Prostate Cancer

Detection and Treatment of Recurrence

Significance and definition of a rising PSA level post irradiation

The use of PSA levels following definitive therapy (either radiotherapy or radical prostatectomy) can detect early recurrences that may be amenable to salvage treatment. A rising PSA profile following radiotherapy is unequivocal evidence of the presence of a residual prostatic neoplasm. However, the definition of a rising PSA level after radiation therapy varies in the literature. A 1996 consensus conference recommended that PSA failure be considered to have occurred after three consecutive PSA level rises, with the rate of failure defined as halfway between the first rise and the previous PSA level. More recently, this definition has been replaced by an absolute PSA rise of 2 ng/mL above the posttreatment nadir PSA level.

Moreover, patients with a rising PSA level after irradiation may be a heterogeneous group, including patients with truly localized failure as well as those with metastatic disease. Also, certain patients will have a slowly rising PSA level after irradiation and may not require additional treatment. In patients who are not treated with androgen ablation, the 5-year actuarial risk of distant metastasis from the time that the PSA level begins to rise is about 50%. A key concept in rising PSA levels is PSA velocity, or more specifically PSA doubling time. Multiple studies have found that a PSA doubling time < 10 to 12 months predicts early clinical relapse if biochemical recurrence is untreated. In addition, studies have documented the real phenomenon of postradiotherapy PSA bounce, which is defined as a rise above the baseline PSA following the initiation of radiotherapy. This may occur in 20% to 40% of men depending on the threshold of PSA rise and is not known to have prognostic significance. Thus, PSA rises should be confirmed over time to ensure that they are durable rather than transient prior to initiating salvage systemic therapy.

Treatment recommendations for recurrence post irradiation

In general, men who have clear evidence of a rising PSA level 2 years after definitive radiotherapy for localized prostate cancer should be advised about the options of hormonal therapy (see next section on "Treatment of locally advanced disease [T3, T4]"), salvage surgery, salvage cryotherapy, observation, or experimental therapy.

If patients have minimal comorbidity, good life expectancy, and only local evidence of disease recurrence, salvage surgery is an option but should be preceded by a bone scan, CT scan, cystoscopy, and extensive counseling, because urinary difficulties after salvage prostatectomy are substantial and highly prevalent. Factors that determine success of salvage surgery after radiation therapy include low (< 4 to 10 ng/mL) preoperative PSA level, low pathologic stage (T3a or less), and prior type of radiation therapy (with brachytherapy and IMRT being favorable). However, no randomized trials have been conducted in this setting to provide level I evidence favoring surgery over other modes of treatment.

Locally Advanced Disease: T3, T4

The treatment of patients with locally advanced prostate cancer is centered on a multimodality and multidisciplinary approach, including radiation therapy (EBRT with or without HDR interstitial therapy), androgen ablation plus EBRT, or radical prostatectomy with or without androgen deprivation.

EBRT with and without HDR interstitial therapy

For patients with locally extensive prostate cancer, local failure remains a potential problem after EBRT. This problem has prompted investigations into alternative means to intensify therapy.

One strategy has been to deliver large fractions of radiotherapy using HDR interstitial techniques in combination with EBRT. The large interstitial fractions, which may be on the order of 5 Gy, deliver a high dose to the prostate but spare normal tissues, due to the rapid dose falloff outside the implanted volume. Early experience with this strategy is encouraging, but long-term data on outcome, particularly in patients with locally extensive disease, and on morbidity are awaited.

Patients with locally advanced prostate cancer probably are not good candidates for permanent prostate implants. Patients with stage T3/T4 tumors are at high risk for gross extraprostatic involvement, and this localized therapy may not offer adequate dosimetric coverage of extraprostatic disease.

As mentioned in the previous section, there may be a synergistic effect between hormonal therapy given in conjunction with radiation therapy. In addition to enhancing apoptosis and producing local cytoreduction, the use of early androgen deprivation may possibly delay or even prevent the development of metastatic disease.

