External beam radiotherapy is an excellent option for some men who have a rising PSA after being treated for early stage (presumed to be localized) prostate cancer with techniques that may include:
- Radical prostatectomy
- Brachytherapy (depending upon the dose of radiation previously delivered and the type of brachytherapy)
- Cryotherapy and
- High-intensity focused ultrasound (HIFU)
As with salvage surgery, the critical question over the years has been exactly how good such so-called “salvage” radiation therapy is likely to be as a clinical option for any particular man.
Salvage brachytherapy has also been used to treat men who are in biochemical failure after primary external beam radiation therapy, but the data on the use of this technique are limited, and we will address this potential form of salvage therapy in a section on ”Investigational forms of salvage therapy.” The remainder of this page will be focused primarily on the use of external beam radiotherapy in the salvage setting.
Salvage EBRT for Men in Biochemical Relapse after First-Line Surgery
The overall data supporting the use of external beam radiation therapy alone as second-line treatment in men who have biochemical failure after radical prostatectomy have never been completely compelling. Here is a brief summary of some of the most important published data:
- Stephenson et al. reported that, in a cohort of 501 men treated with salvage EBRT at multiple institutions between 1987 and 2002, the overall probability of progression-free survival at 4 years was 45 percent. However, at 10 years, the projected probability of biochemical progression-free survival was only 30 percent.
- Pazona et al., reporting data from a single-surgeon series of radical prostatectomy patients after biochemical failure, showed that the overall probability of progression-free survival of these 307 patients at 5 years was only 40 percent. Again, however, the projected 10-year probability of biochemical progression-free survival was just 25 percent.
- Finally, Stephenson et al. published data from an expanded series of 1,540 patients in 2007. Among these patients, salvage EBRT was shown to offer overall probabilities of biochemical progression-free survival of 32 percent at 6 years and of 20 percent at 10 years.
However, we need to be very clear that the news isn’t all bad by any means. Patients in biochemical failure after first-line radical prostatectomy are known to do extremely well if they meet certain criteria prior to salvage EBRT, and it was for this reason that Stephenson et al. collected their data on a total of 1,540 men. These data were used to develop a nomogram that can project the likelihoods of certain types of outcome in exactly such men. Let’s look at three case examples:
- Patient A was initially diagnosed at 67 years of age with a PSA of 4.8 ng/ml, clinical T2a disease, and biopsy-based Gleason score of 3 + 4 = 7 and cancer in 3 of 8 biopsy cores. He was treated with radical robot-assisted laparoscopy (RALP). After the RALP, his PSA dropped quickly to <0.03 ng/ml; however, he was upstaged to T3a disease, and his Gleason score was upgraded to 4 + 4 = 8. Nine months later, his PSA had risen gradually up to 0.22 ng/ml. What is his probability of a good outcome if he now has radiotherapy?
- To calculate this patient’s potential outcome, we need to use the predictive nomogram for salvage radiotherapy outcomes on the Memorial-Sloan Kettering Cancer Center web site
- After opening the salvage radiotherapy nomogram, we entered the following data for this patient: 5 months disease free; a pathological (postoperative) Gleason score of 4 + 4 = 8; a pre-radiotherapy PSA of 0.22; an estimated PSA doubling time of 6 months; and a proposed radiotherapy dose of 7,500 Gy. We also know that this patient had negative surgical margins, a positive seminal vesicle, no lymph node involvement, and no extracapsular extension. He has received no hormone therapy and had an effectively zero PSA post- surgery. If you enter all of these data into the nomogram calculator and press CALCULATE, you get a projected 6-year biochemical progression-free survival for this patient of 15.87 percent.
- Patient B was also diagnosed at 67 years of age with a PSA of 4.8 ng/ml, but he had clinical stage T1c disease, the same Gleason score as Patient A, and he also had 3/8 biopsy cores positive. Like Patient A, he received a RALP, and after the RALP, his PSA also dropped quickly to <0.03 ng/ml; however, his pathological stage was pT2a, his Gleason score was upgraded — but only to 4 + 3 = 7, and he had a single positive margin. He was disease free for 23 months, at which time his PSA had was measured at 0.17 ng/ml. He and his doctor decided to wait 3 months before taking another PSA level, which came back as 0.4 ng/ml. What is Patient B’s probability of a good outcome if he now has radiotherapy?
- Using the same nomogram, and entering appropriate data (including an estimated PSA doubling time of 3 months), this man has an estimated 6-year probability of biochemical progression-free survival of 37.86 percent.
- Finally, let’s look at Patient C. He was diagnosed some years ago, at 53 years of age. His PSA was 3.4 ng/ml, his clinical stage was T1c disease, his biopsy-based Gleason score was 3 + 3 = 6, and he had cancer in 1 of 6 biopsy cores. After an open radical prostatectomy he had an apparently complete recovery of sexual function and continence. His post-surgical stage was pT2a, with no positive margins and no extracapsular extension. He was disease-free for 7 years before showing a small rise in his PSA to 0.05 ng/ml. Three months later the PSA had risen again to 0.06 ng/ml.
- Once again, using the same nomogram, we can predict a 6-year probability of biochemical progression free survival for this man (who is now 60 years of age) of 65.24 percent in response to radiotherapy. (We have estimated his PSA doubling time at 15 months and the calulator requires us to enter his pre-radiotherapy PSA value at the minimum value of 0.1 ng/ml.
