Is It Time to Re-Examine the Prostate Cancer Treatment Paradigm by Targeting the Interaction Between the Prostate and Metastases?

Abstract

In the article that accompanies this editorial, Rusthoven and colleagues add to the growing number of reports suggesting that control of the primary tumor site in men with metastatic prostate cancer will lengthen survival. The authors conducted a review of publicly available data to examine the effect of radiation therapy to the cancer within the prostate on the overall survival of men presenting with metastatic disease. If proven prospectively, the integration of local control in the treatment strategy of men with prostate cancer will be extended from those with regional disease to those with distant metastases at diagnosis. Of importance is that the survival improvement observed rivals that achieved with the addition of chemotherapy to the initial treatment of men with metastatic prostate cancer. If the observation is confirmed, standard therapy will certainly change to a comprehensive strategy that includes control of the primary tumor, chemotherapy, androgen ablation, and, perhaps in some, bone targeting. As the authors note, the study is the largest of its kind and provides additional support for the concept. The secondary analysis they performed links greater benefit to higher radiation doses, which implies that more effective local control achieves a better outcome. As the authors note, the greater effect on the survival observed in those with lower Gleason scores and T stages should be interpreted with caution because it may reflect the efficacy of radiation as monotherapy, as opposed to testing the merits of local control. For example, this does not exclude benefit from local control if a potentially more effective dualmodality approach combining surgery and radiation was used. Also, the observation that lower prostate-specific antigen (PSA) concentrations predict a greater benefit can be explained in various ways. Although tumor volumes and serum PSA concentration may correlate in subsets, an inverse relationship exists in the aggressive forms of the cancer. Thus, investigators should avoid the unsupported view that only patients with lower grade, lower volume cancers (oligometastatic prostate cancer) will benefit from the addition of local control to the primary tumor. Prospective studies should include a detailed evaluation of the relationship between measures of tumor volume (overall, in both the prostate and in distant sites), responsiveness to systemic therapies, and benefit from local control. The authors have identified priority questions. Foremost among these is to define the mechanisms by which local control might exert an effect on survival in the context of metastasis. Elucidation of these mechanisms will help address the following additional queries: Will eradication of cancer in the prostate be sufficient, or must eradication of all cancer within the pelvis, including nodal involvement, be considered? Is surgery, radiation, or the combination of the two the preferred method? Who are the patients most likely to benefit? Does the type of systemic therapy influence the need for control of the primary? These and other dilemmas will be best addressed from an understanding of the influence of the primary tumor and its control on the biology and clinical behavior of the disease. Implicit in the finding is that persistent cancer in the primary tumor exerts an adverse effect on survival that can be reversed by radiation and/or surgery. For clinicians, the most obvious attribution is the avoidance of the morbidity that results from uncontrolled progression of the primary tumor, such as obstructive uropathy, infections, blood loss, and pain, which often decrease the patient’s performance status and limit the ability to apply additional systemic therapies. One could easily accept that avoiding these devastating complications will improve the welfare of patients and lengthen survival. However, several lines of evidence also point to a biologic basis for the contribution of the primary tumor to prostate cancer lethality, and a number of hypotheses have been mounted to explain it. Possibilities include the continued shedding of prostate cancer to distant sites, the bidirectional trafficking of cancer cells or migration of tumor associated stromal cells, or the immunomodulatory effects of the primary tumor. Supporting this notion, Tzelepi et al noted that the prostate is a treatment sanctuary, by demonstrating that persistent viable cancer remains in the prostatectomy specimens of men treated with chemotherapy and androgen ablation, and the specimens express molecular markers linked to treatment refractory progression. In line with these findings are the reports that the majority of prostate glands harbor persistent cancer after maximal androgen signaling inhibition and despite near universal achievement of an undetectable PSA. Taken together, these observations suggest that the prostate serves as a focus of resistance to systemic therapies in some patients that may contribute to accelerating disease progression. Linking the biology accounting for

DOI: 10.1200/JCO.2016.68.4738

Cite this paper

@article{Logothetis2016IsIT, title={Is It Time to Re-Examine the Prostate Cancer Treatment Paradigm by Targeting the Interaction Between the Prostate and Metastases?}, author={Christopher J. Logothetis and A. Aparicio}, journal={Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, year={2016}, volume={34 24}, pages={2810-1} }