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
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."