Unwarranted conclusions about oligometastatic treatment

Tall Allen-
What is the latest about radionuclide therapy? Will targeted radionuclide therapies such as 177 Lutetium‐PSMA have a future role in treatment of (oligo)metastatic prostate cancer as an alternative to life long ADT? Could it even be curative? Haven't we seen promising treatment responses in men with castration-resistant PC with this therapy from Germany and Australia? Maybe at some day Lu PSMA, or similar, can be used at first sign of metastatic spread?

Allen said...
There are no studies, big or small, that show it delays progression at all, let alone by two years.

I am surprised that you claim that I refer to studies that do not exist! Here are some of these studies I was refering to. Plus a citation from each.

Berkovic - Salvage Stereotactic Body Radiotherapy for Patients With Limited Prostate Cancer Metastases: Deferring AndrogenDeprivation Therapy
"Repeated salvage SBRT is feasible, well tolerated and defers palliative ADT with a median of 38 months in patients with limited bone or lymph node PCa metastases"

Decaestecker - Repeated stereotactic body radiotherapy for oligometastatic prostate cancer recurrence
"Repeated SBRT for oligometastatic prostate cancer postpones palliative androgen deprivation therapy with 2 years without grade III toxicity."

Henderson - Oligometastatic prostate cancer: An evaluation of stereotactic body radiotherapy (SBRT)
"Median ADT-free survival was 28 months (95% CI: 10 - 43 months)."

Ponti - Salvage Stereotactic Body Radiotherapy for Patients With Prostate Cancer With Isolated Lymph Node Metastasis
"... the mean time of deferment of palliative androgen deprivation therapy was 23.7 months (range, 2.5-51 months)"

Ingrosso - Stereotactic body radiotherapy in oligometastatic prostate cancer patients with isolated lymph nodes involvement
With a mean follow-up of 30.18 months, local control was achieved in 98 % of the cases, with a median b-PFS [biochemical progression free survival] of 24 months.

Jereczek-Fossa - Salvage Stereotactic Body Radiotherapy for Isolated Lymph Node Recurrent Prostate Cancer
"More than 50% of patients were free of progression at 1 year after the SBRT and one-third remained progression-free at 2 years."

Trippa - Stereotactic body radiotherapy in recurrent lymph nodes metastases from prostate cancer
"Sixteen (40%) of the patients experienced no disease recurrence after SBRT"

The observations of these studies are now tested in randomized trials. I provide links to these plus cite the objectives of these trials.

STOMP:
The aim of this multicenter randomized phase II trial is to assess the impact of MTD [Metastases-directed therapy] on the start of palliative ADT compared to patients undergoing active surveillance.

ORIOLE:
Patients with metastatic prostate cancer disease will usually be placed on hormonal therapy which can work well for a period of time, but hormonal therapy can have side effects that greatly trouble men. Any effort to delay the start of hormonal therapy would be an advantage to the patient. [.....] Therefore, we are studying the effects of stereotactic body radiation treatment on patients with five or fewer prostate cancer bone metastases to determine if we can stall the use of hormonal therapy and/or prevent other bone metastases from developing elsewhere in the body.

OLIGOPELVIS:
This study will explore the role of salvage pelvic image-guided intensity-modulated radiation therapy (IMRT) combined with ADT administered for 6 months in pelvic oligometastatic patients in prolonging the failure-free interval between two consecutive ADT courses, or even to cure selected patients with limited metastatic burden.

I think these trials, when finished, will show a benefit for radiating the metastases. Therefore the treatment I selected is oriented on these studies.

George

Gemlin said...
Maybe at some day Lu PSMA, or similar, can be used at first sign of metastatic spread?

I have a friend that presented with many small lymphnode mets and bone mets when his PCa was diagnosed. He decided to start with a Lu177 therapy. After two shots all these mets were no longer visible on a PSMA PET/CT and did not recur yet one year later. No side effects yet. He has one new lymphnode met now.

They could not remove the cancer fully from the prostate with Lu177 so he got an operation for that.

However, this treatment may have side effects in the long run. Therefore currently in Germany you have to have a chemo first before you can have a Lu177 therapy. So my friend does not get a third shot he would like to have to get rid of the new met. I said consider the risk of side effects and use SBRT instead.

George

Bob-

"Does rapid doubling always mean it's systemic? Can't it be caused by oligomets which might be amenable to SBRT?"

