Tuesday, December 19, 2017

Metastasis-Directed Therapy for Oligometastatic Recurrence - the STOMP trial

Metastasis-directed therapy (MDT) for recurrent oligometastatic prostate cancer is a very controversial topic. Researchers who should know better have made unjustified claims (see this link) and have even posted YouTube videos replete with "gee whiz" cases.

Now we have the first randomized clinical trial on the subject. It's a small Phase 2 trial (62 patients randomized to MDT or Surveillance) called STOMP and it only ran for three years (not long enough to detect survival differences in early metastatic patients). The objective of the study was not to see if MDT extended survival (which is what we really want to know), but to determine whether it extended the period before salvage ADT was required. The authors believe that if that more modest claim is realized, then a larger, longer Phase 3 randomized trial to detect any survival improvement would be justified.

"Oligometastatic" was defined as 1 to 3 detected metastases. Metastases were detected using a Choline PET/CT scan. Metastases could be in the pelvic lymph nodes (stage N1) or in distant locations (stage M1). Due to the small sample size in this study, there was a serious disparity in the number of metastases: the MDT group had fewer detected metastases (58% had only one) than the Surveillance group (29% had only one). From the start, the median number of detected metastases was 2 in the Surveillance group vs. only 1 in the MDT -- the Surveillance group started with a significant disadvantage.

"Recurrent" means after primary prostatectomy or radiation therapy has failed, and in some cases, salvage therapies have failed as well. Primary therapy may have included extended pelvic lymph node dissection (ePLND) with prostatectomy or whole-pelvic radiation along with prostate radiation. In this study, most (76%) had prostatectomy and many of them (85%) had failed salvage radiation.

"Metastasis directed therapy" included spot radiation (SBRT) to detected metastases, or surgical removal of lymph nodes or soft-tissue metastases. In this study, 55% of patients had lymph node metastases. If the patient had already had whole pelvic radiation or ePLND and any cancerous pelvic lymph nodes were detected, only those lymph nodes were removed. Otherwise a salvage ePLND was performed. Some patients were treated with SBRT to individual lymph node metastases, but none were treated with radiation to the whole pelvic lymph node field. Bone metastases were treated with SBRT (in 45% of patients), and one lung met was surgically removed. If metastases were detected on follow up in the MDT group, they were treated if there were 3 or fewer (i.e., whack-a-mole).

"ADT-free survival" is the time from randomization to the time ADT was required for any of three reasons: symptomatic progression, progression to more than 3 metastases (called "polymetastatic progression"), or local progression of baseline-detected metastases. PSA progression was not an adequate reason to start ADT. It is well known that MDT will result in a temporary reduction of PSA that is not sustainable. The goal of any therapy is to treat the disease, not to treat the PSA.

After a median follow up of 3 years, Ost et al. reported that:
  • Median ADT-free survival was 8 months longer in the MDT group
    • 21 months  in the MDT group vs. 13 months in the Surveillance group
    • The difference was not statistically significant with 95% confidence, but was within the pre-specified 80% confidence range*
  • 39% had not started ADT in the MDT group vs. 19% in the Surveillance group
  • 61% started ADT for polymetastatic progression (half of them within one year of treatment) in the MDT group vs 55% in the Surveillance group
  • Location of metastases did not affect ADT-free survival
  • 58% had only 1 metastasis (median=1) at baseline in the MDT group vs 28% in the Surveillance group (median=2).
  • There was no significant difference in ADT-free survival (even at 80% confidence) among those who had a PSA doubling time (PSADT) at baseline of >3 months (only 10 men in each group had a PSADT ≤ 3months)
  • Treatment toxicity was mild
* The authors pre-specified an 80% confidence interval for this pilot study. This is unusual. Ostensibly, this was because they knew they would be implementing an expanded Phase 3 study and only wanted to check for gross differences in this Phase 2 pilot study.  In a more conventional statistical analysis, the hypothesis that MDT affected ADT-free survival would have been rejected. Also, at 80% confidence, they should have accepted the hypothesis that the higher number of metastases in the Surveillance group made a difference - but the authors seem to ignore the inconsistency. Because of this, patients and clinicians are cautioned to not make changes in treatment decisions based on this.

Because "polymetastatic progression" was the endpoint used to determine whether ADT was indicated for treatment, and 39% of the Surveillance group were already starting with 3 metastases at baseline, it is surprising that it took 13 months for a single new metastasis to become detectable in that group, and that for 19% of the Surveillance group, a fourth metastasis never became detectable throughout the 3 years of follow up. In the MDT group, four new metastases had to become detectable after the first ones were eradicated by treatment. 31% (11 of 31) had a second round of treatments, and 6% had a third round of treatments before the sudden appearance of four or more detectable metastases all at once. By setting "ADT-free survival" as the endpoint and making it conditional upon the simultaneous detection of four metastases, they guaranteed that the endpoint would be reached earlier in the Surveillance group. What is surprising is that even with that built-in bias, the difference was not significant with 95% confidence. It is also worth noting that in a pre-planned subgroup analysis, there was no significant difference in ADT-free survival (even at 80% confidence) among those who had a PSA doubling time at baseline of >3 months. Patients with "indolent" metastases did not benefit from MDT. This study does not show that metastatic progression was slowed by MDT. Only an improvement in overall survival time can show that.

