Men with localized high-risk tumors are at significant relapse risk after surgery or radiotherapy.

In the PSA era, most men with newly diagnosed prostate cancer present with clinically localized disease and are curable with surgery or radiation. Among patients with no evidence of metastasis at presentation, radical prostatectomy alone is associated with 10- and 15-year cancer-specific survival rates of 96% and 93%, respectively, and post-operative periods of biochemical progression-free survival of 77% and 75%, respectively.

Approximately 25%-35% of men believed to have localized cancer fail to be cured following definitive local therapy, most of whom require some form of systemic therapy.

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Predicting which patients with localized disease are at risk for failing localized therapy can be done with some accuracy by evaluating several important clinical factors. Prior to surgery, prostate cancer is characterized ac-cording to three main factors: extent of disease (clinical by digital rectal examination), tumor grade (biopsy-based Gleason patterns) and serum PSA level.

For greater predictive value, tables and nomograms that combine these three variables—such as the Partin table and the Kattan nomogram—are used to crunch these numbers and stratify patients according to risk. Following surgery, additional information is available, including surgical margins, level of prostatic capsular invasion, and involvement of seminal vesicles, and lymph nodes. Using these additional data and methods, patients who might have occult metastatic disease that could lead to a recurrence after surgery can be identified, and enrollment in a trial of systemic therapy should be offered.

For patients categorized as high risk for recurrence after local therapy, the timing and type of systemic therapies must be considered. Optimal timing remains unclear and is under investigation. Neoadjuvant therapy (preceding surgery or radiation) allows for earlier exposure of any micro-metastases to treatment.

Since surgical pathology specimens are garnered after neoadjuvant therapy, pre- and post-treatment specimens can be compared, and mechanisms of drug action and resistance potentially elucidated. In contrast, adjuvant therapy (administered after primary localized treatment) targets the primary cancer first. Advocates claim that with the adjuvant course, early prostate removal provides important pathologic information sooner and allows for better staging and patient selection. Patients may also receive systemic therapy concurrent with radiation treatments.

Experience in other cancers demonstrates that multimodal strategies improve patient outcomes. For prostate cancer, various types and combinations of systemic therapies are under investigation. The most commonly used systemic therapies include androgen deprivation therapy (ADT) and chemotherapy.

Neoadjuvant hormonal therapy

In a study by Bolla et al, patients who chose external beam radiation as their local modality had improved disease-free and overall survival with the addition of adjuvant androgen deprivation treatment (N Engl J Med. 1997;337:295-300). In an effort to improve outcomes even more for this population, ongoing and future studies will investigate higher radiation doses, whole pelvis irradiation, the addition of chemotherapy to hormonal therapy, and other treatments.

At present, neoadjuvant hormonal therapy in conjunction with radical prostatectomy for locally advanced disease is not advisable. Studies show it can reduce the incidence of positive margins, but this effect has not correlated with reduced likelihood of biochemical recurrence.