The PSA characteristics of everyone's cancer is different. But considering that you have had the full gamut of treatments, and your PSA is still doubling rapidly, it is likely that it is micrometastatic and systemic. Systemic treatments are called for.

"Regarding IADT, is there a theory as to how high one can safely let PSA rise to before ending vacation?"

No - every MO has his own ideas about that.

"Is there any reason that going back on Lupron won't work for me since I was undetectable while on it? Or is other HT therapy more effective now? "

Just the opposite. It is prognostic for being very effective.

Gemlin said...
What is the latest about radionuclide therapy? Will targeted radionuclide therapies such as 177 Lutetium‐PSMA have a future role in treatment of (oligo)metastatic prostate cancer as an alternative to life long ADT? Could it even be curative? Haven't we seen promising treatment responses in men with castration-resistant PC with this therapy from Germany and Australia? Maybe at some day Lu PSMA, or similar, can be used at first sign of metastatic spread?

I am very excited about developments in nuclear medicine against prostate cancer. I agree that this is exactly the kind of systemic therapy we need, and they may be even more useful if used earlier. So far, all of the published studies have been in patients with very progressed disease (multiple detected metastases, post-chemo, castrate resistant). There is one ongoing study of Lu-177-PSMA among men who are castration-resistant but not detectably metastatic (i.e., advanced, systemic and micrometastatic). One of the really promising developments is the use of cocktails of nuclear medicines that target the cancer in different ways.

I agree with you that if there is any hope of a curative therapy, nuclear medicine will be part of it. Perhaps coupled with immunotherapy to enhance the abscopal effect. Cancer is a hydra-headed monster though, so I am cautious about overestimating the potential. Cancer has the ability to thrive in tissues that are not reached by blood supply, such as perineural spaces that medicines have a hard time reaching.

Allen, thanks for that analysis. The subtleties you probe in your blog post are of enormous value. These things are often what concern me when reviewing studies, since their own confirmation biases seem to often cloud their judgement. I understand what you're saying, and for what it's worth I completely agree with your assessment.

It is so common for things that seem right, not to in fact be right.

This is of keen interest to me, since if in fact my PSA is rising, we'll be considering scans and what not. I'm not sure if they're even warranted in the absence of anything symptomatic. For me, no local "salvage" therapy is likely, and even looking for a hot lymph node is of limited value since they've all been irradiated to 50.4 Gy already anyway. Given what you've been describing here, I'm quite skeptical of any whack-a-mole concept being helpful for me. Ever since the beginning of my treatment, we had planned that the next step in the event of curative treatment's failure would be systemic therapy. I have too many high risk factors to follow up with anything local.

Bob-

I didn't say that SBRT for oligomets is useless - in fact, I said the opposite - that if it's safe, and it doesn't preclude any known beneficial therapy - why not?

The purpose of these trials is NOT to "delay the hateful ADT" it is to extend survival. There is NO evidence- none- that survival is extended for 2 years, with or without adjuvant ADT.

I'm saying that there are no data one way or the other to help decide the question.

The trials for Zytiga and Xtandi did exactly what I advocate here - compare the survival with and without the treatment. This has NOT been done for SBRT of oligomets - do you not understand the difference?

Well put Bob, we are not eager to wreck our good health and give up feeling well based on the TOAD study. My oncologist is not convinced by the study but At the same time, I very much respect the opinions and findings of TA.
My wife and I are very blessed to both enjoy good health while in our 70's. We play golf regularly, walk our dog twice a day, and are very active in the community. I am not ready to give this up to ADT.
I hope you, George and I can stay in touch since we are on a very similar path. We might be of some help to each other along the way.
Woody

In my opinion we have to be clear whether an early hormonal therapy might extend life, or not! Patrick Walsh, for example, thinks, that "So far, there has been no convincing scientific evidence to prove that early hormonal therapy prolongs life." If one accepts this assumption, a complementary local therapy of individual metastases would nevertheless be useful to delay the symptom-related use of hormone therapy.

If, however, it is assumed that early hormonal therapy would be beneficial in metastatic prostate cancer, then their delay through alternative approaches would have to demonstrate superiority, or at least equivalence. An experimental approach not without risk, like Allen told us. Why did not combine both approaches?

