Controversies in Defining
Before any treatment is given for recurrence after radiation failure, it is important to document that the recurrence is only local and not a combination of local and systemic. While treatment of the primary prostate will have some benefits even in patients who have limited metastatic disease (1), we want to separate those patients from those who have only local disease.
There are new scans available that can detect systemic metastasis in patients. One of them is the "FCH-PET" scan. In a recent study, Hannequin et al. presented data on 89 patients who had recurrence based on PSA over 2.0 ng/ml after radiation treatment. 89 patients were evaluated for recurrence. Among these patients, local recurrence after radiation was found in 51%, lymph node recurrence in 32%, and distant metastasis in 17%.
Zumsteg et al. published a retrospective analysis of 2,694 patients who had an external beam radiation at Sloan-Keterring Cancer Center. Local recurrence was seen in 17.6% of patients. Two-thirds of these patients had low or intermediate risk cancer. In 87% of local recurrences, it was the only recurrence site. The authors state in their paper that the prostate is the most common initial site of patients in all risk groups with an increasing incidence that correlates with increasing NCCN risk group (2). Isolated lymph node relapse is rare in all patients, including those at high risk when CT is used for detection (3). Patients who have recurrence locally have a 4-8 times lower risk of prostate cancer-specific mortality compared to those patients who have lymph node or bone recurrence. Local failure was higher for external beam therapy than for brachytherapy and other types of radiation.
1. O'Shaughnessy, M.J. et al. Urology April 2017; 102; 164
2. Hannequin et al. J Clin Oncology 2016; 34; 23
3. Zumsteg, Z S et al. J Urol December 2015; 194; 6; 1624
Role of PSA and PSA NADIR after Radiation
In the past, recurrence after radiation for prostate cancer was defined as the mid point between nadir (the lowest level of PSA after radiation) and the first of 3 consecutive rises in PSA according to American Society for Radiation Oncology [ASTRO] (1).This definition requires some backdating of when Radiation Failure began. Men get PSA checks usually every 6 months after Radiation is completed unless they have high grade disease in which case they may get more frequent PSA tests. If men have high grade disease they may get androgen suppression for several months and their PSA check may also be delayed.
Therefore patients with local recurrence may get diagnosed several years after radiation has failed. This may lead to loss of opportunity for local salvage therapy. This has not been an issue of major concern in the past because treatment options such as savage surgery for local recurrence after radiation failure caused major complications.
Most men achieve a PSA nadir of 0.5 or less within 2 years after radiation but some may take longer. More recently the Phoenix definition uses 'nadir+2' which is defined as as rise in PSA of 2ng/ml above nadir (RTOG-ASTRO Phoenix Consensus Conference (2)).
The Phoenix definition provides substantially lower estimates of biochemical recurrence at five years and substantially higher estimates of biochemical recurrence at 10 years than the ASTRO definition.(3)
According to some data the ASTRO definition may be more reliable for men treated with radiation alone while the Phoenix definition may be more applicable to men who have had combination of radiation with hormonal therapy.(4)
Twenty five percent of all men after radiation also have fluctuating PSA that bounces between tests in the first two years after radiation. This is thought to be due to radiation induced inflammation, prostatitis or cell breakdown (5).
According to Zelefsky and associates from Sloan Kettering Cancer Center the ideal nadir of PSA after radiation should be <0.5ng/ml, as patients developing metastatic progression are found to have higher nadir PSA values (mean of 2.2). Patients with local recurrence have a PSA nadir mean of 1.1 (6).
Dr. Michael Zelefsky is Vice Chair, Department of Radiation Oncology at Memorial Sloan-Kettering Cancer Center, New York.
They studied 844 patients with localized prostate cancer who were treated with conformal radiation. The median duration of follow-up was 9.1 years. A fixed landmark time point at 2 years was used to assess the influence of nadir PSA value as a time-dependent variable on long-term outcomes.
Multivariate analysis demonstrated that nadir PSA ≤1.5 ng/mL at 2 years was an independent predictor of progression-free survival after adjusting for T stage, Gleason score, preradiation PSA value, and radiation dose. The 5- and 10-year cumulative incidences of distant metastases were 2.4% and 7.9%, respectively, in those with nadir PSA levels ≤1.5 ng/mL at 2 years, and were 10.3% and 17.5%, respectively, in patients with higher nadir values. Multivariate analysis showed that the higher nadir PSA value at 2 years (p = 0.002), higher Gleason scores (p < 0.001), and increasing T stage (p = 0.03) were predictors of distant metastases after adjusting for pre radiation PSA values and radiation dose. Multivariate analysis also showed that higher Gleason scores (p = 0.002), and higher nadir PSA values at 2 years (p = 0.03) were risk factors associated with cause specific mortality after adjusting for T stage and pre radiation PSA value.
They concluded that nadir PSA values equal to, or under 1.5 ng/mL at 2 years, is an independent predictor for progression free survival after radiation therapy of prostate cancer. Patients with higher absolute nadir levels at 2 years after treatment should be evaluated for the presence of nonresponding disease, and earlier salvage treatment should be considered.
In a recent study by Emberton, Ahmed and others, it was found that among patients with radiation failure treated with salvage HIFU, those with with a PSA nadir under 0.5ng/ml, had 57% disease-free survival at 3 years, as compared to 20% disease-free survival after salvage HIFU in men who had PSA nadir over 0.5ng/ml. Nadir PSA may be an important predictor to diagnose early local recurrence after radiation failure to institute salvage HIFU or similar therapy.(7)
In summary, men should be evaluated for recurrence if they have any rising PSA 2 years after radiation. Men with local recurrence have mean PSA of 1.1 ng/ml. Men with PSA over 1.5mg/ml at 2 years may develop metastatic disease even if they have not reached a nadir.Waiting for PSA to go higher results in higher number of men developing metastatic disease and dying of prostate cancer.
Stephenson et al reported that waiting till a PSA rise of +2 greater than the nadir PSA may delay the diagnosis and many patients who have local recurrence will not be treated. Such patients may develop metastatic disease and their chances of cure are reduced (8).
1)Int J Radiat Oncol Biol Phys. 1997 Mar 15;37(5):1035-41.
2) Roach M, et al, Int J Radiation Oncol Biol Phys 2006; 965
3) KUPELIAN PA et al Urology. 2006;68:593–598.
5)Sengoz M, et al, Eur Urol 2003; 473
6) Zelefsky MJ, et al, Int J Radiat Oncol Biol Phys; 1350
7) Prostate Cancer and Prostatic Disease (2016) 19, 311–316
8) Stephenson AJ, et al, J Urol 2004; 2239