Showing posts with label cytoreduction. Show all posts
Showing posts with label cytoreduction. Show all posts

Sunday, September 30, 2018

Survival benefit to debulking the prostate with radiation in men with low metastatic burden

The term "debulking" denotes the radical treatment (via prostatectomy or radiation) of the cancerous prostate after distant metastases have been discovered. This first randomized clinical trial of debulking with external beam radiation found that there was no overall survival benefit.

Results of the STAMPEDE randomized clinical trial were published in the Lancet. Like the HORRAD trial (see below), they found there was no survival benefit to radiation debulking among all newly diagnosed men with metastases (Stage M1). Unlike the HORRAD trial, they utilized higher radiation doses.

Newly diagnosed men were treated with standard of care (which at the time meant ADT and docetaxel in 18% of the men) and were randomized to no radiation debulking or hypofractionated radiation, consisting of either:
  • 55 Gy in 20 daily treatments, or
  • 36 Gy in 6 weekly treatments (note: this bioequivalent dose is 15% higher)
However it made a big difference in survival if the men were oligometastatic (1-3 distant metastases). After 37 months median follow-up:
  • Survival increased by 32% (hazard ratio = 0.68) in 819 oligometastatic men
    • 3 yr survival was 81% with debulking vs 73% without debulking
  • No survival increase among the 1,120 polymetastatic men (defined as visceral metastases or 4 or more bone metastases with at least 1 outside the axial skeleton)
Survival increases were also noted among men with only pelvic lymph node metastases (N1M0), in whom whole pelvic radiation may be curative.

Adverse events from the radiation were generally mild:
  • 5% had grade 3 (serious) or higher acute urinary or rectal side effects
  • 4% had grade 3 (serious) or higher late-term urinary or rectal side effects

Based on this and their other randomized clinical trials, men with lower metastatic burden should be treated with ADT+Zytiga or ADT+docetaxel, followed in 2 months with local hypofractionated radiation. Men with higher metastatic burden should be treated with ADT+Zytiga or ADT+docetaxel (it is unknown whether ADT+Zytiga+docetaxel adds any additional benefit). Metastasis-directed therapy is under investigation.

(Update 2/18/2021) Because controversy exists in how to define "low metastatic burden," Ali et al. undertook a secondary analysis of the STAMPEDE trial. They found that the benefit of RT debulking was greatest in two groups:
  1. 1-3 bone metastases (M1b) with no visceral metastases
  2. Only non-pelvic lymph node metastases (M1a) with no visceral metastases
The survival benefit dropped off after 3 bone metastases. There was no benefit in anyone with any visceral metastases (M1c). Metastases are counted based on conventional imaging (bone scan/CT), so metastases found on PET scans do not count towards the total.

(Update 6/7/2022) Long-term follow-up (61 months) of the STAMPEDE trial, confirmed earlier findings:
  • Survival increased by 36% if low burden
  • Survival decreased by 11% if high burden (not statistically significant)
  • No difference in quality of life

BoevĂ© et al. reported the results of 432 men with bone metastases at 28 centers in the Netherlands from 2004 to 2014 (the HORRAD trial). They had received no previous treatments. They all had PSA > 20 ng/ml at the start of treatment and were under 80 years of age. They were randomized to receive either:
  1. Lifelong ADT (an LHRH agonist, starting with 4 weeks of an anti-androgen)
  2. Lifelong ADT + external beam radiation therapy (EBRT) 
The EBRT dose was 70 Gy (35 treatments of 2 Gy each) or 57.8 Gy (19 treatments of 3.04 Gy each), which are biologically equivalent. No whole pelvic radiation or brachy boost therapy was given.

After 47 months median follow-up, the median overall survival was:

  • 45 months in the group that received ADT + EBRT
  • 43 months in the group that received ADT only
The difference was not significant

The authors also looked at survival differences based on:
  • Number of bone metastases (<5, 5-15, >15)
  • PSA at diagnosis (greater or less than 60 ng/ml)
  • Gleason score
  • Stage
  • Age
  • Performance status
  • Painful bone metastases

None made any significant difference in survival.

The time to PSA progression was slightly longer among those who received EBRT (15 months vs. 12 months), but the statistical significance vanished after correction for patient characteristics.

These disappointing results conflict with several retrospective database analyses. This once again illustrates that only prospective randomized clinical trials can prove a causal relation, and that observational studies are confounded by the vagaries of patient selection; i.e., patients who receive debulking in actual clinical practice are the ones who would do better anyway. 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.

Because this trial began over a decade ago, it does not include radiation doses now considered to be curative (around 80 Gy). Nor does it include brachy boost therapy, which was shown to be superior to EBRT alone in high risk patients in the ASCENDE-RT randomized clinical trial. It is also unknown what effect whole-pelvic radiation or metastasis-directed therapy might have had, or whether prostatectomy with or without extended pelvic lymph node dissection (ePLND) may have increased survival.

(update 7/3/22) Dai et al. reported the results of an RCT among 200 men with oligometastatic PCa randomized to ADT alone or ADT with debulking the prostate with radiation or surgery (85% had surgery). After a median follow-up of 48 months:
  • Radiographic progression was reduced by 57% by debulking
  • Mortality was reduced by 56% by debulking
  • PSA progression was reduced by 56% by debulking
These clinical trials began before CHAARTED, STAMPEDE, and LATITUDE clinical trials proved that early treatment with docetaxel and abiraterone improves survival in newly diagnosed metastatic men. It is unknown what effect debulking may have in men pre-treated with those systemic therapies.

Many of these unknowns are being explored in current clinical trials. The randomized clinical trial of debulking at 257 US locations will allow for systemic pre-treatments and either EBRT or surgery. This clinical trial in Canada allows for treatment with surgery, HDR brachytherapy, chemotherapy, and SBRT to metastases. This clinical trial in Europe allows for treatment with  docetaxel, and abiraterone. This clinical trial in Germany randomizes patients to prostatectomy + ePLND or best systemic therapy.

Because radiation and prostatectomy have adverse effects, this study should make patients cautious about having any kind of debulking outside of a clinical trial.

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.