The methodology of drug development has been the subject of extensive dis cussion by a relatively small group of individuals in industry and government who have been intimately concerned with the identification and study of new anticancer drugs. The Chemotherapy Program of the National Cancer In stitute has represented the major focus of initial efforts in drug development, as summarized in the historical perspective presented in chapter 1 and its references. It is no coincidence that the Chemotherapy Program was the origin of the Division of Cancer Treatment, a government entity that has had a pivotal role in the growth of clinical oncology. In an analogous fashion this book presents the methodology employed in the clinical study of anticancer drugs within the broad context of cancer treatment. The research orientation promulgated in the study of new drugs is a central theme in most oncolo gists' approach to the clinical problem of cancer. Therefore, we hope that this book will introduce readers to treatment research in clinical oncology. For the oncologist, the clinical evaluation of antitumor therapy is both part of the day-to-day management of specific patients and the critical considera tion of developing therapeutic alternatives. For physicians in other fields of medicine it is important to acquaint themselves with the basic tools of the oncologist. For people without medical training, including patients who might be interested in treatment research, many of the chapters may be overly technical.

Concepts, Mechanisms, and New Targets for Chemotherapy describes new interconnections between rationally designed and empirically discovered compounds. One route that has not been travelled previously is that of protein kinase C inhibition. This pathway may be exploited to give potent inhibitors, such as the bryostatins, now in clinical trial. A summary is given of the current status of topoisomerase, focusing on recent clinical advances with camptothecin analogs based on connecting empiricism with concepts of drug selectivity. Modification of existing therapies based on the pursuit of leads arising from mechanistic studies is also being applied clinically on a wide scale. Greater understanding should follow from the studies of reversal of the multidrug resistant phenotype, on the use of hydroxyurea to reverse resistance mediated by extrachromosomal DNA, and on various aspects of the fluoropyrimidine pathways. Successful applications of chemotherapy to the treatment of specific diseases include the growing applications of systemic therapy using various skin malignancies. In prostate cancer, estramustine phosphate will likely play an expanding role. Taxanes are restructuring treatment regimens in breast cancer, and high-dose strategies are described with peripheral blood progenitor autografting in the treatment of ovarian and breast cancers.

The decade of the 1990s will see an increasing emphasis on the modulation of chemotherapeutic drug selectivity and in the 'lock and key' approach to new targets to control malignant proliferation. The contents of this volume appropriately reflect these scientific undercurrents. An emerging powerful tool of molecular pharmacology is described by Holcenberg and Wu. Manipulation of genetic expression by modification of messenger RNA is now within our reach, and the basic concepts are suc- cinctly reviewed as a primer on future biochemical engineering of new anti- cancer molecules. Another concept that appears to be worthy of further study in both experimental and clinical chemotherapy concerns obs'ervations on the modulation of activity by the nucleoside transport inhibitor, dipyri- damole. How potentiation of several anticancer drugs occurs has practical, as well as theoretical, ramifications, discussed by Goel and HowelL Finally, O'Dwyer and La Creta present a fresh look at sensitization of chemotherapy by the hypoxic radiosensitizer, SR-2731.

F. M. MUGGIA When faced with the inadequacies of current cancer treatment, we prefer to look at what the future may hold. Quite often, we take for granted the past, preferring research into totally new areas. However, the persistent development of fertile soil may yield surprising rewards for those who choose to build on the knowledge of the past--hence, this symposium on anthracycline antibiotics. Although the anthracycline antibiotics represent much of the present and future of cancer treatment, their actual use c stretches back barely two decades to the pioneering efforts of Aurelio Di Marco, who characterized the antitumor properties of daunomycin and adriamycin. * The clinical application of these two compounds heralded a decade of excitement among oncologists dealing with pediatric tumors, breast cancer, leukemias, and lymphomas, and opened new hope for patients afflicted with sar comas and a variety of other tumors that had been deemed - sistant to chemotherapy. These successes were tempered with the realization that the antitumor effect of anthracyclines could be achieved at times only at the very high price of risking cardiac decompensation and, almost invariably, with the occurrence of alopecia and other acute toxicities. This record of past achievements and problems has slowly given way to a present increasingly illuminated by our ability to modify the distressing toxicities of these agents. Detailed clinical studies supplemented by ingenious laboratory models have gradually elucidated mechanisms and risk factors im plicated in the cardiomyopathy."

