The science experiment continues: Gallium-68, Decipher, SRT, and who knows?

Sometimes my head spins. My pre-RP PSA of 5.5 and 3+4 Gleason score augured well. My April 2015 RALP was performed by a top-tier surgeon. I was continent from day one and had my nerves spared on both sides. The post-op pathology report was encouraging: no extra-capsular extension; seminal vesicles, lymph nodes, surgical margins: all negative. Two-month, five-month, and eight-month post-op ultrasensitive PSAs all undetectable.

I began to think I had won the lottery and all I needed for complete recovery was to get those spared nerves working again.

But my journey was not going to be so easy. Eleven months after surgery, the PSA measured 0.031 ng/ml; three months later, 0.053; three months after that, 0.107; after another month later, 0.129. OK, it was a trend. I signed up preemptively for a Mindfulness-Based Stress Reduction class and got scheduled for the experimental but already well-validated Gallium 68 PET/MRI scan. This scan can spot metastases much smaller than those detectable with last year’s technology. The hope of the treatment team was that salvage therapy, if deemed advisable, could be particularly focused on the site of my recurrent cancer.

A week after the scan, I got the results: negative for any sign of metastases. The nurse practitioner cheerfully congratulated me on my clean scan, but, the way I understood it, this was not the result we were hoping for. If the renascent PSA is not coming from one or a few metastases detectable using the new Gallium 68 scan, there would be no way to target any particular site and really, no way to be confident that the PSA was coming from the area of the pelvis.

On Thursday, I will have my first visit with a radiation oncologist to discuss options. Extrapolating from the trendline of my rising PSA readings, I suspect I’m at 0.16 by now and will be close to .2 (the common measure of biochemical recurrence) by the end of the year. Of course, the numbers often don’t follow a steady path.

In getting prepared for my meeting with the RO, I’m trying to figure out what else there is for him or me to look at.

There are a couple of dings on my pathology report that may be relevant. The pathologist found extensive perineural invasion that had not been noticed in my pre-op biopsy. I believe current research suggests this may not be very significant as an independent risk factor. More ominous is the pathologist's finding of tertiary Gleason 5 which some research papers suggest may justify categorizing the cancer of a Gleason 7 patient as high- rather than intermediate-risk.

For what it's worth, I've also had a Decipher genomic test performed on the prostate tissue which reported my risk as “intermediate”: 6.6% for 5-year metastasis and 6.3% for 10-year prostate cancer specific mortality. Interestingly, the NP mentioned that the RO will have a much more detailed report that will cover many genes other than the 22 that are factored into the Decipher scores.

I have been trying to do some research on the timing of SRT (which is what I assume will be proposed on Thursday). Allen Edel’s article “Does early salvage radiation save lives?” (posted in January 2015 on The “New” Prostate Cancer Infolink) reports on research showing that “early” salvage radiation, defined as therapy administered while PSA is still below 1.0 ng/ml, has the same survival value as adjuvant radiation. If that’s the case, it doesn’t seem as if I’ve already missed the boat. However, an article published in the June 2016 Journal of Urology reported that ¾ of patients who reached 0.4 ng/ml PSA by the time of their SRT had detectable progressions within 5 years. Gee, I'd like to stay out of that crowd, if there's any hope.
The radiation oncologist I’ll be seeing on Thursday is reportedly up on all the cutting edge research, including studies of various agents that have been combined with SRT in experiments that are ongoing or already concluded.

Once I got my positive PSA result, I realized the rest of my life would be a science experiment, one way or another. Although I am trying to make choices that improve my own odds, I’m open to being a guinea pig for new treatments that offer some prospect of better results for those of us that RP does not “cure.” I really don’t like the sound of ADT although the NP was confident that would not be recommended at this time.

Time to take a deep breath and try to listen as carefully as I can to all that the RO has to say on Thursday. Hope I don't forget all my questions. The love of my life will be with me to keep me grounded and stop my head from spinning if it starts to take off.

P.S. I have been a lurker here up until this post but the caring community gathered around this forum has been a source of inspiration and support for which I have been extremely grateful over the past two years.

TA said...
That's where you went astray. It was not the purpose of the PET scan to find where, in the local area, the cancer is. The purpose was to rule out that it has already metastasized to distant locations. If it is known to be distant already, then local treatment would be futile.

You also misunderstand what a PET scan can and cannot detect. It can detect metastases that are about 4 mm in size, but if the mets are much smaller than that, it is unlikely that any PET scan can detect it. A clump of cancer cells is on the order of microns in size (about one-one thousandth the size that a PET scan can detect). These are called "micrometastases" and they can be anywhere - hopefully still confined to the local area.

