use of adjuvant chemotherapy in elderly patients with breast cancer. There are no follow-up recommendations specifically for elderly patients after treatment of early breast cancer. However, American Society of Clinical Oncology breast cancer surveillance guidelines suggest physician office visits every 3-6 months for 3 years, followed by visits every 6-12 months for 2 years, then annually. Women taking aromatase inhibitors should also undergo bone mineral density measurement every 2 years. The new approach to assessment and management of early breast cancer in the elderly outlined in this article should be considered an intermediate step because additional evidence to support clinical practice is still needed. Bearing this in mind, physicians should encourage enrollment of elderly breast cancer patients in clinical trials.

Evaluating the Safety of Erythropoiesis-Stimulating Agents (ESAs) in Patients with Breast Cancer, Lung Cancer, and Hematologic Malignancies: A Meta-Analysis of Randomized, Controlled Trials.

Background: Recent clinical trial data have generated safety concerns regarding ESA use, particularly as to whether the results observed in certain patients with breast cancer, lung cancer, and hematologic malignancies are generalizable to all patients with those tumor types. It is critical that the results of these studies are appropriately integrated into the total body of evidence in order to enable balanced conclusions to be drawn. We conducted a systematic literature review to assess the safety and efficacy of ESA therapy in patients with breast cancer, lung cancer, and hematologic malignancies.Methods: The search was aligned with that conducted by the Cochrane Collaborative group (Bohlius 2006) and was therefore limited to randomized, controlled clinical trials in cancer patients that compared the use of ESAs with either observation (RBC transfusion as required) or placebo and that collected survival data (either long-term or during the study period). Results from trials were meta-analyzed using Comprehensive Meta-Analysis v 2.2 software. Heterogeneity between studies was evaluated using a chi-square test (Q). Random and fixed-effects models were used to estimate an overall odds ratio and 95% confidence interval; the inconsistency statistic, I2, is also provided.Results: For breast cancer, seven studies were identified. Meta-analysis of data from these studies indicated an overall neutral risk of death for patients receiving ESAs, despite the large contribution (weighted at about 40% of the overall result) of the BEST study results (Leyland-Jones, 2005) (Table). Five ESA-controlled lung cancer studies were identified in CIA, one in radiotherapy, and one in anemia of cancer (AOC). In each of the studies in CIA, the ESA groups had neutral survival risks relative to the control group. Meta-analysis of the CIA, radiotherapy, and AOC lung cancer data combined indicated an overall neutral risk of death for patients receiving ESAs (Table). For hematologic malignancies, eight studies were identified (one of which had no deaths). Meta-analysis indicated an overall neutral risk of death for patients receiving ESAs (Table).Conclusions: The results of some studies have suggested a detrimental effect on survival associated with ESA use in certain patients with breast, lung, and hematological malignancies. However, results do not appear to be generalizable to similarly designed, randomized controlled trials conducted in the same tumor types. Additionally, when these studies are integrated into the total body of evidence, ESAs have a neutral effect on survival in these patients. [Display omitted]