Molekulare Bildgebung in der Tumortherapie

Targeted drugs that modulate the function of specific molecules in diseased tissues hold great promise for the treatment of many diseases, including malignant tumors. However, there are several challenges for the efficient evaluation of these drugs in clinical trials as well as for the use in clinical practice. These include (i) the selection of patients likely to benefit from treatment with a specific targeted drug, (ii) finding the right dose and dose schedule, (iii) monitoring target inhibition, and (iv) assessing tumor response to therapy. Standard anatomic imaging continues to play an important role for addressing these challenges, but molecular imaging provides several new opportunities to make the use of targeted drugs more efficient. Using molecular imaging, the expression of drug targets can be assessed noninvasively, the concentration of drugs can be measured in the tumor tissue, target inhibition can be monitored, and tumor response to therapy can be evaluated earlier than with anatomic imaging techniques. Therefore, it is expected that molecular imaging will play an increasing role for guiding molecularly defined therapeutic interventions.     

An overview of precision oncology basket and umbrella trials for clinicians

With advancements in biomarkers and momentum in precision medicine, biomarker-guided trials such as basket trials and umbrella trials have been developed under the master protocol framework. A master protocol refers to a single, overarching design developed to evaluate multiple hypotheses with the general goal of improving the efficiency of trial evaluation. One type of master protocol is the basket trial, in which a targeted therapy is evaluated for multiple diseases that share common molecular alterations or risk factors that may help predict whether the patients will respond to the given therapy. Another variant of a master protocol is the umbrella trial, in which multiple targeted therapies are evaluated for a single disease that is stratified into multiple subgroups based on different molecular or other predictive risk factors. Both designs follow the core principle of precision medicine—to tailor intervention strategies based on the patient's risk factor(s) that can help predict whether they will respond to a specific treatment. There have been increasing numbers of basket and umbrella trials, but they are still poorly understood. This article reviews common characteristics of basket and umbrella trials, key trials and recent US Food and Drug Administration approvals for precision oncology, and important considerations for clinical readers when critically evaluating future publications on basket trials and umbrella trials and for researchers when designing these clinical trials.     

Combined-modality therapy in pancreatic cancer: current status and future directions

The use of chemotherapy with concurrent radiation therapy remains a standard treatment option for patients with unresectable or resected adenocarcinoma of the pancreas. This treatment strategy is based in large part on data from serial Gastrointestinal Tumor Study Group (GITSG) trials, which have included 5-fluorouracil (5-FU). Unfortunately, the majority of patients continue to succumb to the disease process. Recently, there has been a resurgence in clinical trials investigating alternative combined modality treatment strategies for patients with pancreatic cancer. In this review, we will summarize both the mature and more recent data pertaining to combined modality therapy for patients with unresectable or resected pancreatic cancer. Strategies utilizing concurrent gemcitabine, alternative radiation therapy techniques, and/or altered sequencing of therapies will be highlighted. Such modifications to the approach in use since the 1980s will need to be fully considered as clinical trials utilizing chemoradiotherapy regimens and new systemic agents or novel targeted therapies are designed.     

Progress towards gene therapy for cancer

This review highlights the current strategies being employed towards gene therapy of cancer. Conceptually, the most simple diseases to treat with gene therapy would be monogenic inherited diseases, such as hemophilia. However, the vast majority of current gene therapy trials are for treatment of cancer patients, due to the recognition of gene alterations in cancer and the critical need for improvement of cancer therapy. Gene-based therapies for cancer in clinical trials include strategies that involve immuno-therapy, induction of drug sensitivity in tumor cells or resistance to chemotherapy of critical host tissues, and compensation for oncosuppressor loss or ablation of oncogenes. Two broad approaches have been used to deliver DNA to cells, a series of viral vectors and the use of plasmid DNA vectors, which have different advantages with regard to efficiency of gene transfer, ease of production and safety. Examined objectively, many of the first studies in cancer gene therapy clinical trials have provided information of critical importance for the design of more efficient second-generation protocols. Gene therapy represents one of the most important developments in oncology, however, before this can be realized as standard treatment the technical problems of gene delivery and safety must be overcome. Here we focus on methods and strategies used to achieve cancer gene therapy and the current clinical trials.     

Adenoviral strategies for the gene therapy of cancer

Despite slow clinical progress, efforts to develop specific nontoxic cancer gene therapies are increasing exponentially. Adenoviral vectors are one of the most popular vehicles for gene transfer currently being used in worldwide clinical trials for cancer. Over the past decade our knowledge of the adenoviral life cycle together with the discovery of novel tumor antigens has permitted the targeting of adenoviral vectors to specific tumors. Targeting adenoviral vectors to tumors is crucial for their use in clinical applications in order to allow for systemic administration and the use of reduced vector doses. In addition, novel approaches to tumor killing have also been explored, which will have greater potency and selectivity than currently available treatments such as chemotherapy or radiation. This review discusses the basic concepts behind the use of adenoviral vectors for cancer gene therapy and their potential for clinical application, as well as ongoing and completed clinical trials.     

