Biochemically Recurrent Prostate Cancer

About one third of men develop biochemically recurrent disease based only on rising prostate-specific antigen (PSA) in the absence of visible disease on conventional imaging.

For patients with biochemical recurrent prostate cancer, there is no uniform guideline for subsequent management. 

Prudent that biochemical recurrent prostate cancer should initially be evaluated for salvage radiation or prostatectomy, with curative intent. 

In selected cases, high-intensity focused ultrasound and cryotherapy may be considered in patients that meet very narrow criteria as defined by non-randomized trials. 

If salvage options are not practical or unsuccessful, androgen deprivation therapy (ADT) is a standard option for disease control. 

Patients may be followed using PSA doubling time as a trigger to initiate ADT. 

Based on retrospective data, a PSA doubling time of less than 3–6 months has been associated with near-term development of metastasis and thus could be used signal to initiate ADT. 

Once treatment is begun, patients and their providers can choose between an intermittent and continuous ADT strategy. 

The intermittent approach may limit side effects but in patients with metastatic disease studies could not exclude a 20% greater risk of death. 

In men with biochemical recurrence, large studies have shown that intermittent therapy is non-inferior to continuous therapy, thus making this a reasonable option. 

As new imaging (PSMA) strategies are developed, it may alter how the disease is monitored and perhaps managed. 

Patients have no symptoms related to their disease and thus many prefer options that minimize toxicity. 

In the EMBARK trial 60% of subsequent deaths of patients were not attributable to prostate cancer.

In patients with PC with high risk biochemical recurrence (doubling time PDA of less than nine months) enzalutamide plus leuprolide was superior to leuprolide alone with respect to metastasis free survival, and enzalutamide monotherapy was superior to leuprolide alone(Freeland SJ): the combination of enzalutamide plus leuprolide were superior to leuprolide alone, as was enzalutamide for metastasis or death..

Despite undergoing definitive local therapy with radical prostatectomy (RP) or radiation for prostate cancer, many men will go on to develop prostate-specific antigen (PSA) recurrence with no evidence of disease on conventional imaging. 

This disease state is called biochemical recurrence (BCR). 

The Phoenix criteria are used to define BCR postradiation therapy, which requires an increase in PSA of at least 2 ng/mL above the postradiation PSA nadir, whereas BCR post-RP is defined as at least two PSA values that are 0.2 ng/mL or higher.

Estimates for the risk of developing BCR range from 20% to 40%.

There are numerous options for management, including surveillance, salvage radiation, and androgen deprivation therapy (ADT).

Salvage radiation to the prostate bed and pelvic lymph nodes is the standard approach to treating biochemical recurrence.

The concurrent use of antiandrogen therapy with radiation therapy has also demonstrated improved overall survival.

Prostate-specific membrane antigen PET scans can detect recurrent disease at lower prostate-specific antigen levels and improve progression-free survival when these lesions are added to the the radiation treatment plan.

The use of androgen deprivation factors depends on: Gleason score, initial prostate-specific antigen, prostate-specific antigen doubling time, and patient preference.

If androgen deprivation therapy is initiated, intermittent therapy is preferable to continuous therapy.

Postoperative salvage radiation use is not supported by randomized trials, but retrospective comparisons have found an association between the use of SRT and improved long-term outcomes. 

Trock reported the long-term outcomes of 635 men with BCR following RP: classified according to the choice of treatment: Salvage RT (SRT) with or without ADT or observation.

Treatment with SRT was associated with a threefold reduction in prostate cancer–specific mortality compared with observation.

In a pooled analysis of 2,460 patients: The median pre-SRT PSA was 0.5 ng/mL, the 5-year biochemical control rate was 56%, and an association was observed between lower pre-SRT PSA values and improved biochemical control. 

Retrospective studies have also found an association between dose to the prostate bed and biochemical control after SRT.

In a randomized trial of 350 men with BCR after RP comparing 64 Gy in 32 fractions versus 70 Gy in 35 fractions.

Median PSA at randomization was 0.3 ng/mL. 

Dose escalation to 70 Gy increased late gastrointestinal toxicity, but no benefit was seen with regard to efficacy. 

The 6-year freedom from biochemical progression rates were 62% and 61% for 64 Gy versus 70 Gy, respectively. 

