In the past, all forms of metastatic prostate cancer have been considered incurable. In recent years, the FDA has approved six drugs for men with metastatic disease, all of which can increase survival. In a study published in Urology®, researchers demonstrate for the first time that an aggressive combination of systemic therapy (drug treatment) with local therapy (surgery and radiation) directed at both the primary tumor and metastasis can eliminate all detectable disease in selected patients with metastatic prostate cancer.

While the study is only a first step, one-fifth of the patients treated had no detectable disease, with an undetectable prostate-specific-androgen (PSA) and normal blood testosterone, after 20 months. The results suggest that some men who have previously been considered incurable can possibly be cured; investigators also establish a new paradigm for testing various drug combinations in conjunction with local treatment of the prostate to determine which is the best approach (ie, has the highest undetectable disease rate). Such results could not have been achieved with any single therapy alone.

According to lead investigator Howard I. Scher, MD, Chief of the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center in New York City, "The sequential use of the three different modalities helped illustrate the role and importance of each in achieving the undetectable PSA with normal testosterone level end point, which represents a 'no-evidence of disease' status." Longer follow-up is needed to determine whether these patients were in fact cured.

Twenty men with metastatic prostate cancer, five with extra-pelvic lymph nodal disease and 15 with bone with or without nodal disease, were treated with androgen deprivation therapy (ADT), radical surgery that included a retroperitoneal lymph node dissection as needed, and radiation therapy to visible metastatic lesions in bone. ADT was stopped after a minimum of six months if an undetectable PSA was achieved after combined modality therapy. Other patients were treated continuously.

The combined treatment regimen including surgery was well tolerated. Matthew J. O'Shaughnessy, MD, PhD, Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, commented "While the role of local therapy in metastatic prostate cancer is still under investigation, aggressive resection of visible disease performed by experienced surgeons was critical to the outcome."

Of the five patients with extra-pelvic lymph node involvement, four achieved an undetectable PSA after ADT and surgery, while the fifth needed radiation to reach this milestone. However, none achieved the primary end point of undetectable PSA with testosterone recovery at 20 months after initiation of therapy with ADT alone, although one patient had a PSA of <.05 ng/mL with a testosterone level of 47 ng/dL at 39 months.

Of the 15 patients with bone metastases, 14 (93%) reached an undetectable PSA when ADT, surgery, and radiation were used. Ultimately, four (27%) achieved the proposed end point, a PSA of <.05 ng/mL and serum testosterone of >150 ng/dL at 20 months after the start of ADT, which remained undetectable in two patients for 27 and 46 months, respectively.

Commenting on the study, Oliver Sartor, MD, Cancer Research, Department of Medicine and Urology, Tulane University School of Medicine, New Orleans, LA, stated, "The end point deserves special mention, as the end point of undetectable PSA after testosterone recovery has been previously discussed but rarely studied. The authors proposed that this end point may serve as a first step toward establishing a curative paradigm. Many in the field agree, but note that the longevity of effect is essential to prove the point of curability. Regardless, the movement toward a curative paradigm is much needed and the investigators are to be congratulated for setting forth a paradigm that can be used to assess the possibility of cure in a reasonable period of time."

"A multimodal treatment strategy for patients who present with disease that is beyond the limits of curability by any single modality enables the evaluation of new approaches in order to prioritize large-scale testing in early stages of advanced disease. The end point also shifts the paradigm from palliation to cure," remarked Dr. Scher. It is expected that an upcoming Phase 2 trial will further test this endpoint and combined modality approach.