The role of autologous bone marrow transplantation in cancer treatment

Autologous bone marrow transplantation (ABMT) has been increasingly used in the treatment of malignant diseases. Since myelosuppression is one of the major dose limiting factors in cancer chemotherapy, ABMT is effective for hematologic reconstitution after marrow-lethal intensive therapy, which increases the anti-tumor effect. Diseases for which ABMT is indicated are selected on the basis of sensitivity to escalation of drug and radiation dose. These diseases include non-Hodgkin's lymphoma, leukemia, small cell carcinoma of the lung, melanoma, neuroblastoma, metastatic breast cancer and Ewing's sarcoma. Phase I and phase II studies have demonstrated that dose escalation to several times the conventional dosage may be feasible with the use of ABMT. Clinical trials of intensive therapy plus ABMT have produced encouraging results in terms of response rate and long-term survival for selected patients with poor-prognosis malignant diseases which are resistant or refractory to conventional forms of cancer therapy. When these preliminary results are analysed, it is apparent that the outcome of this treatment modality is affected by several factors such as disease status or tumor burden at the time of ABMT, the anti-tumor effect of the pretransplant intensive therapy and the extent of bone marrow invasion by tumor cells. Since ABMT is not yet well established in comparison with allogeneic bone marrow transplantation, carefully designed clinical trials will be required in order to assess the efficacy of ABMT.     

Implications of personalized medicine--perspective from a cancer center

Three advances are dramatically changing the landscape of oncology. First, hundreds of drugs are available that inhibit targets involved in oncogenesis. Second, efforts to reclassify malignant diseases are expanding the number of orphan molecular diseases. Third, the implementation of high-throughput technologies will allow risk of relapse prediction and drug sensitivity. Patients predicted to relapse will be referred to comprehensive cancer centers where new drugs will be tested. It is anticipated that a high number of small, biology-driven clinical trials will report high sensitivity to targeted agents in rare biologically defined diseases. Drug registration and biomarker analysis needs to be revisited to avoid large phase III trials with control arms. The use of high-throughput technologies will lead to the development of virtual cells. These considerations highlight the need for developing a consortium of comprehensive cancer centers to run clinical trials in rare, molecularly-defined populations, and implement high-throughput technologies for daily practice.     

Angiogenesis as a target for cancer therapy

Antiangiogenic drugs are unique for having highly specific targets while carrying the potential to be effective against a wide variety of tumors. Moreover, some of the major limitations of cytotoxic therapies likely will be avoided by this entirely new class of anticancer weapons. After the realization of the potential advantages of antiangiogenic therapy, the field of angiogenesis research is growing exponentially. Still, there is much to learn about the machinery that tumors use to recruit new blood vessels, and the results of the clinical trials will show the best way to apply that knowledge for cancer therapy.     

Localized and locally advanced bladder cancer

Opinion statement Localized and locally advanced bladder cancer represents a heterogeneous spectrum of diseases with different biologic and clinical behavior. It varies with respect to invasive potential, propensity for metastases, and sensitivity to chemotherapy. Although several significant surgical advances have been made over the past 20 years in the treatment of muscle-invasive bladder cancer, resulting in decreases in perioperative morbidity and mortality and improvement of quality of life in patients with continent urinary diversions, the natural history of the disease has remained unaltered. Advances in chemotherapy for metastatic disease have prompted trials of systemic therapy in patients with early stage, high-risk disease administered before or after local therapy consisting of cystectomy or radiotherapy. The data available from nonrandomized and randomized trials have not definitively established the exact role of neoadjuvant chemotherapy and its impact on survival. Even if neoadjuvant chemotherapy does not improve survival, preliminary data suggest that bladder preservation may be possible in selected patients and that such combined therapy will hopefully lead to better patient management. The trials of post-operative chemotherapy provide insufficient evidence to support the routine use of adjuvant chemotherapy in clinical practice as a result of small sample size, confusing analyses, and the reporting of questionable conclusions. New large-scale, multicenter trials are imperative to provide convincing results. A better understanding of the micro-biology of bladder cancer will influence the search for new therapeutic modalities. Molecular-targeted small-molecule therapy and monoclonal antibodies have begun to dominate contemporary studies.     