Salvage radiation should never be used to treat a single locus of detectable cancer because we know there is likely to be more than that. You have to treat what you can't see as well as what you can see. Yes, it would be reassuring to have found a tumor in the local area. Then you would be more comfortable in attributing your rising PSA to local progression, rather than distant micrometastases.

TA, you are correct about the primary purpose of the 68 Ga PSMA PET to rule out it has already metastasized to distant locations, but knowing where it is has helped my RO with radiation planning.

Bobby Mac

Bobby Mac-

Boosting the dose to areas with detectable metastases (called a simultaneous integrated boost or dose painting) is controversial. Others make the argument that, if a higher dose is required to kill the cancer, then the entire area ought to be treated with a higher dose. Unfortunately, recurrence most often occurs at the site of the anastomosis, which is very sensitive to stenosis due to higher doses of radiation. The radiation dose with SRT has been kept lower (up to 70 Gy) than the dose given for primary treatment (up to 80 Gy) because of this. Some would like to see doses increased and argue that the precision of IGRT systems today can do it without excess toxicity. We'll have to see if that gets tried in the future.

To my knowledge, there have been no studies about its use in the salvage setting. There are several ongoing clinical trials in the primary RT setting. If you're interested, you can read about it here:

Dose Painting: simultaneous integrated boost (SIB) to the dominant intraprostatic lesion (DIL)

George_

You misunderstood Tomson's situation, and none of the references you cited are at all relevant to him. He is having a recurrence after prostatectomy, and is contemplating curative salvage RT.The references you cited have to do with the situation of a patient who is newly diagnosed with metastases but with an intact prostate. The hope is that prostate treatment (either RP or RT) in those men will slow down (but not cure) progression. I am hopeful that Tomson can still be cured.

Later analyses have shown that PSA from benign tissue vanishes quickly. Within a few months, that is totally gone.

/www.ncbi.nlm.nih.gov/pmc/articles/PMC3696410/

www.goldjournal.net/article/S0090-4295(08)01520-3/abstract

TA,

Thanks to you (and Bobby Mac and George and Gemlin) for your responses.

With respect to the goal of the PET, I do not think I misheard what the nurse practitioner at UCSF told me about the PET scan prior to its being scheduled when she mentioned that it could be used possibly for some targeted radiation or possibly even surgery. Perhaps she was speaking very hypothetically and did not mean to suggest that this is what the UCSF doctors now think (although that’s the opinion I asked for). I certainly prefer your view that my negative results from the 10/7/16 PET PSMA/MRI are simply good news. However, I believe that a German team might not agree with a categorical statement that the only value of a PET scan is to rule out distal metastases. See Bluemel et al. EJMMI Research (2016) 6:78.

Bluemel and her colleagues gave patients with negative Ga68-PSMA CT standard SRT up to a total dose of 66-70 Gy with a simultaneous integrated boost and sequential boost was administered to the prostate bed. Pathological tracer uptake in the prostate bed without any morphological correlate on CT resulted in an extension of the clinical target volume to this PET-positive area. If a morphological local recurrence was detected on CT, an additional dose escalation up to 76 Gy was administered to the malignant tissue. To be sure, the purpose of the German study was to determine whether the Ga68 results had any impact on salvage radiotherapy planning, and could not determine whether the changes led to long-term benefits. But this paper does suggest that the scan has other possible purposes besides ruling out distal metastases before proceeding with a one-size-fits-all SRT protocol. At least, the German interdisciplinary panel of radiation oncologists, urologists, radiologists, and nuclear medical nuclear medicine physicians thought so. This is all academic for me since my scan results were entirely negative, but it may affect others who chance upon this thread in the future.

In any case, I am quite aware of the limitations of PET/MRI scanning in detecting small metastases. As the same German paper mentions, a PSA level of 1.16 ng/ml was found to be an optimal cutoff for prediction of a positive choline PET/CT scan. Even though Ga68 promises to have a much lower cutoff, it has new limits which my negative results may help define. As much as I’d love to know where my PSA-generating cells are hiding out, I’m apparently not going to get an answer now. I don’t think Dr. Feng, whom I will see on Thursday, is likely to advise active surveillance until a subsequent PET/MRI can find some metastatic lesions. It’s clear that, for me at least, a 0.129 ng/ml PSA proved consistent with an absence of detectable lesions. In addition to the general limitation you mention, the PET/MRI has limited sensitivity for lung nodules smaller than 10 mm.

Dr. Feng may have my PORTOS score handy on Thursday. He is on the advisory board of GenomeDx and one of the authors of the Zhao study you cited. The Decipher analysis was performed in March on referral from UCSF. The NP at UCSF told me that Dr. Feng would have a lot of additional genetic information in hand beyond the genes used to calculate the Decipher score and would be able to look at other things besides the Decipher score to analyze my sitaution. It will be interesting to see what contribution, if any, PORTOS makes to his evaluation of my prospects with SRT. As you understand, I’m still hoping for curative SRT, so it’s a little disconcerting that ¾ of the men in the PORTOS study were categorized as “low PORTOS,” meaning no likely benefit from salvage radiotherapy, but perhaps there is a reason why this percentage was so high in that cohort.