For me, with a Gleason 5 + 4, T3, M1b in primary diagnosis in the winter 2008/2009, this means an intermittent ADT. At the end of the ADT holiday period, the re-entry into hormone therapy is prepared with an antiandrogen (Bicalutamide) which, btw. temporarily enhances PSMA expression, which might be advantageous for subsequent PET imaging. If the PSMA-PET scan two weeks later shows very few (!) lesions, these are treated locally, which is not necessarily by radiotherapy (RT) - also HiFu, Cryo or IRE would have to be considered. To reduce the side effects of hormone therapy I use estrogen.patches and metformin, as well as vigorous physical activity. Works with me so far, current PSA: <0.008ng/ml under ADT3.

TA et al:
The studies where oligomets were treated don't qualify strictly as a controlled study but the point I was trying to make which you didn't respond to is that there have been plenty of studies including TOAD which show the effectiveness of ADT compared to doing nothing. So we know it extends life by up to 50% albeit , for some, it's a crummy life. We also have been told separately that treatment of oligomets with SBRT or some other therapy along with small doses of Lupron kills those mets and kills others which surface later with more therapy thereby extending life and minimizing the use of ADT.
I know you're saying well that's not a controlled study because A and B were not two arms of a trial where the composition of the participants were picked blindly from the same population.

Does that invalidate the results? Were the results of the SBRT studies bogus? Is treatment of individual mets unfounded and poor clinical practice? Is it malpractice? Are you saying that it's shortsighted and will result in earlier than necessary death?

You're clearly warning that by choosing to delay ADT we're taking an unnecessary risk so you're obviously putting no credence behind treatment of oligomets due to the nature of the studies not due to the results of the studies. You're saying the process was faulty so the results cannot be trusted. I'm asking why the results of one process (ADT alone) cannot be compared to the results of another process (treatment of oligomets).

Bob

Allen,

I had agreed with you already that there are no randomzied trials available yet which show a survival benefit for metastases directed therapy. However, I will probably no longer be around when the results of such studies are available let alone being included in the guidelines.

Zytiga and Xtandi were initially approved for patients that had already failed chemo. In this case you only need a relatively short observation period to determine overall survival. In the case of metastases-directed therapy before or during an intermittent ADT, the patients will live much, much longer and results of prospective, randomized trials that include a sufficient number of patients will take up to 20 years or longer. I think you cannot require such results before using the treatment in this case, taking into account the low toxicity of the treatment.

I also do not think that the authors of the studies I mentioned all agree with you that their studies are pretty much useless and provide no evidence at all.

Allen said...
The purpose of these trials is NOT to "delay the hateful ADT" it is to extend survival.

At least it was the objective of the studies I mentioned above. I cited the following from these studies: "defers palliative ADT", "postpones palliative androgen deprivation therapy", "ADT-free survival was", "deferment of palliative androgen deprivation therapy was" .....

Allen said...
There has never even been a retrospective case-matched database analysis

There is a small one now though: Benefits of Using Stereotactic Body Radiotherapy in Patients With Metachronous Oligometastases of Hormone-Sensitive Prostate Cancer Detected by [18F]fluoromethylcholine PET/CT In the full text you will see that they matched the control group to the treated group.

LowRoad said...
In my opinion we have to be clear whether an early hormonal therapy might extend life, or not!

For that I would like to cite James Mohler, the chair of the NCCN prostate cancer panel, in saying one should not start with ADT early: Dr. Mohler on Overuse of ADT in Prostate Cancer and NCCN Guidelines
He also refers to the following studies in a presentation. These studies did not determine any difference between starting ADT early oder late for patients with lymph node metastases:
Wong - Role of Androgen Deprivation Therapy for Node-Positive Prostate Cancer
and this:
Schroeder - Early Versus Delayed Endocrine Treatment ...
 
Therefore I do not think that I am risking my life if I do not start with ADT at the earliest.

George

Tall Allen said:
"ADT can extend your life. The trade off is a diminished QOL now with extended survival vs better QOL now with significantly shorter survival."
Since I do not understand " Cox retrogression " and other statistical methodologies, can someone who does, extrapolate from the Toad Trial , with some approximation , the answer to this question.
Take 200 men. Same age, same Gleason score, same primary treatment , same time until biochemical recurrence.
100 men take immediate ADT and 100 men defer treatment for 20 months.
How many are alive in each of the two arms at the end of 60'months.