Felix Feng: Thank you for the introduction and I’d like to thank Silke and Aurelius for inviting me to present.

So, here are my disclosures. None are directly relevant to today’s talk. I want to begin with a brief overview. Over 1.2 million patients are diagnosed with prostate cancer worldwide each year. This is something that this audience knows well. In the United States, where I’m from, over one third of patients with localized prostate cancer are treated with radiation therapy. Depending on the disease characteristics, about 15-70% of prostate cancer patients recur after definitive radiation. The reason I give you these statistics is to point out that these figures suggest that over 100,000 men may present with recurrent disease after upfront radiation every year. This is clearly a patient population that we need to address.

I think one of the first things to discuss is how we define a PSA recurrence after radiation. The Phoenix Consensus Definition put forth by the RTOG-ASTRO states that, “A PSA recurrence is a PSA increase by two nanograms per milliliter or more over the nadir PSA”, and this was published by Mack Roach and a committee of others many years ago.

However, the truth is that many clinicians do not wait for the Phoenix criteria to be achieved before evaluating for recurrence. In fact, the NCCN Guidelines states that, “A recurrence evaluation should be considered when PSA has been confirmed to be increasing after radiation even if the increase above nadir is not yet two nanograms per milliliter, especially in candidates for salvage local therapy who are young and healthy”.

Today, I’m going to discuss the management of a PSA recurrence after definitive radiation therapy. I’m going to first focus on the work up in the context of imaging and potential biopsy. Then I’m going to discuss local therapy for local recurrences. Now, other important aspects to discuss are local therapy for regional or distant recurrences, as well as systemic therapy. This will be the focus of subsequent talks that at this session… at this conference.

First, a question. What is the significance of a local recurrence after radiation therapy? This is data from Mike Zelefsky’s group and at Memorial Sloan Kettering. In this study, he analyzed 382 patients who underwent post-treatment biopsies after definitive radiation therapy for prostate cancer. 30% of the biopsies were positive and this is shown in the red line, 22% had significant treatment effect shown in the green line, and 48% were negative shown in the blue line.

As you can tell from these cumulative incidence plots, positive post-treatment biopsies are associated with increased incidence of distant metastases. This has been validated by multiple other groups including the RTOG and the RTOG 9408 trial.

If local recurrence is important, I think the first thing that we should think about in the context of PSA recurrence is: Is a patient a candidate for local therapy or not a candidate for local therapy? Who really are the best candidates for local therapy? Well, here are some of the guidelines I go by: Original clinical stage T1-T2 who are no negative, long life expectancy, PSA less than 10, long interval to recurrence, long PSA doubling time, and organ-confined at the time of recurrence. While these are criteria that suggest the best candidates, I will confess that I don’t always adhere to all these guidelines.

That being said, candidates for local therapy should undergo imaging for local recurrence with prostate MRI and trust plus-minus biopsy, but it should also undergo imaging for distant metastases with bone scan and PET CT or PET MR. In this case, the PET can be PSMA or fluciclovine or choline PET. We’ve heard a lot about this in previous talks at this meeting.

I want to begin just giving you a little bit of perspective on local imaging. So, this is data from Mark Emberton’s group about detection of a local recurrence using multi-parametric MRI. This is from 77 patients who underwent a transperineal prostate mapping with five millimeter sampling. So, a lot of biopsies of the prostate after radiation, as well as MRI targeted biopsy with multi-parametric MRI. On the left, you can see the cancer detection rates. What you can see is that there actually isn’t a major difference in the cancer detection rates between the transperineal prostate mapping and the MRI guided biopsies. There might be a slight increase in the TPM, but not by much. When you do a core-based comparison, which is shown on the right side, what you can see is that the MRI-based approach is much more efficient in detecting cancer. You end up getting a lot less number of cores, but a lot more positive findings on the per quarter basis. I believe that MRI-based imaging is warranted to look for a local recurrence.

At the same time, local imaging is just a component of the work up here. We also have to think about imaging for distant metastases. We’ve already heard this at this meeting, but advanced PET imaging has changed our ability to detect disease at low PSA levels. So, this is data from our team at UCSF with the UCLA team as well. This was a prospective PSMA PET study performed on 635 patients, including 169 treated with definitive radiation therapy. All the PET detected lesions were validated with a histopathologic assessment or a composite endpoint based on imaging and PSA follow up. The main point here is that even at PSAs of 0.5 or below, there’s close to a 40% rate of detecting disease. So, this is far below the nadir plus two definition that’s used by the Phoenix criteria. 