The Boerhaave Committee for postgraduate Medical Education decided to organize a course on cancer treatment covering selected solid tumors, in which they felt important chan ges were emerging in the basic biologic, diagnostic and therapeutic concepts. Current management of cancer patients is intimately dependent on precise morphologic diagnosis, clinical staging and the proper application of all treat ment modalities. Many prominent investigators and clinicians of major can cer centers in the United States, Canada, and Europe con tributed by lecturing and during the panel discussions. This book is the tangible outcome of the productive ex changes during the meeting held December 6-8, 1979. In ovarian cancer the usefulness of histologic grading in determining prognosis has become clear. The most impor tant advance for the management of the patient is th- careful staging procedure, based on new concepts of tumor spread coupled with treatment tailored to the extent of disease. Survival appears to be directly related to the extent of the tumor mass. This has resulted in description and application of optimal cyto-reductive surgery. Radiotherapy and chemotherapy can both effectively eradi cate small amounts of tumor."

Where do you begin to look for a recent, authoritative article on the diagnosis or management of a particular malignancy? The few general oncology textbooks are generally out of date. Single papers in specialized journals are informative but seldom comprehensive; these are more often preliminary reports on a very limited number of patients. Certain general journals frequently publish good indepth reviews of cancer topics, and published symposium lectures are often the best overviews available. Unfor tunately, these reviews and supplements appear sporadically, and the reader can never be sure when a topic of special interest will be covered. Cancer Treatment and Research is a series of authoritative volumes which aim to meet this need. It is an attempt to establish a critical mass of oncology literature covering virtually all oncology topics, revised frequently to keep the coverage up to date, easily available on a single library shelf or by a single personal subscription. We have approached the problem in the following fashion. First, by dividing the oncology literature into specific subdivisions such as lung can cer, genitourinary cancer, pediatric oncology, etc. Second, by asking emi nent authorities in each of these areas to edit a volume on the specific topic on an annual or biannual basis. Each topic and tumor type is covered in a volume appearing frequently and predictably, discussing current diagnosis, staging, markers, all forms of treatment modalities, basic biology, and more."

Where do you begin to look for a recent, authoritative article on the diagnosis or management ofa particular malignancy? The few general onco logy textbooks are generally out of date. Single papers in specialized journals are informative but seldom comprehensive; these are more often prelimi nary reports on a very limited number of patients. Certain general journals frequently publish good indepth reviews of cancer topics, and published symposium lectures are often the best overviews available. Unfortunately, these reviews and supplements appear sporadically, and the reader can nev er be sure when a topic of special interest will be covered. Cancer Treatment and Research is a series of authoritative volumes which aim to meet this need. It is an attempt to establish a critical mass of oncology literature covering virtually all oncology topics, revised frequently to keep the coverage up to date, easily available on a single library shelf or by a single personal subscription. We have approached the problem in the following fashion. First, by div iding the oncology literature into specific subdivisions such as lung cancer, genitourinary cancer, pediatric oncology, etc. Second, by asking eminent authorities in each of these areas to edit a volume on the specific topic on an annual or biannual basis. Each topic and tumor type is covered in a volume appearing frequently and predictably, discussing current diagnosis, staging, markers, all forms of treatment modalities, basic biology, and more."

Experimental chemotherapy continues to be at the forefront of cancer thera- peutics. Topics covered in the preceding volume on cancer chemotherapy in this series such as study of drugs by alkaline elution, the development of the antimetabolite tiazofurin, and the treatment of germ cell tumors have become informative references to current experimentalists and practitioners. In even earlier volumes, reviews of the platinum compounds, anthracyclines, and osteosarcoma represent topics associated with such rapid progress requiring a look back to provide the appropriate perspective. Similarly, we venture to predict that the topics in this volume will become useful landmarks for future drug development and disease strategies. In the area of drug development, what is being learned about old, estab- lished antineoplastics is raising renewed expectations that it will be translated into improved applications and patient benefit. For example, we now have the ability to modulate the action of alkylating agents and fluorinated pyri- midines to achieve greater sensitivity. A new compound for an old target, trimetrexate, an antifolate that does not polyglutaminate, will have a role not only in treatment of neoplastic diseases, but also protozoal infection.

As in CANCER CHEMOTHERAPY 1, this volume brings to the reader highlights in three different areas of cancer therapeutics: new concepts and models; drug classes; and clinical settings. Topics were chosen because of their timeliness or probable current impact in cancer treatment. Authors were selected on the basis of their ability to provide a critical overview of specific subjects and their involvement in original work. I shall review the aims of this second volume, and then elaborate on the scope of its con tents. The principal aim of the volumes on cancer chemotherapy in the' Cancer Treatment and Research' series, as stated in the preface to the first volume, is to assemble in a concentrated form selected ingredients of chemothera peutic progress. These ingredients are to include concepts in therapeutic strategy, pre-clinical studies, development of major classes of compounds, identificatlon of new directions and of landmarks of clinical progress. Thus we do not foresee overlap with series which provide an yearly update of chemotherapy in an encyclopedic manner, or reviews of cancer chemother apy. Unlike those publications, our volumes are not intended to seek a place in shelves as a reference manual. It is this Editor's hope that persons repre senting various biomedical disciplines will seek the' Cancer Treatment and Research' chemotherapy volumes to survey advances in the field at regular intervals."