This study used a Choline PET (F18, I presume) scan to detect metastases. We recently saw that there is a clinical trial at Johns Hopkins to detect and treat oligometastases using the more accurate PSMA PET scan. While outcomes may be improved with a more accurate scan, it will undoubtedly eliminate many patients from the oligometastatic pool of patients.

This study did not investigate whether salvage radiation to the entire pelvic lymph node field would have had better outcomes than spot SBRT treatment. We are still not very good at finding cancerous lymph nodes (see this link) and the treatment field is inadequate most of the time (see this link).

Importantly, this study does not address whether it is beneficial or detrimental to delay start of ADT. The 8-month delay in the start of ADT may result in 8 months that the cancer is systemically multiplying and evolving. The TOAD trial suggested that early amelioration of the micrometastatic burden in recurrent patients may have a greater influence on survival than any selective evolutionary pressure that starting earlier may exert. It furthermore showed that overall quality of life was unaffected by the earlier ADT start. ADT is the standard of care when metastases have been discovered. Clinical trials of oligometastatic MDT should include ADT use in both arms to give a realistic appraisal and to be ethical.

While this trial was done among recurrent patients, the STAMPEDE trials (see this link and this link), the CHAARTED trial, and the LATITUDE trial among newly-diagnosed patients proved that aggressive systemic therapy, as early as possible after metastases are discovered, provides a significant survival advantage.

It is important that patients understand the very real risk of avoiding systemic treatment when there are known metastases. While it risks little to treat those oligometastases that can be safely treated, we must understand that there is no known survival benefit to doing so. There is a known risk to delaying systemic therapy. Dr. Ost wrote to me, "MDT does not replace ADT and our results should not be interpreted in that way."


  1. There's a lot to be said about such a study. Is 18F choline or fluorocholine PET/CT the most accurate way to assess lymph nodes and/or bone metastases or is is with 68Ga-PSMA-11 PET/CT or PET/MRI. Are bone metastases better detected with 18F NaF PET/CT or is 68Ga-PSMA-11 PET/CT just as good? For me, based on my clinical experience I want some study to show me that something is equivalent to Combidex-Enhanced MRI (CEM) for nodal metastases or better. I have yet to see that. I am reviewing the head-to-head studies to try to ascertain if one imaging study is better or equivalent than another. Right now, in the USA, none of these PET/CT or PET/MRI are FDA approved in prostate cancer. That's absurd.

    I need to read the full paper to see if this study was for men with PSAR as it appears to be and for men who are ADT naive. I have 34 years experience with ADT and IAD (intermittent androgen deprivation) and in the context of PSAR I cam convinced that a number of men will go into complete remission (CR) and be able to have years of no treatment without recurrent PC. In our patients that received ADT using 3 drugs (called ADT3), and in whom ADT was used in men with PSAR, the time off ADT or IAD (intermittent androgen deprivation) exceeded a median time of 5 years. And in men receiving ADT2 using an LHRH-A + an anti-androgen the median time off was 24 months. So I am not sure that the goal of men NOT needing to go on ADT is such an important goal, especially if the assessment of nodal disease might be inaccurate 2° to the limitations of choline PET/CT. I do recall a handful of patients evaluated by Jelle Barentsz with both choline PET/CT and Combidex where only nodal metastases that were large were seen with the PET/CT vs Combidex seeing metastases as small as 4mm in dimension. With MRI magnets going to 7T that resolution may come down to 2mm.

    It seems to me that basic questions re imaging accuracy and how to properly use ADT remain controversial. Rarely do I see men on ADT having total and free testosterone or measurements of bone resorption markers (BRMs) despite androgen deprivation (AD) being a known cause of osteoclast stimulation.

    1. Dear Dr. Strum,

      Perhaps I can save you some work. For the relative accuracy of the various PET scans, see:
      (Paired comparison tests are highlighted in the table)

      For lymph node detection, see:
      In the subsection on USPIO MRI, there's a reference to Jelle Berentz's study where he is able to find LN mets as small as 2 mm - about half as small as the best PET scans. I very much agree that it's a shame we don't have Combidex MRIs in the US.

      The Ost study was only among men with PSA-recurrent PC. They used the European Ass'n of Urology definitions of PSA recurrence. 48% of the Surveillance group and 39% of the MDT group had received ADT as an adjuvant therapy at the time of their initial or salvage treatment, which was a median of 5 years prior to recurrence.

  2. The first link above is to the Dietlein et al 2017 article entitled: PSA-Stratified Performance of (18)F- and (68)Ga-PSMA PET in Patients with Biochemical Recurrence of Prostate Cancer. J Nucl Med 58:947-952, 2017. I had the earlier paper from 2015 from this group but not the 2017 one. Thank you for this. I am now through reading the 2017 paper page by page and also looked at the supplemental material for this article. I have made a number of annotations on this pdf which I have sent to you via email. I am a strong believer that collaboration and collegiality will bring us closer to clarity and answers.

