Survival from cancer has improved quite dramatically over the past three decades as a result of advances in early detection, adjuvant and other aggressive therapeutic strategies, and the widespread use of combined modality therapy (surgery, chemotherapy, and radiotherapy). Cancers such as testicular, childhood leukemia, and Hodgkin's lymphoma are now considered amenable to cure, patients with common cancers such as breast or colorectal can look forward to a vastly improved disease free and overall survival, and patients with potentially incurable disease can look forward to living for extended periods of time as a result of better disease control (Meadows 1980; Ganz 1998a; Schwartz 1999; Aziz 2002b; Aziz and Rowland 2003). However, the therapeutic modalities mentioned are associated with a spectrum of late complications ranging from minor and treatable to serious or, occasionally, potentially lethal. One-fourth of late deaths occurring among survivors during the extended survivorship period, when the chances of primary disease recurrence are negligible, can be attributed to a treatment-related effect such as a second cancer or cardiac dysfunction. Most frequently observed sequelae include endocrine complications, growth hormone deficiency, primary hypothyroidism, and primary ovarian failure (Sklar 1999). Also included within the rubric of late effects are second malignant neoplasms arising as a result of genetic predisposition (e.g., familial cancer syndromes) or the mutagenic effects of therapy. These factors may act independently or synergistically. Synergistic effects of mutagenic agents such as cigarette smoke or toxins such as alcohol are largely unknown.
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