Relationship between tumor size and curability of prostatic cancer by combined chemo-hormonal therapy in rats

Nearly all men with metastatic prostatic cancer respond to androgen ablation, demonstrating that at least a portion of their cancer cells are androgen responsive. Unfortunately, however, individual prostatic cancers contain clones of androgen-independent, in addition to androgen-responsive, cancer cells. Due to this tumor cell heterogeneity, essentially all patients treated with androgen ablation alone eventually relapse to a state unresponsive to further antiandrogen therapy; cures are rarely produced. To produce cures, additional nonhormonal therapy targeted at the androgen-independent prostatic cancer cells within the patient should be combined with androgen ablation targeted at the androgen-dependent cancer cells. The validity of such combined chemo-hormonal therapy was tested using, as the experimental model, two members of the Dunning system of serially transplantable rat prostatic cancers. Specifically the slow growing, well differentiated H and the fast growing, poorly differentiated G Dunning sublines were used, since these cover the clinical extremes observed for human prostatic cancers. The chemotherapeutic agent used in combination with surgical androgen ablation (i.e., castration) in these studies was Cytoxan. These studies demonstrate that for both the H and G cancer-bearing rats, the mean survival following combined chemo-hormonal therapy was increased above that found for castrate or Cytoxan when either was used as monotherapy. In addition, an inverse relationship between tumor size at the time of initiation of therapy and the ability of the combined chemo-hormonal therapy to cure animal bearing either the H or G sublines was demonstrated. Such combined chemo-hormonal therapy could only cure a proportion (i.e., 30-40%) of H or G tumor-bearing animals if initiated when the tumor was less than or equal to 0.2 cm3 in size. In contrast, if the tumor was 1-2 cm3 in starting size when the chemo-hormonal therapy was initiated, no animal was cured. Neither of the monotherapies (i.e., castrates or Cytoxan alone) could cure any animals regardless of the starting size.