An experimental approach to chemotherapy for occult metastases: a quantitative model

Abstract

The population doubling time (PDT) of LMC 1 tumour cells in axillary and inguinal lymph nodes of tumour-bearing rats was estimated during the occult development of secondary tumours. Values increased with time and 13 days after implantation of the primary the PDT and the mean cell cycle time were the same, suggesting all tumour cells were in cycle. This information was used to predict the optimum time for administration of cyclophosphamide (CP) and to design rational treatments combining surgery with chemotherapy. 150 mg/kg CP, given 13 ± 1 days after implantation of the primary, reduced the incidence of metastases from 50% (in the surgery alone group) to zero. If the primary was left in situ reseeding was rapid and the incidence of metastases increased with time from drug administration. Within 13 days 50% of rats had metastases. However, a second dose of 150 mg/kg CP given at this time again reduced the incidence rate from 50% to zero. Lymph node metastases in rats given surgery alone reached 8–10 mm mean diameter (T 8–10 ) 47.0 ± 3.0 days after implantation of the primary. The equivalent T 8–10 values for metastases reseeded from once- and twice-treated primary tumours should be about 60 (47 + 13) and 73 (47 + 26) days respectively. The observed values were 57.4 ± 6.0 and 57.6 ± 2.6 days. The reduced value for twice-treated animals suggest a greater number of cells present than expected, and this may be due to either an increase in ‘seeding’ efficiency or in the number of clonogenic cells shed from the primary tumour after the second dose of CP.