Catálogo de publicaciones - libros

Drug resistance of human tumors to a variety of chemotherapeutic agents remains the major cause of cancer treatment failure. Although multiple mechanisms of drug resistance may occur in parallel or sequentially at all different levels of drug action, one resistance mechanism was identified within the last two decades that very likely represents the most frequent cause for the development of drug resistance in cancer cells: the phenomenon of multidrug resistance (MDR). MDR, the simultaneous resistance toward structurally and functionally unrelated cytostatic drugs, depends mainly on the presence of different transporter proteins, their genetic polymorphisms, and their regulation/deregulation. Thus, decreased uptake and/or increased efflux, lowered net accumulation, and, in consequence, less efficiency of anticancer drugs is the clinical hurdle. The biology of the most prominent members of the MDR-associated, membranespanning ATP-binding cassette (ABC) transporter proteins (MDR1, MRP1, and BCRP), their transport mechanisms, and the spectra of cytostatic drugs are summarized in this chapter. The clinical importance of these MDR-associated molecules (their basal and therapy-induced expression) is discussed for different solid tumors with respect to clinical outcome parameters. Resistance profiling and response prediction as essential prerequisites for tailor-made, patient-individual MDR reversal as well as intervention strategies targeting functional, translational, and transcriptional levels are evaluated.

The pharmacological rational for regional cancer therapy is based on delivering a high dose intensity of the chemotherapeutic drug, resulting in an advantageous tumor cure/normal tissue complication differential (high therapeutic ratio). Only patients with an anatomically confined tumor and technical feasibility of antitumor therapy administration are expected to reach clinical benefit. Specific pharmacological characteristics of the delivered drug are of potential additional benefit. The pharmacological background of intraperitoneal chemotherapy, isolated hepatic perfusion, and isolated extremity perfusion are given as an example of the advantages and opportunities of regional anticancer therapy.

When treating patients with solid tumors one is faced with a plethora of factors that may influence clinical outcome. Drugs tested with success on tumor cells in vitro do not always turn out to be that promising when used in humans. It is clear that although a drug may have strong activity on tumor cells in vitro, the usefulness of this drug also depends (for instance) on its availability when injected in the body. Factors such as pharmacokinetics, toxicity profile, intratumoral distribution, and activity in hypoxic or acidic regions are likely to be of even greater importance than the cytotoxic potential of a drug. To allow better prediction of the activity of a drug in the clinical setting, the use of clinically relevant animal models is imperative. Here we describe the use of animal models for solid tumor therapy and in particular regional treatment application.

Brachytherapy is an established technique inradiation oncology. The radiation source is placed into the tissue, next to or directly into the tumor. In contrast to percutaneous implantation of applicators into superficial tumors or insertion of applicators into body cavities, interventional minimally invasive application of brachytherapy addresses the internal organs, particularly the liver, which is a common site of metastatic and primary tumor manifestations. For interventional application of radiation treatment agents to hepatic malignomas, two methods are currently used: the percutaneous approach using cross-sectional imaging, usually computed tomography, for guidance of applicator positioning and radiation therapy planning purposes, and the transarterial approach, using angiographic as well as scintigraphy techniques for targeting and dosimetry. Percutaneous afterloading has been shown to be suitable for treatment of lung malignomas as well. This chapter reviews the indications, methodology, and clinical outcome of both interventional modalities, percutaneous interstitial brachytherapy and transarterial radioembolization, in hepatic malignomas.

In this chapter regional cancer treatment of tumors/metastases of the peritoneum, liver, lung, pleura, and the limbs is summarized and, especially, surgical technical principles and prerequisites of regional chemotherapy are described. Regional chemotherapy can be applied via vascular or cavital access. Prior to regional therapy extra-regional tumor spread has to be excluded and the individual anatomy of the region to be treated must be clarified. Intraoperatively, a skillfull management and postoperatively a thoughtful monitoring of the patient is mandatory. Therefore, a close collaboration between different medical specialities is necessary.

