Ask the Experts – Christopher L Amling

Question 1. When is it appropriate to use adjuvant radiation therapy (RT) for patients with high-risk pathology instead of waiting for PSA to rise?

Answer
The historical practice was to treat most with adjuvant radiation if they had adverse pathologic features, but that was before PSA could be detected at ultrasensitive levels. Like most urologists, my usual practice is early salvage radiation, initiating treatment when the PSA becomes detectable but it still very low. Some patients are at a very high risk for biochemical recurrence, such as those with significantly elevated preoperative PSA levels, widespread extracapsular extension, multifocal positive margins or seminal vesicle invasion. In these cases, adjuvant radiation is reasonable to consider since these men will very likely require it and there is good evidence that radiation is more effective when PSA is low. However, we don’t know if early salvage therapy might be equally efficacious in this setting. There are three ongoing clinical trials addressing this question. One of the problems with radiation too early after radical prostatectomy is that many patients are regaining their continence. It is thought that radiation before continence recovers might delay or halt this recovery. Depending on when continence is achieved, this might delay radiation therapy such that true adjuvant radiation is impossible.

Question 2.  Does the use of ultrasensitive PSA in patient with high-risk pathology following prostatectomy have a role?

Answer
Yes. Since we can detect PSA at ultrasensitive levels, we can initiate salvage radiation early to those who are definitely going to require postoperative radiation, avoiding overtreatment of some. One question is at what PSA threshold we should define PSA-failure to initiate salvage therapy. Most commonly, biochemical recurrence has been defined as a PSA greater than 0.2 ng/mL postoperatively. Since there is strong evidence that salvage radiotherapy is more effective when PSA is lowest, my practice is to initiate this therapy when PSA shows a progressive upward trend even at ultrasensitive levels, or certainly when it reaches a threshold of 0.1 ng/mL, especially in those men who have high risk pathologic features.

Question 3. In view of recently reported data from RTOG 9601 [N Engl J Med 2017;376:417-428], when is it appropriate to add ADT to consolidative radiation therapy following prostatectomy?

Answer
This was the first study to show that the addition of 24 months of antiandrogen therapy (bicalutamide) to salvage radiation results in better overall and prostate cancer-specific survival, and a lower incidence of metastatic progression compared to radiation alone. The question is whether these results can be extrapolated to support the use of more potent androgen deprivation therapy (ADT) in this setting, like LHRH-agonists or antagonists. I believe that it can. However, since androgen deprivation therapy, especially LHRH-agonists, can have significant adverse effects, the question is whether all men should receive this combination therapy (radiation plus ADT), especially since many will respond to radiation alone. Perhaps we should risk-stratify these patients to select for ADT only those who are likely to benefit from it. Another question is whether these results can be applied to adjuvant radiation as well. These decisions are generally made by radiation oncologists but it would seem to me that the addition of ADT to both adjuvant and salvage radiation should be considered, especially in those with high risk disease.

Question 4. What is the role of fiducial placement into the prostatectomy bed during consolidative radiation therapy?

Answer
To my knowledge, fiducial marker placement is reserved for those treated with external beam radiation as primary therapy, not after radical prostatectomy. I’m not aware of fiducial markers being used in the adjuvant or salvage radiation settings.

Question 5. Will novel imaging modalities (such as advances in PET techniques) that can more accurately pinpoint sites of recurrence guide the use of salvage radiation?

Answer
Yes, I believe that they eventually will. New advanced imaging modalities, including PET scans of various types, are showing improved sensitivity and specificity in detection of both bony and soft tissue metastases compared to standard imaging with bone scan and CT. In a salvage radiation clinical setting in which these studies suggest widespread distant disease, salvage radiation therapy may have a limited role. In contrast, if imaging suggests local recurrence in the absence of metastatic foci, salvage radiation is like to be most effective. The problem now is that PET scan imaging is not accurate enough at the very low PSA levels at which decisions about salvage radiotherapy are made. Until we have imaging studies which can accurately detect location of recurrence at very low PSA levels, they’re going to have a limited role in informing the salvage vs adjuvant radiation discussion.