Levamisole: known effects on the immune system, clinical results, and future applications to the treatment of cancer

Levamisole has been used in a wide array of clinical research and treatment settings over the past two decades, ranging from such diseases as helminthic infestations to various autoimmune diseases. Numerous preclinical evaluations and clinical trials with levamisole in the cancer arena have been sponsored by the National Cancer Institute and other agencies worldwide with the hopes of demonstrating anticancer activity. Trials in advanced breast cancer, lung cancer, colorectal cancer, melanoma, and lymphoproliferative diseases have generally been negative or inconclusive. However, there is some indication that levamisole may be useful by itself as an adjuvant therapy for resected melanoma; recently it has been shown to be effective in combination with fluorouracil (5-FU) as adjuvant therapy for tumor-node-metastasis (TNM) stage III (Dukes' C) colon carcinoma. In the aggregate, the past 20 years of clinical experience with levamisole has resulted in as many questions as answers. However, further testing of the anticancer activity of levamisole can be expected in clinical research trials over the next few years. Hopefully, these future trials will include studies of the mechanisms of action of this agent.     

Germ cell tumor clinical trials in North America

The management of germ cell tumors (GCT) in men has been the focus of intense clinical investigation over the past 25 years. Following clinical trials which demonstrated that GCTs are curable, considerable effort has been directed at refinement of the multidisciplinary treatment plan. During the past decade, there has been a major emphasis on identifying those clinical prognostic features most closely associated with a high likelihood of a complete response (good risk) and a low likelihood of complete response (poor risk). Randomized good- and poor-risk clinical trials have been conducted which clarify the role of bleomycin and the number of cycles of therapy in good-risk patients and the role of high-dose cisplatin (200 mg/m(2)/cycle) and ifosfamide in poor-risk patients. The efficacy of high-dose chemotherapy with stem cell rescue has led to a randomized trial of its use following standard induction therapy as compared to standard induction therapy in previously untreated poor-risk patients. Salvage chemotherapy for patients in first or second relapse, or those who have not achieved an initial complete response, initially tested the role of ifosfamide; efforts are now focused on the role of paclitaxel and high-dose therapy in specific patient subgroups. High-dose chemotherapy with stem cell rescue is the treatment of choice for patients in second relapse with gonadal primary tumors who have responsive disease and factors which predict a reasonable likelihood of achieving a disease-free status. A general understanding of tumor biology and specific knowledge regarding GCTs will be very important in the next decade of discovery as the pathways of malignant transformation, progression, and drug resistance become better known and serve as targets for new therapy.     

Clinical Effects of Interferon Therapy with Special Emphasis on Antitumor Efficacy

Both natural and recombinant interferons (IFNs) exert antitumor effects in man. Much work has to be done to construct optimal use of the IFN system. Its physiological role is not fully understood. Various IFN effects are described, all of which probably play a role for clinical effectiveness. Doses and schedules are discussed and pharmacokinetics and side-effects described. IFN therapy of benign and malignant tumor disease is pursued as clinical trials. Efficacy on various diseases is reported in the present article. Combination therapy is suggested for the future.     

Progress in ovarian cancer: an overview and perspective

Ovarian cancer remains the number one gynecologic killer in the Western world. However, there has been significant progress in understanding the genetics of ovarian cancer and in development of more effective therapies. The current optimum approach to therapy consists of cytoreductive surgery followed by combination chemotherapy. Clinical trials have established that carboplatin plus a taxane (usually paclitaxel) can be considered to be the treatment of choice for most patients with advanced disease. Most patients will achieve a clinical complete remission with such a combination. However, the median time to progression is less than 2 years, and for patients with optimal stage III disease, median survival will be approximately 5 years. Clinical trials are currently evaluating new combination chemotherapy regimens and the role of maintenance therapy in improving time to progression and overall survival. There has been a great deal of progress in understanding the genetics of epithelial ovarian cancer. The relationship between mutations in BRCA1 and BRCA2 genes and inherited predisposition to ovarian cancer has been of major clinical importance. While 90% of ovarian cancer cases are still considered to be sporadic, identification of the molecular events associated with hereditary ovarian cancer will lead to an increased understanding of the pathogenesis of sporadic disease as well since the two diseases share many clinical features. Development of high throughput screening methodology, such as CDNA microarray analysis, will lead to identification of additional genes which are important in the development of ovarian cancer, and will help define new targets for therapy and prevention as well as potential new biomarkers for early detection. The next generation of clinical trials will be focused on evaluating chemotherapy together with new molecular therapies, such as signal transduction inhibitors, anti-angiogenesis agents, and inhibitors of matrix metalloproteinases.     

EORTC Imaging Group

Imaging data have the potential to provide information on disease profiling pertaining to diagnosis, prognosis, selection of therapy, monitoring of response to therapy and pharmacokinetic information of drugs. Selection of the most appropriate imaging modality for a specific task will be vital for diagnosis, stratification, treatment response or treatment efficacy, toxicity assessment, and treatment outcome measures (progression-free survival). The EORTC Imaging Group was formed to establish and maintain the scientific and clinical value of advanced imaging in EORTC clinical trials. The group focuses on the development of specific analytical and review procedures as well as quality control procedures, in the context of clinical trials conducted by the EORTC groups.     

