Novel therapies for PSA progression in the absence of imagable disease following local therapy

Prostate cancer is only temporarily controlled with androgen ablation (AA) therapy and subsequent chemotherapy, secondary to the development of molecular mechanisms of resistance [1]. Additionally, molecular mechanisms of tumor resistance are increased in metastatic disease compared to primary tumors [1-7]. Potential mechanisms of resistance to therapy recently have been identified, including the overexpression of bcl-2, p53 mutations, and the multidrug resistance protein MRP [2-9]. For example, the development of androgen-independent disease is associated with an increase in the overexpression of the antiapoptotic protein bcl-2 [1,2]. McDonnell et al. demonstrated increased overexpression of bcl-2 in tumors obtained from patients with hormone-refractory prostate cancer (HRPC) in comparison to tumors from patients with hormone-naive disease [1]. Recent studies also demonstrated that the overexpression of bcl-2 is associated with resistance to chemotherapy [9]. In prostate cancer, mutations in p53 are more common in metastatic disease compared to primary tumors [3,4]. Mutated p53 is found in 25% of advanced hormone refractory disease, but in less than 10% in earlier disease [3]. Although it is clear that more effective systemic therapies are needed in the treatment of prostate cancer, these data suggest that targeting such therapies before AA, with minimal disease, before the development of molecular mechanisms of therapy resistance, may further improve antitumor activity. This chapter reviews the data on the use of both systemic standard therapies (AA or the early use of chemotherapy) and novel therapies that might be considered or studied in patients with PSA progression and no imagable disease after local therapy. The use of local salvage radiation therapy will be considered elsewhere, and is not covered in this chapter.