Concepts, Mechanisms, and New Targets for Chemotherapy describes new interconnections between rationally designed and empirically discovered compounds. One route that has not been travelled previously is that of protein kinase C inhibition. This pathway may be exploited to give potent inhibitors, such as the bryostatins, now in clinical trial. A summary is given of the current status of topoisomerase, focusing on recent clinical advances with camptothecin analogs based on connecting empiricism with concepts of drug selectivity. Modification of existing therapies based on the pursuit of leads arising from mechanistic studies is also being applied clinically on a wide scale. Greater understanding should follow from the studies of reversal of the multidrug resistant phenotype, on the use of hydroxyurea to reverse resistance mediated by extrachromosomal DNA, and on various aspects of the fluoropyrimidine pathways. Successful applications of chemotherapy to the treatment of specific diseases include the growing applications of systemic therapy using various skin malignancies. In prostate cancer, estramustine phosphate will likely play an expanding role. Taxanes are restructuring treatment regimens in breast cancer, and high-dose strategies are described with peripheral blood progenitor autografting in the treatment of ovarian and breast cancers.

The decade of the 1990s will see an increasing emphasis on the modulation of chemotherapeutic drug selectivity and in the 'lock and key' approach to new targets to control malignant proliferation. The contents of this volume appropriately reflect these scientific undercurrents. An emerging powerful tool of molecular pharmacology is described by Holcenberg and Wu. Manipulation of genetic expression by modification of messenger RNA is now within our reach, and the basic concepts are suc- cinctly reviewed as a primer on future biochemical engineering of new anti- cancer molecules. Another concept that appears to be worthy of further study in both experimental and clinical chemotherapy concerns obs'ervations on the modulation of activity by the nucleoside transport inhibitor, dipyri- damole. How potentiation of several anticancer drugs occurs has practical, as well as theoretical, ramifications, discussed by Goel and HowelL Finally, O'Dwyer and La Creta present a fresh look at sensitization of chemotherapy by the hypoxic radiosensitizer, SR-2731.

Experimental chemotherapy continues to be at the forefront of cancer thera- peutics. Topics covered in the preceding volume on cancer chemotherapy in this series such as study of drugs by alkaline elution, the development of the antimetabolite tiazofurin, and the treatment of germ cell tumors have become informative references to current experimentalists and practitioners. In even earlier volumes, reviews of the platinum compounds, anthracyclines, and osteosarcoma represent topics associated with such rapid progress requiring a look back to provide the appropriate perspective. Similarly, we venture to predict that the topics in this volume will become useful landmarks for future drug development and disease strategies. In the area of drug development, what is being learned about old, estab- lished antineoplastics is raising renewed expectations that it will be translated into improved applications and patient benefit. For example, we now have the ability to modulate the action of alkylating agents and fluorinated pyri- midines to achieve greater sensitivity. A new compound for an old target, trimetrexate, an antifolate that does not polyglutaminate, will have a role not only in treatment of neoplastic diseases, but also protozoal infection.

Where do you begin to look for a recent, authoritative article on the diagnosis or management of a particular malignancy? The few general oncology textbooks are generally out of date. Single papers in specialized journals are informative but seldom comprehensive; these are more often preliminary reports on a very limited number of patients. Certain general journals frequently publish good indepth reviews of cancer topics, and published symposium lectures are often the best overviews available. Unfor tunately, these reviews and supplements appear sporadically, and the reader can never be sure when a topic of special interest will be covered. Cancer Treatment and Research is a series of authoritative volumes which aim to meet this need. It is an attempt to establish a critical mass of oncology literature covering virtually all oncology topics, revised frequently to keep the coverage up to date, easily available on a single library shelf or by a single personal subscription. We have approached the problem in the following fashion. First, by dividing the oncology literature into specific subdivisions such as lung can cer, genitourinary cancer, pediatric oncology, etc. Second, by asking emi nent authorities in each of these areas to edit a volume on the specific topic on an annual or biannual basis. Each topic and tumor type is covered in a volume appearing frequently and predictably, discussing current diagnosis, staging, markers, all forms of treatment modalities, basic biology, and more."

The methodology of drug development has been the subject of extensive dis cussion by a relatively small group of individuals in industry and government who have been intimately concerned with the identification and study of new anticancer drugs. The Chemotherapy Program of the National Cancer In stitute has represented the major focus of initial efforts in drug development, as summarized in the historical perspective presented in chapter 1 and its references. It is no coincidence that the Chemotherapy Program was the origin of the Division of Cancer Treatment, a government entity that has had a pivotal role in the growth of clinical oncology. In an analogous fashion this book presents the methodology employed in the clinical study of anticancer drugs within the broad context of cancer treatment. The research orientation promulgated in the study of new drugs is a central theme in most oncolo gists' approach to the clinical problem of cancer. Therefore, we hope that this book will introduce readers to treatment research in clinical oncology. For the oncologist, the clinical evaluation of antitumor therapy is both part of the day-to-day management of specific patients and the critical considera tion of developing therapeutic alternatives. For physicians in other fields of medicine it is important to acquaint themselves with the basic tools of the oncologist. For people without medical training, including patients who might be interested in treatment research, many of the chapters may be overly technical."

