Salvage radiation is curative in roughly half of all cases.
There are many factors that contribute to an unfavorable prognosis, including
waiting too long, high PSA and rapid PSA doubling time, adverse post-surgery
pathology (stage, Gleason score, positive margins), and high Decipher or
CAPRA-S score. But, other than a detected distant metastasis, none can predict
failure of salvage therapy. For the first time, there seems to be a genetic
signature that predicts when adjuvant or salvage radiation (A/SRT)
will succeed.
The study is all the more impressive because of the many top
prostate cancer researchers attached to it, representing a collaborative effort
from many top institutions: Harvard, University of Michigan, Johns Hopkins,
Northwestern University, University of California San Francisco, Mayo Clinic
and others.
The process
Zhao et al. started with data on 545 patients who had a prostatectomy at the
Mayo Clinic between 1987 and 2001. They attempted to find patients who were
matched on pre-RP PSA, Gleason score, stage, and positive margins, but differed
on whether they received A/SRT or not. They also had to have complete
information on diagnosis and whether they eventually had metastatic
progression. This yielded 98 matched pairs. They then did complex genetic
screening of archived tissue samples from those prostatectomy patients, focusing
on 1800 genes that have been implicated in response to DNA damage after
radiation. They found 24 genes that were correlated with occurrence of
metastases after salvage radiation. After correcting for other factors, they
determined what they call a “Post Operative
Radiation Therapy Outcomes Score (PORTOS).” A PORTOS of zero (called a “low”
PORTOS) means it predicts no benefit from salvage
radiotherapy. A PORTOS greater than zero (called a “high” PORTOS) predicts a
benefit from salvage radiation.
Validation
The next phase was
to predict how well the 24-gene signature would predict salvage radiation success
in a larger data set. They analyzed 840 patient records from patients treated
at the Mayo Clinic from 2000-2006, Johns Hopkins (1992-2010), Thomas Jefferson
University (1999-2009) and Durham VA Medical Center (1991-2010). They were able
to find 165 matched pairs – half treated with A/SRT, half with no radiation. Tissue
samples were screened and scored, and 10-year incidence of detected metastases
was obtained. 1 in 4 men were categorized as “high PORTOS,” 3 in 4 were “low
PORTOS.”
In the “high PORTOS”
group:
- Only 4% suffered metastatic progression if they had A/SRT
- 35% suffered metastatic progression if they did not have A/SRT
- They had an 85% reduction in 10-year incidence of metastases after A/SRT, which was statistically significant.
In the “low PORTOS”
group:
- 32% suffered metastatic progression if they had A/SRT
- 32% suffered metastatic progression if they did not have A/SRT
None of the other
prognostic tools (Decipher, CAPRA-S, or Prolaris) that are sometimes used to
predict metastases after prostatectomy could predict the response to A/SRT.
Caveats
This should be
interpreted with caution for several reasons:
It was retrospective,
and therefore subject to selection bias. That is, the physicians may have
decided on the basis of patient characteristics or other disease
characteristics not captured here to give A/SRT to some patients, but not to
others. Only a prospective, randomized trial can tell us if the association
with PORTOS is the cause of the differential response.
Among the disease
characteristics the researchers were unable to capture for this study were the
time between prostatectomy and A/SRT, PSA at time of A/SRT/maximum PSA reached,
nadir PSA achieved after prostatectomy, PSA doubling time, extent of positive
margins, Gleason score at the positive margin, and comorbidities. Patients were
not treated uniformly with respect to radiation dose received and duration of
adjuvant androgen deprivation therapy (ADT). Only 12% received any adjuvant ADT,
and only 12% received adjuvant (rather than salvage) radiation.
Metastases were
detected by bone scan and CT. Lymph node dissection, if performed, was limited.
It was detected in 4% of the “low PORTOS” group, but in none of the “high
PORTOS” group. It is unclear how today’s newer PET scans would affect outcomes.
Radioresistance
Prostate cancer has
long been known to be radioresistant relative to other cancers. To understand
radioresistance, we must first understand how ionizing radiation (X-rays or
protons) kills cancer cells. The radiation causes a chemical reaction
with water and oxygen to generate molecules known as “reactive oxygen species”
or ROS. One such ROS molecule, the hydroxyl radical, inserts itself into the
cell’s DNA to break both strands of the double helix, called “double strand
breaks.” The cell dies when it can’t replicate because of those double strand
breaks.
Radiobiologists cite
5 reasons for radioresistance:
1. Hypoxia
Prostate cancer thrives in an oxygen-poor environment, and
often does not have a good blood supply that brings oxygenation. It therefore
requires more radiation to provide adequate ROS, especially into thick tumors.
2. Cell-Cycle Phase
As a cancer cell attempts to build new DNA and replicate, it
goes through several phases. In one of those phases, the “S phase,” the cell is
building new DNA. It is particularly radioresistant in this phase. Radiotherapy
is typically carried out over a period of time in multiple fractions, rather
than in a single shot, to allow the cancer cells to cycle into more
radiosensitive phases. However, in a recent lab study, McDermott et al. showed
that fractionated radiation increases the population of radioresistant S-phase
prostate cancer cells.