    Given that there are now thousands of men throughout the world who have had various PET/CT studies using various radiotracers, the number of head-to-head studies are scant. This has been a recurring theme in the imaging of virtually all cancers, including and it seems especially with prostate cancer. Given the billions of dollars globally spent on Tc99 bone scans and on CT scans of the abdomen and pelvis (plus the cost of misdirected therapies resulting from huge numbers of false negative results), it is appalling that head-to-head studies are relatively few. In the 2017 Dietlein article only 25 patients were studied with both 68Ga-PSMA-11 and 18F-DCFPyL radiotracers.

    And reading the section on this head-to-head comparison it is not clear if patients were post-RP, post-RT, post-HIFU (the authors included HIFU patients as if they received RT). And the comparison in this cohort of 25 patients focuses on # of lesions detected rather than the impact of one radiotracer vs the other on how the patient is subsequently managed. Additionally, if you look at Figure 4, I am not convinced that Patient #3 shows superiority of one radiotracer over the other. The other 2 patients in Figure 4 apparently had 68Ga “signal extinction artifact” between the kidneys. I just ordered an article by Fennessy that might be a solution to this signal extinction:

    Fennessy N, Lee J, Shin J, et al: Frusemide aids diagnostic interpretation of (68) Ga-PSMA positron emission tomography/CT in men with prostate cancer. J Med Imaging Radiat Oncol 61:739-744, 2017.

    From reading the abstract I do not know if the issue of signal extinction in the anatomic area between the kidneys was focused on. I will complete my replay in a separate post.

    Stephen B. Strum, MD, FACP
    Medical Oncologist specializing in PC
    Member of ASCO, AUA, ASTRO

  3. Rest of the above post:

    And getting back to the Dietlein paper from 2017, and focusing on the 25 patients with both radiotracers used, I wonder how these patients were verified to be true positives or true negatives.

    Dietlein et al do not mention the impact of high Gleason score on PSA expression. There is a low PSA leak with GS 8-10. Thus the narrow PSA range in their paper of 0.5-3.5 needs to be challenged re the use of such imaging in those with confirmed GS 8-10. In their paper they do not say who read the Gleason scores. Were these pathologists expert in PC? I am an ex-pathologist (lymph node and bone marrow disease) and I know that observer disagreement in areas like lymphomas and prostate cancer are very high. I routinely have obtained expert 2nd opinions with patients under my care. Also, most general pathologists and even some experts do NOT quantify the amount of Grade 4 in patients with GS 7. If the GS is (3,4) the amount of grade 4 can be as low as 5% or as high as 49%. If GS (4,3) the amount of grade 4 can be as high as 95% or as low as 51%. I would speculate that for GS (3,4) this objectifying of amount of grade 4 is important as per the pioneering work that was published by McNeal and Stamey on the importance of Grade 4 vs prognosis.

    Regarding the 2nd link to lymph node detection via Combidex:
    I have known Jelle since 2003 after his NEJM article with Harisinghani from Mass General. Many of my patients have been studied and continue to be evaluated in Nijmegen by Barentsz. We spoke together in an RSNA meeting in Chicago not long ago on the issue of staging of PC. I just emailed 2 articles in which he mentions 2 mm node with met detection via Combidex-Enhanced MRI (CEM).

    And the Ost et al study is of interest in that it brings up the issue of oligometastatic prostate cancer (OMPC). Here is where I wish Combidex was available since we have used Combidex to essentially use RT in an attempt to cure patients with nodal metastases limited to a radiation field.

    Just reading the Ost et al abstract has me wondering if the results are statistically significant. I am perplexed at the “end point” being ADT-free survival, with the surveillance group being 13 months versus the MDT group being 21 months with a p value of 0.11. And their study used choline PET/CT for imaging, so I wonder how many men were inappropriately-treated with MDT (i.e., they received radiation based on imaging where nodal metastases were missed (as we have seen comparing choline PET/CT with Combidex. Combidex-Enhanced MRI (CEM) would seem to me to be superior to any of the PET/CT radiotracers used in imaging (and it should be far cheaper with no radiation exposure).

    Your website is excellent with a wealth of great information. I wish many of the issues you raised were more appropriately addressed in a manner that as a clinician (medical oncologist) focused on prostate cancer x 34 years should be focused on the frontline real-life experiences of men with this disease.
    I cannot fathom why Combidex was rejected by the FDA given that it is simply an iron nanoparticle used as a contrast agent with MRI. And the very same nanoparticle has been used in tens of thousands of patients in various peer-reviewed papers. That there are so few head-to-head studies comparing various imaging modalities in a clinically meaningful fashion is to me "criminal". The explosion of medical papers in the peer-reviewed literature opens so many doors but the conclusivity of these articles is often lacking and most men with PC today still are getting Tc99 bone scans and CTs of the abdomen and pelvis and being told based on these insensitive imaging techniques what they should do. Given the high false negative rates of ≈ 50% many of these men are receiving local therapies when their approach might more likely cure them if more accurate staging was done.
    Stephen B. Strum, MD, FACP
    Medical Oncologist specializing in PC
    Member of ASCO, AUA, ASTRO