This data has also been shown by multiple other groups including the study from Australia and, again, detection rates in 276 patients treated with definitive radiation therapy. I think the main take-home is that 15-30% of patients have isolated local failures and the patterns of recurrence were demonstrated, although they weren’t biopsy-proven in the study.

That being said, these PSMA PET studies in the context of radiation failures allows to determine the patterns of disease recurrence following primary radiotherapy. We’ve heard a lot about lymph node therapy or lymph node approaches in the previous session. Here you can see the pattern of recurrence in the context of lymph nodes. There’s a lot of recurrences in the common iliac, external iliac, and the retroperitoneal regions with some involvement in the internal iliac and presacral as well. This helps us kind of design further therapies.

The other point to bring up is that when we talk about PET approaches, the truth of the matter is, I think we all use whatever PET agents we have access to. This is a study from the UCLA group showing that PSMA PET detects more legions than Axumin PET was just published on Lancet Oncology. These were patients who underwent both PSMA PET and Axumin imaging with the interpretations done by experts in these areas. You can see particularly in the lymph nodes and also in distance sites, PSMA outperforms Axumin PET.

Going back to our roadmap of managing a PSA recurrence after definitive radiation, again, I think the key point is: Is the patient a candidate for local therapy? Then that dictates what kind of imaging we do. If they are a candidate for local therapy, we can have multiple outcomes. The first outcome is that there is no evidence of distant metastases or region metastases, and the trust biopsy is positive for local recurrence. The second outcome, which I’m going to discuss first, is that there’s either metastasis present or the biopsy is negative for a local recurrence. In that context, we would recommend observation or androgen deprivation therapy plus-minus metastases directed therapy, which Dr. Piet Ost will be discussing later in the session.

For patients with an isolated local recurrence, there are many different options. I call this the Wild West of treatment, because there’s also relatively little evidence what is better than any other option. The options can include salvage brachytherapy, salvage radical prostatectomy plus-minus lymph node dissection, high-intensity focused ultrasound, cryotherapy, and now there’s starting to be phase one and two studies of SBRT as salvage following initial radiation failure.

How do we choose between these different salvage options for local recurrences? This is the European guidelines that was published a few years ago and these are guidelines for second-line therapy after treatment with curative intent. What you can see is that there is a level three recommendation, Grade B, to treat highly selected patients with localized prostate cancer and histologically proven local recurrence with salvage prostatectomy. That being said, the recommendation is due to the increased rates of side effects in the context of salvage prostatectomy. These should be performed only in experienced centers by experienced surgeons. Also, one should discuss or offer HiFu, cryo, or salvage brachytherapy in patients without mets as well. I think basically what this tells us is that there is no definitive consensus for which salvage approach we should use. 

Now, there was a nice review published by Paul Nguyen and his team a few years ago on detoxicity and efficacy of different salvage therapy types. What you can see here is that for brachytherapy, prostatectomy, cryotherapy, and HiFu, there are different rates of incontinence shown here, different rates of bladder neck strictures, and also different rates of fistula. However, what is impressive is that the five-year failure-free survival rates are approximately the same for all modalities, about 52-56%.

That being said, all these studies for salvage therapies are retrospective. You can look at the total number of patients and the majority of them are smaller. When you look, there’s actually not that many of these studies. I think the majority… The largest number of studies are done in the context of salvage prostatectomy, though I think that the salvage brachytherapy field is starting to catch up here.

So, I want to point to one of the very few prospective studies in this setting, it’s a prospective phase two trial of a basically salvage LDR brachytherapy for locally recurrent prostate cancer after external beam radiation therapy. 92 patients. This is large… a large study in this particular context. You can see the doses, but the primary endpoint was late GI/GU adverse events. About 14% of patients had these events and this actually was considered okay because anything above 20% was considered unacceptable. So, this was acceptable. There was no pre-treatment characteristics that predicted the occurrence of late treatment-related GI/GU adverse events.

In conclusion, there are a significant subset of prostate cancer patients with PSA recurrences after definitive radiation. Positive post-treatment biopsies are associated with metastatic progression. Advanced imaging approaches allowed detection of recurrences at PSA levels lower than the nadir plus two definition. I know if Howard Scher is in the audience, he’ll ask me about the clinical meaning of these recurrences, but I think that remains to be defined. Treatment approaches for biopsy-proven local recurrences, again, in the absence of metastatic disease, include salvage brachy, prostatectomy, HiFu, and cryotherapy. Ultimately, the decision for which salvage therapy should be made by the comfort level of the physician and the experience of the treating center.

Thank you for your time.