These data support the use of 64 Gy in 32 fractions, or equivalent shorter fractionation schedules, as standard. 

Even this dose may be more than necessary s EORTC 22911 used 60 Gy in 30 fractions in the adjuvant setting and showed a substantial improvement in biochemical control after RP.

The pelvic lymph nodes are a common site of recurrence after SRT to the prostate bed.

In three-arm randomized trial of 1,792 patients undergoing SRT after RP, including a comparison between radiation therapy to the prostate bed alone versus treatment to the prostate bed plus pelvic nodes. 

All patients in this comparison received short-term ADT, and the five-year freedom from progression was improved by the addition of pelvic nodal radiation therapy: 89.1% versus 82.7%.

There was also a trend in favor of pelvic nodal radiation therapy with respect to the development of metastatic disease.

Pelvic nodal radiation therapy has a modest increase in late-grade 3+ toxicity of 6% versus 4.9% for genitourinary events and 1.1% versus 0.4% for gastrointestinal events. 

The benefit from nodal radiation therapy might be greater in those patients with a higher PSA level before radiation therapy. 

There is good evidence to support the use of radiation therapy to the pelvic nodes and the prostate bed.

The outcome of prostate bed radiation therapy might also be improved by the addition of ADT: RTOG 9601 trial, 760 men with PSA recurrence after RP were randomly assigned to receive 2 years of bicalutamide or placebo in addition to SRT to the prostate bed. 

The Overall survival at 12 years was 76.3% for bicalutamide versus 71.3% for placebo.

The benefit of bicalutamide may be greater in men with a higher PSA level before radiation therapy, as well as in those with a higher Decipher score.

GETUG-16 tested 6 months of luteinizing hormone-releasing hormone analog treatment of 743 patients who were randomly selected to receive prostate bed radiation therapy alone or radiation therapy plus 6 months of goserelin: 6 months of ADT led to an improvement in PSA control, and a significant improvement in metastasis-free survival,but no difference was seen in overall survival at 12 years (86% for radiation therapy plus goserelin and 85% for radiation therapy alone.

In summary, there is good evidence that 2 years of bicalutamide improves overall survival in men having SRT to the prostate bed, but there is no proven advantage for 6 months of ADT.

Molecular imaging has been used to stage patients with prostate cancer, starting with bone scans, 18F-NaF PET, 18F-fluorodeoxyglucose PET, and, more recently, 18F-flucicovine PET. 

These imaging studies are used to determine the presence of local recurrence, regional nodal involvement, and distant metastases. 

The vast majority of patients being considered for SRT have no evidence of disease on these imaging modalities, and radiation therapy planning depends on previously defined consensus tumor volumes. 

This has changed with the introduction of radiopharmaceuticals that target PSMA, a transmembrane protein that is overexpressed on prostate cancer cells.

Two PSMA PET radiopharmaceuticals are currently approved by the U.S. Food and Drug Administration: DCFPyL (18F-piflufolostat) and 68Ga-PSMA-11 (68Ga-gozetotide): in the BCR setting there is a positive predictive values ranging between 84% and 92%.

Presacral and para-aortic ganglia can mimic nodal disease, and knowledge of normal anatomy is important so as to not irradiate normal ganglia. 

In a cohort of patients with a PSA less than 2.0 ng/dL, PSMA PET detected recurrence in 50% of patients, with 30% of patients having disease outside of the consensus tumor volumes.

In a separate cohort with a PSA less than 1.0 ng/dL, PSMA PET detected disease outside of the consensus tumor volume in 19% of patients.

The most common locations of recurrence outside of the consensus tumor volumes are the bones and perirectal lymph nodes. 

 A trial demonstrated that patients who had PSMA-positive disease that was not included in the treatment plan experienced disease recurrence faster than did those whose disease was covered.

For men with BCR who have received postoperative SRT or who are not candidates for SRT, ADT is an option. 

BCR is generally an asymptomatic state, and the initiation of ADT has important effects upon quality of life and long-term health consequences.

Analysis demonstrates no difference in overall survival or prostate cancer–specific mortality between patients with BCR undergoing immediate versus delayed ADT.

There was also no difference for prostate cancer–specific mortality when comparing immediate with delayed ADT. 