A broad range of temperatures is useful in oncology. Thermoablation (heat alone) requires temperatures of >45 to 50°C and is only clinically possible in circumscribed lesions. High-intensity focused ultrasound (HIFU) and nanotherapy are suitable methods. The largest volume heated is the whole body, using whole-body hyperthermia (WBHT); 42°C is the highest temperature permitted. Clinical experience and some positive studies suggest, however, that higher temperatures (e.g., 43°C) are required at least in certain specific (e.g., hypoxic) parts of the tumors to increase local control in conjunction with radiotherapy and/or chemotherapy and to be beneficial for patients. Dedicated multiantenna applicators operating in the radiofrequency range (60–200 MHz) must be designed for each indication accounting for the anatomical region. Magnetic resonance monitoring is the first candidate for noninvasive control. The technical problems have been solved to integrate such applicators into an MR-tomograph. Although commercially available systems (for regional hyperthermia) are adequate for pelvic and extremity tumors, adaption/optimization is still desired for abdominally disseminated disease. Here, the termpartbody hyperthermia has been created, for which a large number of clinical indications (gastrointestinal tumors) exist.

Over the last decade, radiofrequency thermal ablation (RFA) has become an accepted treatment modality for unresectable primary and metastatic liver tumors. It can be performed either percutaneously, laparoscopically, or via an open approach. With experience, indications and selection criteria have been determined for each tumor type. RFA has become the first-line therapy for unresectable HCC before chemotherapy or chemoembolization. It is also used as a bridge to transplantation. The purpose of RFA for unresectable colorectal liver metastasis is to debulk the liver in these patients who are predicted to die of liver failure owing to tumor progression. Neuroendocrine liver metastases benefit from debulking with RFA because of the frequent presence of debilitating symptoms from hormonal oversecretion. A selected group of patients with non-HCC, nonneuroendocrine, and noncolorectal liver metastases and without evidence of extrahepatic disease on imaging studies may benefit from debulking of the liver involvement with RFA and when other conventional modalities have failed. RFA provides effective local tumor control with minimal morbidity and short hospital stay. Recent studies also suggest a survival advantage of RFA for colorectal liver metastases and HCC.

Primary and secondary liver tumors are common. Without a definitive treatment, most patients will succumb to their disease usually within 12 months. As to date, neither regional nor systemic chemotherapy alone has made any significant impact on longterm survival, whereas liver resection or ablation can prolong overall survival in selected patients. However, only a small proportion of patients are suitable for liver resection. Cryoablation alone or in conjunction with resection and intra-arterial chemotherapy is another important tool, which considerably increases the scope of patients who can be treated with a curative intent. This review presented current data on cryoablation therapy for primary and secondary liver tumors.

Photodynamic therapy (PDT), which utilizes a photoactivated drug (photosensitizer) to destroy malignant or certain other undesirable tissue, is approved by health agencies worldwide, mainly for the treatment of early- and late-stage lung cancer and premalignant and obstructive esophageal cancer. The clinical and scientific development of PDT began in the early 1970s at Roswell Park Cancer Institute in Buffalo, NY. This paper presents the history of this process at Roswell Park.

Utilizing-high frequency sound waves to define internal structures, ultrasound (US) provides an opportunity not only to diagnose disease but also to target treatment to malignant tumors. US has several advantages over other radiology-assisted techniques that highlight its important role as a component of anticancer therapy. US provides an opportunity to administer therapy with real-time guidance. In other words, the physician can deliver treatment while synchronously visualizing the US images to ensure proper targeting. By placing US transducers within gastrointestinal (GI) lumens, periluminal structures can be readily visualized with US. The concept has led to the development of rigid US probes that can provide high-quality images of perirectal organs, such as the prostate, and, in recent years, endoscopic ultrasound (EUS). The creation of these US-endoscopy hybrids permits placement of high-frequency US probes in close proximity to structures that can be difficult to image with percutaneous US. EUS is not only limited to abdominal viscera, but can also image thoracic organs as well and therefore provides the endoscopist with minimally invasive access to evaluate and potentially treat abdominal and thoracic malignancies. This chapter will discuss US-based delivery of regional cancer therapy, introducing the reader to the methods and requirements for successful treatment. Examples of therapy will be provided; however, an in-depth discussion of indications and results for specific cancers will be reserved for chapters focusing on specific regional therapies.