We aren’t going to get into all of the details of whether a Gleason score of 3 + 4 = 7 is a better prognistic indicator than a Gleason score of 4 + 3 = 7 and other details. The critical issues for a patient with a rising PSA after surgery to understand are threefold:
- Your chances of doing well if you have external beam radiation therapy can be estimated using the nomogram referred to … but this nomogram is not perfect; some men may have results that fall outside the predicted estimates given by this nomogram because it is only a statistical model. It gives you some idea of what you can reasonably expect as a result, not an absolute prediction.
- You are likely to do better if you have radiation sooner rather than later. Indeed, one of the other results of the data collected by Stephenson et al. showed that men who have radiotherapy as second-line treatment after biochemical failure of radical surgery are likely to do better if treated while their PSA is < 0.5 ng/ml.
- You always have the option of adding hormone therapy to the radiation therapy (and we will discuss this issue under another heading). For men who are liable to respond poorly to salvage radiation alone (like Patient A above), this may be a wise choice and should certainly be discussed with your doctors.
Salvage EBRT for Men in Biochemical Relapse After Brachytherapy
The role of salvage EBRT when patients relapse after first-line brachytherapy is nothing like as well defined as the situation after surgery. And there are a numbers of issues to be considered:
- The first issue is whether additional radiotherapy of any type is acceptable. This will depend entirely on the radiation dose already delivered to the prostate itself and the surrounding tissues. What cannot reasonably be risked is excessive radiation to nearby tissues such as the bladder and the rectum that are fundamental to the patient’s overall quality of life.
- The second issue, given the above, is the appropriate dose of radiation that can be delivered to the patient patient in question.
- The third issue is whether, if the patients was treated with permanently implanted brachytherapy seeds, these seeds are likely to significantly impact the scattering of radiation within the prostate during the process of external beam radiation.
- The fourth is whether the external beam radiation should be combined with hormone therapy for maximal therapeutic impact.
Some physicians might argue that the use of salvage external beam radiation in patients who have failed brachytherapy is “investigational.” Others who have extensive experience of combination brachytherapy with external beam radiation as first-line treatment are more likely to believe that this is a perfectly reasonable clinical option. The one thing that is certain is that we do not, as yet, have extensive data that allow us to predict the effectiveness of this form of salvage therapy when first-line brachytherapy fails.
Salvage EBRT for Men in Biochemical Relapse After Cryotherapy
The most current data on the use of external beam radiation in treatment of first-line cryotherapy failure that we are aware of was published by Hepel et al. in July 2008. In their study, which included 13 patients who were actually treated for biochemical failure following cryotherapy, radiation was delivered using intensity modulated radiation therapy (IMRT) with daily image guidance, i.e. image-guided radiation therapy (IGRT). According to the authors, this made it possible to deliver the same high radiation doses used for the treatment of prostate cancer in the absence of prior cyrotherapy: a minimum target dose of 73 Gy, resulting in a mean target dose of > 75 Gy.
After a median follow up of almost 3 years, the rate of late toxicity observed in these 13 patients (treated between 1997 and 2007) was no higher than what would be expected for radiation treatment in the absence of prior cyrotherapy. There had been no late toxicities of grade 3 or grade 4; and only 2 patients developed late toxicities of grade 2, which were resolved with conservative interventions.
The authors note that PSA control in their study “is encouraging.” Their patients were all medium to high-risk, median follow-up at the time of publication was 33 months, and biochemical control had been achieved in most of the patients. However, the authors rightly observe that the small size of their series and the available length of follow-up makes it impossible to draw conclusions about the long-term value of this form of salvage therapy in first-line brachytherapy failure as yet.
Finally, external beam radiation is starting to be used as a form of salvage therapy for patients in biochemical relapse after treatment with high-intensity focused ultrasound (HIFU). And once again, the theory seems sound but the available data are very limited.
Pasticier et al. (a French group) have published data on the use of salvage EBRT in 45 men with a rising PSA after first-line HIFU. Of these 45 men, 32 were treated with salvage EBRT alone and the remaining 13 received a combination of EBRT + hormone therapy. We will focus on the results shown in the 32 men whom received salvage EBRT alone.
- The projected overall 5-year biochemical progression-free survival rate is 64 percent.
- For patients who had positive biopsy findings post-HIFU, the 5-year biochemical progression-free survival rate reached 80 percent
- For patients with post-HIFU biochemical failure but negative biopsy findings, the 5-year biochemical progression-free survival rate was 44 percent.
The authors conclude that salvage radiotherapy for local recurrence after HIFU is feasible, with no unexpected toxicities. They state that the early oncologic results are encouraging when isolated local recurrence is proven but longer follow-up is needed before any significant conclusions can be drawn about the value of this form of treatment.
This has been a long section. However, the potential role of radiation therapy as a second-line treatment for men who have biochemical failure for various forms of first-line therapy is a critical one. In the opinion of The “New” Prostate Cancer InfoLink, the two most fundamental issues for discussion between a patient and his doctor are:
- The potential of salvage radiotherapy to induce a clinically meaningful response in the individual patient, based on whatever prognistic indicators are available, and
- The risks posed by the side effects of radiotherapy given the treatment which the patient has already received.