I want to base my treatment decisions on the best biological predictors of tumor behavior and weigh the options in light of the best evidence of their prospective benefits and toxicities.

Here’s a statement by one doctor that summarizes what I think I am now facing even if I’m a “high PORTOS” guy with possibly better than average prospects that SRT will effect a cure:

“[T]he use of salvage radiation post prostatectomy is associated with significantly higher rates of both acute and long-term toxicity, including gastrointestinal and genitourinary complications. [Citation] In fact, impotence after salvage radiotherapy is almost universal. [Citation.] Given the aforementioned benefits and toxicities, the ultimate decision to proceed with salvage radiotherapy depends on the clinician’s judgment that the recurrence is localized to the prostatic fossa.” M Kolodziej, Am J Manag Care 2014;20-S275.

Now I’m trying to think of what questions to ask my new doctor on Thursday. Certainly, I will follow up on the issue of ADT. As much as the side effects are very discouraging, I have not rejected it. The UCSF team has yet to suggest it. While watching my PSA rise from undetectable to 0.129 with a doubling time of less than 4 months, they have not shown urgency about getting me started on any new therapy. As you probably know, UCSF did a study that found rapid doubling often cools off by the time the PSA climbs out of the range detectable only on ultrasensitive tests.

ADT will certainly be on my agenda Thursday, but, as I mentioned in my original post, the NP didn’t think there was any likelihood that ADT would be recommended at this time. Not sure why UCSF leans towards SRT without ADT but I suppose it is based on something. I’ll find out Thursday whether Dr. Feng agrees with this.
Thanks for the encouraging words about mindfulness. I spent all-day Saturday in a silent retreat, but it’ll take a lot more practice before it becomes any kind of second nature. Thankfully, I appear to have plenty of time.

Finally, in answer to the specific question -- what am I waiting for? (asked by you and Gemlin), I have been waiting for appointments. Dr. Carroll's NP saw me on September 2 when my PSA had reached .107 and said she would check with Dr. Carroll on timing for a PSMA PET MRI as the next step before deciding on any further treatment. Radiology could not fit me in before October 7. I was unable to get another appointment to see the NP until October 21 at which point she said that Dr. Carroll wanted me to see Dr. Feng. Dr. Feng's people called to tell me that the soonest he could see me was December 8 at which point I blew up. At this point, I have not been offered any followup therapy by UCSF. Frustrating to read about superior results from "very early" SRT and be told that the norm at UCSF is to wait until I graduate to the "early" category (i.e., >0.2) before SRT would be called for. But this will all be addressed more definitively on Thursday and, by my back of the envelope (er, Excel) extrapolations, I will likely remain in the "very early" cohort for a couple more months. Maybe Dr. Feng will bring a new urgency to what I refer to as my "science experiment."

Tomson

P.S. George asked where I got my PSMA PET/MRI. It was at UCSF where they have done over 200 of them in the last year. They are apparently one of two sites in the U.S. that are compiling data so that the Gallium-68 test can be approved by the FDA and get covered by Medicare. UCSF told me that the resolution was better than the 4 mm which Allen mentioned but I'm sure there are different ways to measure that. I remember hearing 1 mm as well, but I couldn't quickly locate any support for that. Also, waiting for PSA to reach .5 ng/ml before doing the Gallium-68 scan would rule out its use in most (?) cases for which SRT would likely be curative. Isn't .5 a point above which SRT is much more likely to fail? I haven't looked into this, but I imagine Dr. Carroll thought it was of some clinical value to send me to radiology at 0.107 (up to 0.129 by the time I actually got the scan) although, of course, it is of some interest to find out how low you can go and get useful results. I checked George's post in other thread and, if I read it correctly, 50% of Ga68 scans where PSA <.5 turned up evidence of metastasis.

UCSF told me that Medicare will cover the MRI and I will be billed $1,600 to cover the cost of manufacturing the Ga-68 PSMA radiotracer which gets whipped up fresh for each patient. I heard another patient grousing that an experimental protocol like this should not be billed to the patient, but I'm able to pay so, if it helps guide my treatment in the optimal direction, I'm on board. Australians are paying a much smaller premium, I think, about $450US ($600AU), despite a similar issue with their Medicare. But UCSF does have a pretty new building--actually a pretty new campus--to amortize.

It's kind of you to say you read the paper "differently" rather than "more carefully" but my hunch is "more carefully" is closer to the truth. I zeroed in on the language on page 3 of the paper describing the protocols in general terms (page 3), and you plumbed the details of the treatments that were actually recommended (pages 3 and 4).

