Goldie and Coldman Hypothesis

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An important corollary to tumor growth is the development of drug resistance resulting from spontaneous mutations that occur with cell proliferation, independent of the resistance inherent to the heterogeneity in cell kinetics described earlier. Goldie and Coldman had hypothesized that this occurs at a rate of 1 of 105 cells per gene.7 If 1g tumor, the minimum size for detection, contains 109 cells, then such a tumor might contain 104 clones resistant to any given drug. However, resistance to two drugs would be seen in fewer than 1 cell in a 10-g (1010 cells) tumor. This idea is consistent with the known observation that combination chemotherapy is more effective than single-agent regimens. Nevertheless, single agents have remained successful in the treatment of

Gompertzian Growth Kinetics

figure 2.2. Gompertzian model of tumor growth (x-axis, time for tumor growth; y-axis, tumor volume).

figure 2.2. Gompertzian model of tumor growth (x-axis, time for tumor growth; y-axis, tumor volume).

certain tumors, such as Burkitt's lymphoma at sizes greater than 1 g.8 This hypothesis is one basis for the idea that chemotherapy should theoretically be started when tumor burden is smallest, to be effective; concomitant or alternating administration of noncross-resistant drugs is preferred to sequential chemotherapy. However, delaying therapy does not necessarily result in decreased responsiveness in many cases.9,10 Similarly, administration of chemotherapy preoper-atively, although it may be predicted to be more beneficial based on this model, does not confer any significant improvement in the clinical outcomes in resectable early-stage breast cancer. This model also assumes a stepwise development of resistance to individual agents and thus does not account for multidrug resistance patterns.

Tumor cell growth kinetics are complex and poorly understood. There are no available models that accurately describe all aspects of clinical behavior of solid tumors. The heterogeneous genetic abnormalities of different tumors underlie their behavior, making it impossible to make broad predictions.

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