The current body of evidence from three large randomized trials (RTOG 92-02, RTOG 85-10, and European Organisation for Research and Treatment of Cancer [EORTC] 22863) suggests that immediate long-term androgen deprivation in conjunction with EBRT improves outcomes among men with locally advanced or high-risk (Gleason score ≥ 8) prostate cancer compared with radiation therapy alone. An analysis of RTOG 85-31 by Horwitz et al (Int J Radiat Oncol Biol Phys, 2001), which employed early indefinite androgen deprivation, demonstrated that patients with locally advanced disease (T3N0) had improved cause-specific failure and distant metastatic failure compared with those treated using EBRT alone. Furthermore, a comparison to RTOG 86-10, which studied similar patients treated with only 4 months of hormonal therapy, favored the long-term approach. The EORTC trial randomized 415 patients and demonstrated a 15% overall survival benefit to 3 years of combined therapy vs radiation therapy alone. This result was confirmed by Warde et al in a large randomized trial of 1,205 locally advanced patients reported in 2011. The addition of radiation therapy to lifelong hormonal deprivation improved overall survival by 7% at 7 years with minimal additional toxicity. These studies have confirmed that EBRT with long-term hormonal therapy is necessary for management of locally advanced or high-risk prostate cancer as compared to hormonal therapy alone, due to improvements in local control as well as systemic control, and this combination should be considered a standard initial therapy for high-risk men.

Radical prostatectomy with or without adjuvant therapy

Surgical monotherapy can be considered a reasonable option for patients with locally advanced prostate cancer. Stage T3 disease can be successfully treated with low morbidity and significant reductions in risk of local recurrence, with clinical overstaging, up to 26% (Yamada et al, J Clin Oncol 1994). Well-differentiated and moderately differentiated cancers have cancer-specific survival rates of 76% at 10 years, comparable to those of other treatment modalities.

The Mayo Clinic has one of the largest radical prostatectomy series for T3 disease, comprising more than 1,000 patients. In this population, 34% of whom received adjuvant therapy, 15-year cancer-specific survival and local recurrence rates were 77% and 21%, respectively. In an Eastern Cooperative Oncology Group (ECOG) clinical trial, 98 men who were found to have nodal metastases following radical prostatectomy and pelvic lymphadenectomy were randomized to receive immediate androgen deprivation or be followed until clinical disease progression. At a median follow-up of 7 years, 18 of 51 men in the observation group had died, compared with 4 of 47 in the treatment group (P = .02). In one interesting series, Briganti et al found that adjuvant radiation therapy with androgen deprivation therapy was associated with a survival benefit (biochemical and prostate cancer–specific) in node-positive men treated with radical prostatectomy initially, even after adjustment for known confounders. This finding suggests that local tumor control may prevent distant failure in this disease.

Treatment of node-positive disease

Whether any local treatment adds to the overall survival duration in patients with known nodal involvement is debatable. Until recently, the standard of care had been to perform frozen-section pathologic analysis on pelvic lymph nodes at the time of radical prostatectomy, prior to removal of the prostate. If this analysis revealed micrometastases, radical prostatectomy was thought to be contraindicated. Although retrospective in nature, recent data from several American centers, including one large study from the Mayo Clinic, have shown a survival benefit in men who undergo radical prostatectomy despite the presence of micrometastases to regional pelvic lymph nodes. These men tend to do better and survive longer when started on early hormonal therapy, either with orchiectomy or an LHRH analog.

Radiation therapy. There are also compelling data that long-term survival is achievable in these patients with combination radiation and hormonal therapy. Data from the MD Anderson Cancer Center indicate a benefit to pelvic/prostate radiation therapy plus immediate hormonal manipulation compared with hormones alone. A subset analysis of patients with node-positive disease from RTOG 85-31 revealed immediate hormonal therapy plus radiation therapy resulted in 5- and 9-year cause-specific survival rates of 84% and 76%, respectively. Therefore, aggressive locoregional therapy appears to be effective in this cohort of patients with nodal involvement.