Goldie-Coldman model of resistance
Resistant cells arise by chance mutation as a tumour grows, so the chance of a cancer already containing resistant cells rises with its size. The model argued for treating early and for alternating non-cross-resistant drugs.
Overview
James Goldie and Andrew Coldman adapted Luria and Delbruck's bacterial mutation analysis to tumours in 1979: resistance to a drug arises spontaneously at a rate per cell division, so the probability that a tumour of a given size harbours resistant cells is a function of its size and the mutation rate. Their conclusions were to start chemotherapy as early as possible and to alternate non-cross-resistant regimens to pre-empt resistance. Alternating schedules largely failed in trials, but the underlying logic survives in modern evolutionary models and in the case for adjuvant therapy of micrometastatic disease.
How it works
Probability that no resistant cell exists in a tumour of N cells with mutation rate u is about exp(-u·N); resistance is therefore expected once tumours exceed roughly 1/u cells.
- First quantitative theory of acquired resistance
- Justified adjuvant treatment of small tumour burdens
- Ancestor of modern evolutionary models
- Alternating regimens did not improve outcomes in trials
- Ignores pre-existing and adaptive resistance
- Mutation rates poorly known
Latest papers
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