PubMed1998
As clinical oncologists, our ultimate goal in treating patients with cancer is to be able to cure their disease with a combination of treatment modalities directed at the primary tumor (surgery or radiation), and potential metastases (chemotherapy). The validity of this multimodality approach to treating cancer was initially demonstrated with the successful treatment and cure of highly chemosensitive childhood cancers, such as Wilms' tumor, and these cures were only realized when adjuvant chemotherapy was included with local control measures. We attribute our treatment successes in childhood cancers to the use of cytotoxic chemotherapy, and we attribute our inability to cure many adults with more common forms of solid tumors to the ineffectiveness of chemotherapy in these diseases. Curing disease is not the goal of most pharmacological interventions in nonmalignant diseases. With the exception of antimicrobial and anticancer chemotherapy, most of the common classes of drugs are administered with the intent of controlling the disease or the symptoms caused by disease. We administer antihypertensive agents to control blood pressure, but the underlying cause of the hypertension is not cured by this therapy. If the hypertension recurs after antihypertensive therapy is stopped, we would conclude that the therapy was successful at controlling the disease. However, if a patient's tumor relapses after completing anticancer chemotherapy, the anticancer therapy would be considered to be unsuccessful. By setting lofty goals for our therapy, we increase the probability that the treatment will not meet our own and our patient's expectations. Schipper et al. [J Clin Oncol 1995;13:801-805] proposed that we abandon the "killing paradigm," which dictates that the treatment of cancer is directed toward eradication of all cancer cells, and that we adopt a "regulatory model" of cancer. This model views cancer as a maladaptive, constantly evolving process in which cancer cells differ only slightly from normal cells as a result of a few critical genetic changes that lead to dysregulation of growth. The treatment approach under this new paradigm is debulking of tumor burden with standard multimodality therapy followed by control of residual disease by "reregulation" of the remaining cancer cells. Controlling growth and spread of this residual disease would be accomplished with non-cytotoxic agents which target pathways that are responsible for the dysregulation in cancer cells. We are now on the verge of having the capacity to test this new paradigm of cancer. Advances in our understanding of the pathogenesis of many common forms of cancer at a molecular level have led to a revolution in anticancer drug development. A number of new agents that target a variety of critical molecular targets, such as the farnesyl transferase inhibitors that block ras oncogene activation, the matrix metalloproteinase inhibitors that block the enzymes involved in tissue invasion and metastasis [Editor's note: please see "New Drugs on the Horizon, page 271], and the angiogenesis inhibitors that block new vessel formation in growing tumors, are now being clinically tested. These new classes of anticancer drugs are aimed at regulating or controlling cancers rather than killing them. The potential utility of targeting the critical molecular lesion in tumor cells is illustrated by the efficacy of all-trans-retinoic acid in acute promyelocytic leukemia (APL). Although the capacity of all-trans-retinoic acid to induce complete remissions by inducing terminal differentiation of leukemic blasts was discovered empirically, the subsequent demonstration that the pathognomonic 15:17 translocation that is present in up to 90% of cases of APL results in the production of a dysfunctional retinoid receptor appears to explain the specificity and high level of activity of retinoid therapy in this disease. This is the first example of a cancer that can be treated by specifically targeting therapy to a pathogenetic molecular lesion. Retinoids are now being used in combination with standard chemotherapy for the treatment of APL, an example of the successful application of combining a molecularly targeted agent with conventional cytotoxic chemotherapy. The development and use of molecularly targeted agents for the treatment of cancer may require us to view cancer in a new light and to adjust our goals and expectations of its treatment as well as the endpoints of our clinical trials. However, pharmacologically controlling cancer may result in an equally acceptable outcome for our patients if it leads to what Schipper et al. termed a "functional cure."