I'm not sure I understand all of the terms, but it appears I missed the point that most of the change in treatment recommendations due to finding on Ga-68-PSMA PET were associated with lymph node metastases outside the pelvic region ... or am I still missing the point? If the change in treatment recommendations was based on the opportunity to zap distant mets discovered by the PET-CT, I understand these would not have been treated as U.S. standard of care unless weight-bearing bones were involved. Still, for what it's worth, when I gave my informed consent to be part of the Ga-68 investigation, I was told that one of the benefits of the test was that they might find small mets that could be subjected to some kind of focused treatment (in addition to standard SRT). I didn't make this up, and I'm curious about whether this was a misunderstanding, but I will probably not pursue this with Dr. Feng on Thursday as my test turned up nothing.

I understand your comments on dose painting, limitations of the PORTUS study, and the need to be careful about information from PAs and NPs. Fortunately, I will have an opportunity in three days to talk all this through with a highly credentialed radiation oncologist/researcher.

The tendency of rapid doubling times to cool off is described in the 2011 paper Poor agreement of prostate specific antigen doubling times calculated using ultrasensitive versus standard prostate specific antigen values: important impact on risk assessment.: "Agreement between prostate specific antigen doubling time calculated using ultrasensitive vs traditional prostate specific antigen values is poor. Ultrasensitive prostate specific antigen doubling time is often significantly more rapid than traditional prostate specific antigen doubling time, potentially overestimating the risk of clinical recurrence."

More recently, a 2005 review Ultrasensitive prostate specific antigen and its role after radical prostatectomy: a systematic review.states: "Ultrasensitive prostate specific antigen kinetics may improve the positive predictive value for detecting cancer recurrence. However, the usefulness of prostate specific antigen doubling time at the ultrasensitive level remains controversial." I don't have access to the full text of either of these publications so I am only excerpting conclusions from their abstracts.

<<I was told that there are no studies that show adding ADT to SRT is beneficial.>> I'm surprised you were told this. I think a number of retrospective analyses have supported benefits. The GETUG-AFU 16 study is the first randomized trial comparing SRT versus SRT and short-course ADT as salvage treatment for biochemical recurrent prostate cancer after radical prostatectomy. The results are fairly encouraging: Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin aka Zoladex. Patients assigned to radiotherapy plus goserelin were significantly more likely than patients in the radiotherapy alone group to be free of biochemical progression or clinical progression at 5 years (80% vs 62%). Again, the article is behind a paywall so I can only repeat what what appears in the abstract. See Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. There is also a comment and reply on this paper here. From what I've gleaned so far, the RO will likely recommend SRT or SRT plus ADT on Thursday so I will be looking more closely at this in the next few days.

<<If you have 10 mets and a PSA value of 0.5 ng/ml doctors expect the PSMA PET/CT to show only 5 of these mets....>> I don't understand how this can be right. Aren't metastases that are too small to be detected also too small to be counted? How do they figure out how many are too small to be counted so that they can make a meaningful statement about what percentage are detected?

Re oligometastases, thanks for the link to that lively thread. On balance I'm glad that my PSMA PET/MRI turned up no mets so I don't have to wrestle with those issues ... at least yet.



Tomson

Waiting until your PSA > 0.02 could be "playing with the fire". Have you read this study?
"This study provides clinicians and patients with a clinically meaningful predictive tool that can aid with joint decision making. Early intervention with SRT (with or without ADT) at detectable PSA levels before exceeding a commonly used threshold dose of 0.2 ng/mL is associated with improved outcomes of FFBF and DM compared with delayed intervention at higher PSA levels."
Contemporary Update of a Multi-Institutional Predictive Nomogram for Salvage Radiotherapy After Radical Prostatectomy

Gemlin,

Thanks for the link (I'll have to read the report later as I'm off to Mindfulness-Based Stress Reduction class in a few minutes). I'm aware of evidence that very early salvage treatment (i.e., before PSA reaches the traditional 0.2 cutoff) confers substantial advantages over early salvage treatment (PSA between 0.2 and 0.5). I have certainly been concerned watching my PSA double approximately every 3 months since February.

I will see an RO tomorrow morning for the first time since before my decision about primary treatment. As my RO is listed as one of the authors of the report to which you link, he will presumably apply the updated nomogram to my case and justify any way in which his recommendations diverge from what that nomogram would suggest. So far, the "waiting" in my case has all been a function of UCSF's recommendations and their scheduling constraints. Most recently I have waited five weeks since the negative Ga-68 PET/MRI scan to get to see the the RO. Perhaps the next wait will be to see how long it will take to get a berth in the radiation bay!

T

Tomson,

may I ask what Dr. Feng's views were? After the discussion in this thread I wonder what Dr. Feng did recommend regarding the start of salvage radiation.

George