Prospects for therapeutic inhibition of neuroblastoma angiogenesis

Despite aggressive therapy, survival for advanced stage neuroblastoma remains poor with significant long-term morbidity in disease survivors. High-risk disease features are strongly correlated with tumor vascularity, suggesting that angiogenesis inhibitors may be a useful addition to current therapeutic strategies. However, challenges include the well-known clinical heterogeneity and embryonal origins of this disease, which suggests a complex regulation of neovascularization that may be distinct from epithelial-derived carcinomas. We will review what is understood about angiogenesis-related signaling in neuroblastoma. In particular, we will present evidence that angiogenesis-related molecules are differentially expressed in primary neuroblastomas in a pattern suggesting promotion of a pro-angiogenic phenotype in high-risk tumors and an anti-angiogenic phenotype in low-risk tumors. We will also discuss a variety of vascular inhibition strategies that have been used in neuroblastoma preclinical models including specific inhibition of vascular endothelial growth factor (VEGF) and methionine aminopeptidase 2 (MetAP2). Recent observations that the combination of angiogenesis inhibitors with conventional chemotherapy provides synergy without additive toxicity, suggests the potential use of angiogenesis inhibitors as an adjunct between cycles of conventional cytotoxic therapy. Further identification of critical angiogenic signaling pathways and evaluation of specific inhibitors in preclinical neuroblastoma models should provide justification for future selection and evaluation of angiogenesis inhibitors in clinical trials for high-risk neuroblastoma patients.     

Collaborative clinical trials: quality or quantity?

PURPOSE: To review the merits of using the limited available resources--patients, money, clinical scientists, and ideas--in various types of clinical trial. CONCLUSIONS: Two types of trial represent a poor use of resources: (a) nonrandomized trials that provide no insight into biologic mechanisms and are not precursors to testing new strategies in comparison with standard treatment in randomized trials; and (b) small randomized trials that are difficult to interpret because of a high rate of false-positive and false-negative trials. Very large trials that can detect small differences in survival for patients with common tumors are appropriate, but a similar design to detect transient improvements due to palliative therapy represent a poor use of resources. Larger gains in therapeutic index will require the recognition of tumor heterogeneity and the conduct of small trials that are based on biologic hypotheses, and which provide mechanistic information in patients; two examples are provided. Ultimately, strategies that may be individualized among a group of patients with histologically similar tumors will need to be evaluated against the current standard (and homogeneous) treatment.     

Application of vitamin D and derivatives in hematological malignancies

The role of vitamin D in the inhibition of malignant cell proliferation in hematological malignancies is indicative of its future use in cancer therapy. An understanding of the biochemical mechanism by which vitamin D and its derivatives exert their effects will prove to be useful in the development of clinically applicable therapies involving vitamin D. While the use of vitamin D in clinical trials against acute myeloid leukemia and myelodysplastic syndrome has been met with few successes thus far, in vitro and in vivo studies as well as epidemiological correlations between vitamin D deficiency and cancer have implicated the great potential of the use of vitamin D derivatives in effective therapies against neoplastic diseases. For these reasons, a focus on current understanding of role of vitamin D and derivatives in hematologic malignancies is relevant and the goal for this review.     

Neoadjuvant therapy for resectable pancreatic cancer

The length and quality of life of patients with localized pancreatic cancer will be maximized by accurate preoperative assessment of resectability, a standardized technique of tumor resection, and the routine use of protocol-based adjuvant or neoadjuvant therapy. Continued efforts to enroll patients with localized and advanced pancreatic cancer into well-designed clinical trials should remain a high priority for oncologists across all disciplines. At present, preoperative therapy remains investigational but has a sound clinical basis and remains a reasonable alternative to up front surgery. Future clinical trials for resectable pancreatic cancer will lead to progress only if the principles of multidisciplinary cancer care and quality assurance are incorporated into their design and conduct.     

DNA methyltransferase inhibitors for cancer therapy

Aberrant DNA methylation patterns, including hypermethylation of tumor suppressor genes, have been described in many human cancers. These epigenetic mutations can be reversed by DNA methyltransferase inhibitors, which provide novel opportunities for cancer therapy. Clinical concepts for epigenetic therapies are currently being developed by using azanucleosides for the treatment of leukemias and other tumors. These trials will greatly benefit from the inclusion of molecular markers for monitoring epigenetic changes in patients and for maximizing biologic responses. In addition, novel inhibitors need to be developed that result in a direct and specific inhibition of DNA methyltransferase activity. Several recent developments indicate that rational design of small molecule DNA methyltransferase inhibitors is feasible and that this approach can result in the establishment of novel drug candidates. The use of novel DNA methyltransferase inhibitors in clinical trials that allow monitoring of drug-induced DNA methylation changes should provide the foundation for improved epigenetic cancer therapies.