Showing posts with label M1. Show all posts
Showing posts with label M1. Show all posts

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."

Thursday, August 25, 2016

Is prostate-specific radiation still of any value in men diagnosed with distant metastases? Redux

Sometimes called “cytoreductive treatment” or “debulking,” removal of the primary cancer has been used effectively in other cancers, using either radiation or surgery to increase cancer-specific survival time. In the previous post (see this link), we looked at the evidence for “closing the barn door after the horses are out.” The bottom line was a highly qualified maybe.

Rusthoven et al. probed the National Cancer Database (NCDB) for patients who were newly diagnosed with metastatic prostate cancer between 2004 and 2012. The dataset included:
  • ·      6382 men with metastatic prostate cancer, all treated with androgen deprivation therapy (ADT).
  • ·      538 of them also received prostate radiation (RT) following diagnosis.
  • ·      Some had prostatectomy rather than radiation.
  • ·      There was complete information on PSA, Gleason scores and comorbidities.
  • ·      In addition, age, year, race, clinical stage, lymph node stage, chemotherapy treatment, treating facility and insurance status were used in multivariate analysis.
At a median follow-up of 5.1 years, and after compensating for all the above-mentioned variables:
  • ·      Overall survival was 38 percent greater among those who had RT.
  • ·      Median overall survival was 55 months among those who had RT, 37 months among those who didn’t.
  • ·      5-year overall survival was 49 percent with RT, 33 percent without it.
  • ·      RT was associated with greater overall survival among those who survived at least 1 year, at least 3 years, and at least 5 years.
  • ·      Survival was similar for RT and prostatectomy.
Based on what we’ve learned about early use of docetaxel and androgen deprivation therapy (ADT) from the CHAARTED and STAMPEDE studies, chemo+ADT has become the standard of care. However, during the time period examined by this study, early chemotherapy was not often used. While the authors looked at chemotherapy use, it was most probably the treatment of last resort in the most progressed cases. Therefore, whether RT or surgery is of any benefit after early use of chemotherapy is still very much an open question.

This database analysis makes a compelling case for conducting a prospective randomized trial for early use of radical radiation therapy when metastases have been detected at the time of diagnosis. The radiation would include the whole pelvic area with spot treatment of distant metastases. Because the optimal sequencing of RT and chemo is unknown, this would have to be a 2X2 design. That means there would be 4 arms: one with chemo followed by radiation, one with chemo only, one with radiation followed by chemo, and one with radiation only. Because few patients in the US are initially diagnosed with metastases, this would have to be a multi-centered trial, or perhaps a European trial. What is unclear is who will undertake such a study and how will it be financed.

While waiting for that trial (and it will probably be a long time before we have any outcomes, even if one were already begun), the patient diagnosed at the outset with metastases should initiate this conversation with a radiation oncologist. As we saw in the earlier commentary, the answer continues to be maybe, but with somewhat more justification for considering such treatment.

Update (3/29/17):

Parikh et al. reported a similar National Cancer Database analysis on 6,051 newly diagnosed metastatic patients treated between 2004 and 2013. 622 received local therapy, 52 RP. Men who received local therapy were: 
  • younger
  • had fewer comorbidities
  • lower T stage
  • Gleason score <8
  • Negative lymph  nodes
Five-year overall survival was 47% among those who received local therapy, 17% among those who did not. The difference remained significant after an attempt was made to correct for patient risk characteristics.

Update (3/3/18):

Dall'Era et al. reported on their analysis of the database from the CDC Breast and Prostate Cancer Data Quality and Patterns of Care Study. They looked at 9-year prostate cancer-specific survival of men with either locally advanced or metastatic prostate cancer. After correcting for patient risk characteristics, they found that prostate-directed treatment (radiation or surgery) was only associated with increased survival among those with locally advanced prostate cancer, but not among those with metastatic prostate cancer.

While this is another encouraging retrospective analysis, it is subject to selection bias - the men who received local therapy had fewer risk characteristics. It is worth noting that a similar thing had occurred with breast cancer. Several retrospective studies had suggested that resection of the breast tumor  plus axillary lymph nodes increased survival even when distant metastases were detected. However, Badwe et al. reported that when women were prospectively randomized to that treatment or no such treatment, there was no survival difference. Only a randomized clinical trial like this one  at MD Anderson, or this one in Canada, or these others in Europe (ISRCTN06890529,  NCT02454543, NCT01957436, NCT00268476) can decide this issue for prostate cancer. Until we have those results, patients have to weigh that uncertainty against the very serious adverse effects of radical treatment, especially of surgery where it is likely that the prostate tumor penetrance will be extensive, and where extensive pelvic lymph node dissection may result in lymphedema and lymphocele.

Is prostate radiation still of any value when diagnosed with distant metastases?

