Introduction

B-cell acute lymphoblastic leukemia (B-cell ALL) has historically accounted for approximately 2% of childhood ALLs diagnosed in the United States each year. This malignancy has clinical, histologic, immunophenotypic, and cytogenetic features similar to those of Burkitt lymphoma, a high-grade B-cell non-Hodgkin lymphoma (NHL). Hence, B-cell ALL and Burkitt lymphoma are usually considered to represent a spectrum of the same disease process. In children, the distinction between Burkitt lymphoma with bone marrow involvement and B-cell ALL is arbitrarily based on the degree of marrow infiltration. Patients who have less than 25% replacement of normal marrow with lymphoblasts are considered to have advanced (stage IV) Burkitt lymphoma, whereas those with more extensive marrow replacement are given the diagnosis of B-cell ALL. These two groups are treated with the same protocols used for patients with advanced-stage Burkitt lymphoma that has not disseminated to the marrow (stage III). Although limited-stage Burkitt lymphoma is also thought to be included in this disease spectrum, it is less common in children than are the advanced forms and is treated with much less intensive therapy. Hence, in describing treatment, we will focus on stages III and IV Burkitt lymphoma and B-cell ALL.

Advances in our understanding of the molecular pathogenesis of these malignancies and improvements in treatment outcome have been striking over the past 20 years. Currently, a 75% to 85% event-free survival rate can be expected for children with B-cell ALL. By contrast, less than 50% of these patients were event-free survivors 20 years ago.

Introduction

While approximately half of all patients with cancer can be cured, either by locoregional therapy (surgery or radiation) or by systemic chemotherapy, this success is not gained without a price – that of toxicity to normal tissues, either during treatment or afterwards. Prominent among the late effects of treatment is the development of second malignancies, for radiation and chemotherapy are both carcinogenic (Boice, 1988; Boffetta and Kaldor, 1994). The protean toxic manifestations of cancer therapy arise because of the lack of selectivity of present treatment approaches, a shortcoming that is hardly surprising when it is considered that the therapeutic effects of radiation and chemotherapy were first recognized, and have subsequently been enhanced, almost entirely as a consequence of empirical observations. Thus, all new approaches to cancer treatment are directed towards improving the therapeutic index, i.e., decreasing toxicity while achieving similar, or preferably better, tumor cell kill. While empirical clinical trials remain the mainstay of research directed towards the improvement of therapeutic results, it seems probable that optimal therapeutic indices, in which curative therapy is associated with minimal toxicity (i.e., tumor-specific therapy), will only be achieved by the identification of major biological differences between neoplastic cells and their normal counterparts that can be exploited therapeutically (i.e., the identification of an ‘Achilles heel’ in the tumor cell).

Cancer is now the biggest target disease for gene therapy protocols worldwide. Despite significant advances in the treatment of cancer in the last two decades, most tumors remain resistant to all current treatment modalities – surgery, radiotherapy, chemotherapy, and biotherapy. Local methods such as surgery and radiotherapy are often only effective in the absence of metastatic disease. Despite tremendous effort over the last fifty years, only a very small proportion of human cancers are cured by chemotherapy.

Gene-based therapy is a novel therapeutic approach to treating cancer which has been made possible only by recent and remarkable progress in our understanding of the molecular biology of cancer. Gene therapy can be described as the transfer to human cells and the expression of genetic material for a therapeutic purpose. Currently there are over two hundred gene therapy protocols active worldwide specifically aimed at single gene defects such as cystic fibrosis and a growing number of cancers. This book outlines the diverse approaches being attempted to develop effective future cancer therapies.

The last decade has seen dramatic advances in our understanding of the mechanisms involved in the control of cell growth and their deregulation in cancer. Certain classes of genes encode proteins that play distinct roles in the processing of signals from the outside of the cell to the nucleus. Any changes to the delicate system of control by these oncogenes or tumor suppressor genes may result in the formation of cancer.