However, there was a longer time to local and distant progression for men receiving immediate ADT, however there  is no clear benefit for overall survival or prostate cancer–specific mortality in the PSA recurrent population.

Given the lack of a clear overall survival benefit in the general BCR population, multiple studies have tried to determine which patients with BCR are at highest risk for progression and death and, therefore, may benefit from ADT therapy. 

Antonarakis et al reported on the natural history of 450 men with BCR, and found the median time from surgery to BCR was 3 years and the median metastasis-free survival after PSA recurrence was 10 years.

 They reported that PSA doubling time was the strongest predictor of metastasis, finding that men with short PSA doubling times were more likely to develop metastases compared with men with a PSA doubling time greater than 15 months.

In addition to PSA doubling time, other factors that have been identified for risk of disease progression and prostate cancer–specific mortality are initial PSA, Gleason score, pathologic findings at RP-seminal vesicle involvement, extraprostatic extension, and intraductal carcinoma, time to BCR, and PSA level at BCR.

Current guidelines suggest that intermittent ADT therapy can be offered to patients with higher-risk BCR, with most definitions of high risk including PSA doubling time less than 10 to 12 months, Gleason score 8 or greater, or biochemical relapse interval of up to 18 months.

Crook et al, compared intermittent ADT with continuous ADT in men with BCR after radiation therapy. 

Intermittent ADT consisted of ADT therapy for 8-month cycles, followed by observation, with ADT reinitiated when PSA reached more than 10 ng/mL. 

There was no difference in the primary endpoint of overall survival when comparing intermittent ADT versus continuous ADT no differences remained after stratifying based on Gleason score, PSA level, or time since completion of radiation therapy. 

Notably, those treated with intermittent ADT reported better quality-of-life scores. 

Based upon these findings and other data,44 intermittent dosing is the preferred strategy when initiating ADT for BCR.

The side effects and long-term health consequences of ADT must be weighed against the potential for disease progression and patient preferences. 

Using PSMA PET scan allows for earlier detection of disease on imaging, leading to stage migration: Patients who historically would be considered N0 and M0 are being recharacterized as N1- and M1-positive patients. 

In the CONDOR trial changes in the treatment plan based upon PSMA PET found that 64% of patients had a change in their care plan based upon the results of the PSMA scan. 

Notably, not all of the changes in care included escalation to systemic therapy, with 28% adding systemic therapy to previously planned local salvage therapy, 21% transitioning from systemic therapy to local salvage therapy, 24% initiating therapy when observation had been planned, and 4% transitioning to observation from planned treatment. 

Prior to the use of PSMA PET, salvage radiation therapy was normally given at the time of PSA recurrence, and it was believed that earlier treatment is better than later treatment. 

That  practice has been questioned in light of using PSMA PET to detect the site of recurrence in men with BCR. 

Recurrence can often be detected at relatively low PSA levels, and it is striking that the site of recurrence is often outside the prostate bed 

This has led to the possibility of later image-directed SRT as an alternative to earlier prostate bed radiation therapy for PSA recurrence alone. 

Advantages of this delay include targeting of radiation therapy to the site of recurrence and omission of radiation therapy in patients with recurrent polymetastatic disease.

Evidence for PET imaging–directed therapy comes from the STOMP trial, which randomly assigned patients with BCR to observation or metastasis-directed therapy based upon PET imaging.

Using ADT-free survival as a primary endpoint, they reported a median ADT-free survival of 21 months for the metastasis-directed therapy group and 13 months for the surveillance group.

This led to the practice of including PSMA PET–positive disease in radiation plans. 

Emmett et al provide evidence supporting the use of radiation therapy with a negative PSMA PET.

They reported 3-year freedom from progression in a prospective nonrandomized study of men with BCR post-RP who underwent PSMA PET scans. 

In men with negative PSMA PET scans, the 3-year freedom from progression was higher if they received radiation therapy (82.5%) than if they were observed without treatment (66%), indicating that there may be a freedom from progression benefit in treating PSMA PET–negative patients with BCR.

PSMA PET imaging has clearly demonstrated an increased sensitivity for detecting disease earlier and at lower PSAs. 

It remains to be seen whether survival is improved when treatment plans are changed based upon PSMA PET findings when conventional imaging is negative. 


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