In some cancers, debulking the tumor, also called cytoreduction, either with radiation or surgery, has been found to slow progression. Is that true of prostate cancer? In theory, removing the prostate from the metastatic equation may have any of several benefits:
  • ·      It reduces the cancer cell load available to spawn new metastases.
  • ·      The original cancer in the prostate may be especially able to signal the creation of a bone environment conducive to metastases.
  • ·      Castrate resistance may set in earlier in the original tumor, and those resistant cells may metastasize.
  • ·      The abscopal effect: radiation-destroyed cancer cells present antigens to the immune system.
But there is a contrary hypothesis as well; i.e., that removing the initial tumor actually accelerates the metastatic process. Under this hypothesis, the original prostate tumor suppresses certain growth factors and angiogenesis factors, which keeps the cancer dormant. There are also concerns that surgical debulking may release viable cancer cells into systemic circulation (see this commentary).

Cho et al. looked at the records of men treated from 2003 to 2011 at the Yonsei Cancer Center in Seoul, South Korea who were originally diagnosed with distant metastases. In all, they found 38 men who had external beam cytoreductive prostate radiotherapy (PRT), and all of them had palliative radiation of distant metastases as well. Their “control group” comprised 102 men, 39 of whom had palliative radiation of metastases, but not of the prostate. Almost all had androgen deprivation therapy.

The authors point out that the only patient characteristic that was significantly different between the two groups was age. 71 percent of the group that received prostate radiation was under 70, but only 49 percent of the controls. It is worth noting that although the differences weren’t statistically significant on this small sample size, there was a consistent pattern. Those who received prostate radiation were not only younger, but had better performance status, lower initial PSA, more likely to have just one metastasis and less likely to have more than five, and were less likely to have visceral metastases. So it is possible that the PRT group had the better survival prognosis regardless of whether they got the prostate radiation.

After a median of 34 months of follow-up, the following statistically significant differences in outcomes were reported:
  • ·      Median PSA nadir: 0.61 ng/ml for PRT group, 1.12 ng/ml for controls
  • ·      Percent achieving a PSA nadir <4 ng/ml: 87 percent for PRT group, 55 percent for controls
  • ·      3-year overall survival: 69 percent for PRT, 43 percent for controls
  • ·      3-year biochemical failure free survival: 52 percent for PRT, 16 percent for controls
Within the control group, the differences in outcomes were not statistically significant between the 39 patients who received palliative radiation and the 63 patients who had no radiation at all.

There was no severe urinary or rectal toxicity. However, there were some severe cases of leukocyte and platelet depression because of the palliative treatment of bone metastases.

Although performance status, as well as number and kind of metastases were correlated with overall survival, on multivariate analysis, only PRT was significantly correlated.

On the surface, there seems to be a case for cytoreductive prostate radiation here, but caution is warranted. The PRT group had consistently better numbers from the start. It seems likely that they received PRT because of their better outlook. This kind of selection bias seems to be driving the results. We see it especially in the multivariate analysis: the factors like age, performance status and number and kind of metastases are already subsumed into the selection of PRT patients, so they do not appear to be independently significant. This is also too small a sample size to be able to make any real judgments. For that, we will have to wait for some future randomized clinical trial.

There have been a few other such studies. Culp et al., in their analysis of the SEER database, found that metastatic men who had their prostates removed or treated with brachytherapy had longer prostate-specific survival than those who had no de-bulking. Their analysis did not account for the extent of bone metastases, whether pelvic lymph node dissection was performed, or whether they received systemic treatment (ADT or chemo), and the same selection bias may be at work as in the Cho study.

Antwi and Everson performed a similar SEER database search, this time adjusting for socio-demographic factors and tumor attributes, and found that prostatectomy in metastatic men was associated with a 72 percent reduction prostate cancer-specific mortality; brachytherapy was associated with a 54 percent reduction. Fossati et al. also looked at the SEER database and found that there was a subset, those with prostate cancer-specific 3-year mortality risk of less than 40 percent, who benefited from cytoreductive therapy.

The closest we have to a randomized clinical trial was a pilot case-controlled prospective study, reported by Heidenreich et al., of 23 men with 1-3 bone metastases, no visceral metastases, non-extensive lymph node involvement, who were all hormone responsive and were treated with prostatectomy. This was compared to a case-control group of 38 men with metastatic prostate cancer who only received hormone therapy. The prostatectomy group had longer time to castration resistance (40 months vs. 29 months), longer progression-free survival (39 months vs. 27 months), and longer prostate cancer-specific survival (96 percent vs. 84 percent with median 3-4 years of follow-up). The overall survival was similar.

We are left with intriguing hints, but no reliable data. Surgical de-bulking carries risk of incontinence and almost certain impotence, considering nerve-bundle preservation would be unlikely. Radiation carries less urinary and sexual risk, but is not risk free. If it is beneficial at all, full pelvic radiation would probably be optimal for slowing cancer progression. The use of SBRT and multi-modal therapies, like brachytherapy boost and adjuvant ADT, have yet to be explored.

Unfortunately, there seem to be few clinical trials, although clinicians are doing this selectively with some patients. There is a randomized clinical trial at MD Anderson (NCT03678025). A registry in Dallas (NCT02170181) includes metastatic patients treated with SBRT prior to chemotherapy. Rutgers Cancer Institute in NJ has a clinical trial (NCT03456843) of surgical de-bulking. The Los Angeles VA is combining prostatectomy, metastasis-directed SBRT and 6 months of advanced hormone therapy (Lupron, Zytiga and apalutamide) for newly diagnosed patients with 1-5 metastases.