Treatment of Locally Advanced Disease

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Risk Assessment

• The most important pathologic criteria predicting prognosis after radical prostatectomy are Gleason score, surgical margin status, and presence of non-organ-confined disease (e.g., extracapsular extension, seminal vesicle invasion, lymph node involvement).
• Serum PSA is the single most important follow-up parameter in evaluating patients after definitive treatment with either surgery or radiation. A reasonable surveillance schedule should include a history and physical examination and serum PSA every 3 months during the first year, every 6 months for 4 years, and yearly thereafter. 
• Risk assessment is best performed by a combination of serum PSA level, T stage, cancer grade, and extent of cancer on biopsy.

Radical Prostatectomy

• The use of radical prostatectomy for management of locally advanced prostate cancer has decreased. 
• In part, the shift in paradigm is due to the recognition that prostatectomy alone is often insufficient. 
• Improved risk assessment has permitted better identification of these patients before treatment. 
• Advances in delivery of RT and recognition that combined modality treatment (e.g., RT and AD) improved outcomes compared with monotherapy have further contributed to the migration away from surgery for high-risk and locally advanced tumors. 
• Radical prostatectomy can cure some men with high-risk disease features, and the addition of adjuvant and combined therapy may further improve outcomes of surgery alone.
• Biochemical progression after radical prostatectomy is difficult to assess, given the frequent use of adjuvant therapy (e.g., RT or AD). Without the use of secondary treatment, 5-year biochemical relapse is higher than 60%.  
• Biochemical progression after prostatectomy for pathologically advanced tumors depends on the definition applied. Five-year rates of biochemical recurrence have been as high as 65% to 72% when a PSA threshold of 0.2 ng/mL is used; less stringent thresholds such as 0.4 ng/mL may yield recurrence rates of 26% at 5 years and at least 50% at 10 years. Seminal vesicle involvement not only increases the risk of biochemical recurrence but also significantly increases the risk of local recurrence after radical prostatectomy.
• Patients with high-grade disease who fail early and display a short doubling time may have a survival as early as 7 years.  
• Further follow-up is necessary to truly define the true impact of clinical failure.
• Patients with higher biopsy Gleason score and more elevated serum PSA level are at increased risk of failure after surgery. 
• Overall, the actuarial PSA-free survival after surgery in high-risk men is approximately 50% at 5 to 7 years.
• Radical prostatectomy alone can result in cancer-free survival in at least half of men at 8 to 10 years despite clinically advanced disease.
• The risk of cancer recurrence after surgery can be quantitated on the basis of pathologic stage, cancer grade, and surgical margin status.
•  Neoadjuvant androgen deprivation therapy before radical prostatectomy does not appear to improve cancer-specific or overall survival.

Adjuvant Radiation Therapy

• Withholding regional or systemic therapy until after the prostate has been removed may (1) prevent delay in time to surgery, (2) reduce operative morbidity, and most importantly (3) identify those men with adverse pathologic features or evidence of residual disease who truly need additional therapy, thereby avoiding overtreatment in those found to have more favorable disease. 
• The selection of appropriate adjuvant therapy remains difficult because knowledge of the ultimate site of failure (discriminating local-regional from distant recurrence) determines the actual type, timing, and efficacy of such intervention.
• Recent data show improved biochemical control when using radiation therapy after radical prostatectomy. 
• The use of adjuvant RT is associated with a range of biochemical-free survival, from 50% to 88% at 5 years. 
• This appears to be an improvement (30% to 50%) compared with the results of surgery alone in high-risk patients.
• Early use of secondary therapy, be it RT or AD, may be beneficial in locally advanced tumors, as well as at the time of biochemical recurrence in select patients.
• Adjuvant radiation therapy improves local control and reduces biochemical relapse in selected patients after radical prostatectomy and likely improves metastasis-free and overall survival.
• The benefit of adjuvant radiation therapy may be greatest in cases of positive surgical margins.
• Improved outcomes of adjuvant radiation therapy are associated with dose escalation.

Adjuvant Androgen Deprivation

• There is some evidence supporting a benefit of early AD after radical prostatectomy in high-risk men with locoregional disease spread.
• In a study of retrospective reviewed data of men with stage pT3b cancer it was found that early, adjuvant AD positively affected time to progression and cancer-specific survival. 
• These findings were true not only with seminal vesicle invasion but also with limited lymph node disease, with a 10-year cause-specific survival of 94% after prostatectomy and adjuvant AD with a single positive lymph node. Similar findings arose from the Eastern Cooperative Oncology Group (ECOG 7887) study randomizing men with nodal metastases after radical prostatectomy (cT1-T2) to immediate (adjuvant) or delayed AD. 
• At a median follow-up of 11.9 years, men receiving adjuvant AD had improved overall (HR, 1.84), cancer-specific (HR, 4.09), and progression-free survival (HR, 3.42).

Radiation Therapy 

• The contemporary trend is to treat high-risk or locally advanced prostate tumors with methods other than surgery.
• The focus has shifted to improving outcomes by combining RT with AD, often in conjunction with whole-pelvis irradiation.
• Overall survival after RT alone for stage C cancer is approximately 60% to 70% at 5 years and below 50% at 10 years. 
• In high-risk patients, defined by individual parameters alone or in combination, the 5-year progression-free survival rates after RT are typically less than 50%.

Neoadjuvant Androgen Deprivation and Radiation Therapy

• Neoadjuvant and concurrent androgen deprivation appears to be appropriate in high-risk patients undergoing radiation therapy.
• Adjuvant androgen deprivation after radiation therapy may benefit those with very high-risk disease.

Androgen Deprivation

• Early androgen deprivation may improve survival.
• Alternative methods of androgen manipulation (antiandrogen, intermittent) remain investigational.

 Quality of Life

• The early institution of AD in men with prostate cancer, whether it is localized or locally advanced, must be balanced against the known side effects and long-term morbidity.
•  Only recently has the impact of AD been appreciated and reported on bone events, cognitive function, and quality of life. 
• The multimodal approach with AD and RT may increase the relative toxicity compared with each intervention alone.

References

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