Neoplastic disease confined to the liver is an important worldwide problem. In the industrialized nations, metastatic disease of the most common cancers involves the liver in upwards of 50% of cases. Primary hepatic tumors are virtually epidemic in most third world countries and certainly constitute one of the ten most common causes of cancer deaths on a worldwide scale. Amazingly, little specific attention has been devoted to therapeutic approaches of liver and biliary tumors until recently. We attribute this apparent lack of interest to the uniformly poor progno sis of patients so afflicted, and attribute the renewed interest to the exciting new developments in diagnostic and therapeutic technology as well as in tumor biology. The purpose of this book is to collect in one volume an integrated selection of articles that would provide the therapist with a comprehensive, yet practical, overview of liver cancer. We believe the contributors to the book are superbly qualified experts on the various subjects and provide in-depth information on respective fields. The edit ing process for us was not only educational but thrilling as the high quality and complementary nature of the chapters became evident as we received them. Be cause many areas in the field of liver cancer are controversial, the reader will notice that contradictory opinions are presented by some of the authors."

As in CANCER CHEMOTHERAPY 1, this volume brings to the reader highlights in three different areas of cancer therapeutics: new concepts and models; drug classes; and clinical settings. Topics were chosen because of their timeliness or probable current impact in cancer treatment. Authors were selected on the basis of their ability to provide a critical overview of specific subjects and their involvement in original work. I shall review the aims of this second volume, and then elaborate on the scope of its con tents. The principal aim of the volumes on cancer chemotherapy in the' Cancer Treatment and Research' series, as stated in the preface to the first volume, is to assemble in a concentrated form selected ingredients of chemothera peutic progress. These ingredients are to include concepts in therapeutic strategy, pre-clinical studies, development of major classes of compounds, identificatlon of new directions and of landmarks of clinical progress. Thus we do not foresee overlap with series which provide an yearly update of chemotherapy in an encyclopedic manner, or reviews of cancer chemother apy. Unlike those publications, our volumes are not intended to seek a place in shelves as a reference manual. It is this Editor's hope that persons repre senting various biomedical disciplines will seek the' Cancer Treatment and Research' chemotherapy volumes to survey advances in the field at regular intervals.

Where do you begin to look for a recent, authoritative article on the diagnosis or management ofa particular malignancy? The few general onco logy textbooks are generally out of date. Single papers in specialized journals are informative but seldom comprehensive; these are more often prelimi nary reports on a very limited number of patients. Certain general journals frequently publish good indepth reviews of cancer topics, and published symposium lectures are often the best overviews available. Unfortunately, these reviews and supplements appear sporadically, and the reader can nev er be sure when a topic of special interest will be covered. Cancer Treatment and Research is a series of authoritative volumes which aim to meet this need. It is an attempt to establish a critical mass of oncology literature covering virtually all oncology topics, revised frequently to keep the coverage up to date, easily available on a single library shelf or by a single personal subscription. We have approached the problem in the following fashion. First, by div iding the oncology literature into specific subdivisions such as lung cancer, genitourinary cancer, pediatric oncology, etc. Second, by asking eminent authorities in each of these areas to edit a volume on the specific topic on an annual or biannual basis. Each topic and tumor type is covered in a volume appearing frequently and predictably, discussing current diagnosis, staging, markers, all forms of treatment modalities, basic biology, and more."

Neoplastic disease confined to the liver is an important worldwide problem. In the industrialized nations, metastatic disease of the most common cancers involves the liver in upwards of 50% of cases. Primary hepatic tumors are virtually epidemic in most third world countries and certainly constitute one of the ten most common causes of cancer deaths on a worldwide scale. Amazingly, little specific attention has been devoted to therapeutic approaches of liver and biliary tumors until recently. We attribute this apparent lack of interest to the uniformly poor progno sis of patients so afflicted, and attribute the renewed interest to the exciting new developments in diagnostic and therapeutic technology as well as in tumor biology. The purpose of this book is to collect in one volume an integrated selection of articles that would provide the therapist with a comprehensive, yet practical, overview of liver cancer. We believe the contributors to the book are superbly qualified experts on the various subjects and provide in-depth information on respective fields. The edit ing process for us was not only educational but thrilling as the high quality and complementary nature of the chapters became evident as we received them. Be cause many areas in the field of liver cancer are controversial, the reader will notice that contradictory opinions are presented by some of the authors."