3. Repair of DNA damage
Non-cancerous cells that can’t repair the DNA damage, commit
suicide (called apoptosis). Many
non-cancerous cells are able to repair the DNA damage and survive. Fractionation
gives them time to self-repair. Cancerous cells usually lack that DNA-repair
mechanism and most cannot undergo apoptosis. If they are not killed
immediately, they die when they try to replicate. However, some cancerous cells
may escape destruction by turning the genetic cell repair mechanism back on.
4. Repopulation
Some cancers grow so quickly that fractionated radiation
gives them time to grow back between treatments. This is not the case for prostate cancer.
5. Inherent radioresistance
Some kinds of cells are inherently impervious to radiation
damage; muscle, nerves, and stem cells are radioresistant, as are melanoma and
sarcoma. Prostate cancer stem cells, thought to play a role in prostate cancer
proliferation, are inherently radioresistant. A recent lab study
showed that radiation may paradoxically activate stem-cell like features of
prostate cancer cells, turning them into radioresistant stem cells.
How should PORTOS be
used?
GenomeDx is already supplying PORTOS to post-prostatectomy
patients who order Decipher. Should it be used to guide A/SRT decision-making?
Given the caveats (above), there are many uncertainties in how predictive it
actually will be when it is used prospectively in larger patient populations.
But the information is certainly interesting.
I wonder whether PORTOS reflects a genetic change that occurs in local prostatic
cancer cells as they undergo a change (called “epithelial-to-mesenchymal
transition” (EMT)) into metastatic-capable cells. Or is it a genetic
characteristic, there from the start? A recent study
showed that 12% of men with metastases have faulty DNA-repair genes. (This
included 16 DNA-repair genes, compared to the 24 in the PORTOS study). Such
faults occurred in 5% of men with localized prostate cancer, and 3% in men with
no prostate cancer. DNA-repair mutations seem to accumulate as the cancer
progresses. It may well
be that PORTOS is an early detector of systemic micrometastases. Perhaps it
will be found to be redundant to detection of small metastases using new PET
indicators. I
would love to see a PORTOS analysis on metastatic tissue as well (lymph node,
bone and visceral) and maybe on circulating tumor cells to see whether
radioresistance is an acquired trait of PC progression. If it is an early
indicator of metastatic progression, it may already be too late for primary
radical therapy.
While a “high” PORTOS suggests that A/SRT will be curative,
only a quarter of the men had a high PORTOS. Does that really mean that
three-quarters of recurrent men should give up on curative therapy? If PORTOS
is not an indicator of EMT, I hope that those recurrent cancers still can be
cured. But it may mean that certain adjuvant measures may be required,
including higher radiation doses, systemic therapies that are known to enhance
radiation effectiveness, and investigational adjuvant therapies.
•
A/SRT doses are typically in the range of 66-70
Gy. Some A/SRT studies used doses as high as 72-76 Gy. With modern IGRT/IMRT
technology, such doses may be delivered with acceptable toxicity. Also, if
larger lesions can be identified with the new PET scans and multiparametric
MRIs, it may be possible to deliver a simultaneous integrated boost dose to
those lesions.
•
ADT has been shown to reduce hypoxic cancer
survival and inhibit DNA repair. It is possible that prolonged neoadjuvant use,
perhaps with second-line hormonal agents (Zytiga or Xtandi) may improve
radiation cell kill. Docetaxel, which has shown limited usefulness in
non-metastatic patients, may prove useful in low-PORTOS situations. Perhaps
immunotherapy can play a role as well.
• There are many investigational agents that may
enhance radiosensitization. PARP1 inhibitors (e.g., olaparib) and heat shock
protein inhibitors may prove useful in restoring radiation sensitivity (see this link). PI3K/mTor inhibitors and HDAC inhibitors (e.g., vorinostat) may
increase cell kill in hypoxic conditions (see this link) and to cancer stem cells (see this link). Cell oxygenation may be enhanced by a measure as simple as 15
minutes of aerobic exercise before each treatment (see this link).
There are common supplements like resveratrol and soy isoflavones, and drugs
like statins, aspirin, and metformin that have shown promise as
radiosensitizers in lab studies.
It is possible that PORTOS may also prove useful in
predicting radiation response among newly diagnosed unfavorable risk patients.
GenomeDx currently requires
whole-mount prostate specimens. I don’t know if PORTOS can be done on biopsy
cores, or if it provides any prognostic information beyond what the conventional
risk factors (PSA, Gleason score, stage and tumor volume) provide. It would
have to be similarly validated before we would be able to incorporate it in
primary therapy decision-making.
This test is very expensive. For now it only is available
along with Decipher, which costs about $4,000. Medicare may cover it, but
private insurance may or may not. Always get pre-authorization first.
