Review of Current Treatment Intensification Strategies for Prostate Cancer Patients

Abstract

Prostate cancer (PCa) used to be one of the most common nondermatologic cancers in men that can be treated only with surgery. However, a revolutionary breakthrough came in the 1980s with the introduction of long-acting luteinizing hormone-releasing hormone (LHRH) agonists for the curative treatment of PCa. This paradigm shift contributed to the combined use of androgen deprivation therapy (ADT), chemotherapy, and radiotherapy for the treatment. The latest data highlight the use of treatment intensification (TI), i.e., combined use of radiotherapy (RT) and hormonal or drug treatments, for localized or locally advanced PCa. Indeed, the results of combined modality treatments have shown a reduction in disease-specific mortality and improved overall survival. Although TI seems promising, more research studies are warranted to confirm its efficacy. This review summarizes the latest available outcome results of pivotal trials and clinical studies on the efficacy of TI.

Keywords: ADT; LHRH agonist; prostate cancer; radiotherapy/radiation therapy; treatment intensification.

Figure 1

Mechanism of radiotherapy and onset of resistance in prostate cancer (PCa) cells. Radiotherapy (RT), such as external beam RT (EBRT) or high-dose-rate brachytherapy is one of the main treatment options for PCa. The basic principle of this therapy is causing massive and simultaneous DNA damage (double-strand breaks (DSB), single-strand breaks (SSB), and base modifications) that cancer cells cannot recover from, eventually leading to their death. However, in many cases, PCa cells develop resistance to RT through four different mechanisms (4R): repair, redistribution, repopulation, and reoxygenation [19,20]. PARP1 and ATR senses SSB and ATM primarily does DSB. These factors activate downstream signaling pathways and renders cancer cells to survive from DNA toxicity. Aside from repairing DNA lesions, cancer cells can avoid the indirect effect of radiation by redistributing cell cycle, reoxygenizing to hypoxic cells, and rapidly proliferating after IR uptake. These mechanisms help cancer cells survive from IR-induced toxicity.

Figure 2

A schematic diagram of treatment intensification for patients with prostate cancers. Localized prostate cancer stage can be categorized into two groups: localized and locally advanced groups. Typical radiotherapy treatment for low-risk localized PC is monoradiotherapy such and brachytherapy (BT) or external-beam radiation therapy (EBRT). For high-risk PC patients, combined treatment of radiotherapy with hormonal therapy so called Androgen deprivation therapy (ADT) clearly shows improved recovery rate.