Treatment of small-cell carcinoma of the lung monitored by sequential flow cytometric dna analysis

Treatment-induced cell-kinetic changes in patients with small-cell carcinoma of the lung were studied, with the objective of exploiting the changes for improving the treatment. Flow-cytometric DNA analyses on fine-needle aspirates of metastases were used to monitor the cell cycle perturbations. Volume changes of metastases were determined by caliper measurements, and the white blood cell counts were used as an indicator of the toxicity. Fourteen metastases in 11 patients were studied during a total of 14 courses of treatment with cyclophosphamide, 1-(2-chloroethyl)-3-cyclohexyl-1 -nitrosourea, vincristine, and methotrexate. The cell cycle changes preceded tumor reduction. They consisted of a relative decrease in G₁ cells starting on Day 1, maximal on Days 3 to 5. Simultaneously, there was an increase in the S phase. This was followed in some patients by an increase in G₂ + M starting on Day 3, maximal on Days 4 to 6. The maximal changes observed in the cell cycle were: G₁, 70% to 1% S, 32% to 90% and G₂ + M, 14% to 88%. The tumor volume changes started on Day 2 and were highly variable, ranging from a brief partial remission to a complete remission. In contrast, the time course of the white blood cell count changes were fairly uniform. Two indices, designated the sensitivity index and the therapeutic index, were calculated to compare quantitatively the tumor volume changes and the white blood cell count changes. The pretreatment S-phase size was used as an indicator of proliferative activity. The evidence indicated that differences in tumor sensitivity were responsible for the variable initial tumor reduction. A large initial cell kill did not guarantee a successful outcome of the treatment. A previously demonstrated heterogeneity of individual tumors is a likely explanation for this phenomenon.