Xofigo has been a game-changer in the treatment of prostate
cancer metastatic to bone. Not only does it provide significant pain palliation
and reduce skeletal-related adverse events, but it slows down progression of
the disease, increasing median survival by about 30%. Unlike external beam
radiation, it can be used when there are many widely distributed metastases.
Several new studies looked at a potentially important new
radiotherapy. Lutetium 177 is a low-energy beta particle emitter. In this case,
low energy is a good thing because it limits the distance the beta particles
(actually electrons) can travel through tissue. Ideally, we want internal radiotherapies
to deposit their energy in tumor tissue only; radioemitters that deposit their
energy over long distances are too toxic for internal therapeutic applications.
Xofigo (radium 223 chloride) is an alpha particle emitter (a helium nucleus consisting
of 2 protons and 2 neutrons). Alpha particles are very heavy and can travel
only a short distance through tissue; however, they deposit a lot of energy in
the tissue they interact with, efficiently killing cancer cells in a small
radius. One can safely hold a glass vial of Xofigo in one’s hand because it
can’t penetrate beyond the thickness of the glass or penetrate skin. Because beta
particles are thousands of times smaller than alpha particles, they can travel
farther through tissue, but their cell-killing power is less.
Another desirable quality in radiotherapeutics is a
half-life long enough to allow for convenient treatment and time in the body to
kill off cancer cells, but short enough so that it doesn’t hang around too long,
accumulate in the liver and kidneys, and kill healthy tissue. Both Ra-223 and
Lu-177 fit that criterion.
Ra-223 is chemically similar to calcium, so tissues that uptake
calcium, uptake radium as well. That means principally bone, especially in
highly metabolically active sites like bone metastases. However, calcium is ubiquitous in the
human body, so small amounts of radium may accumulate in other tissues, causing
Lu-177 by itself has little therapeutic use; however,
scientists have attached it to an antibody found mostly on the surface prostate
cancer cells, at least 95% of them, called prostate
surface membrane antigen (PSMA). The radioactive Lu-177 is chemically
bonded to a monoclonal PSMA antibody, called J591, which finds its way to
prostate cancer cells anywhere in the body. Unlike Xofigo, which only attaches
to bone metastases, Lu-177-anti-PSMA attaches to any metastasis – bone, lymph node or visceral. It can potentially
treat systemic micrometastases as well. It has the ability to potentially kill
many more cells because of the increased range of the beta particle. And
because it does not attach to non-prostatic tissue, the toxicity is more limited.
Lu-177 has another important benefit that Ra-223 lacks: it
emits small amounts of highly penetrating gamma rays. The gamma rays are not
powerful enough to kill tissue, but they can be detected by a 2D gamma ray
camera (scintigraphy), or a 3D SPECT scan. This means that we can see even
small metastases that the radiotherapy is attacking; it is both therapeutic and
diagnostic (sometimes called theranostic).
The table below summarizes some of the key characteristics
of Ra-223 and Lu-177.
Alpha particles (95%)
Beta particles, gamma rays
Tissues that uptake calcium
Prostate cancer expressing the prostate specific membrane
Destroys metastases in:
Bone only (areas of active calcium uptake)
Bone, lymph nodes, viscera, systemic micrometastases
Shorter range:<0.1 mm or about 8 cells
Longer range: ~0.25 mm or about 125 cells
Cancer cell killing power:
Gamma camera (scintigraphy) or SPECT
Gastrointestinal, edema, myelosuppression
Myelosuppression: platelets, neutrophils & leukocytes
Tagawa et al.(2013)
published the results of a Phase II clinical trial that demonstrated
Lu-177-anti-PSMA resulted in declines in PSA among patients with metastatic
castrate-resistant prostate cancer. In a follow-up analysis
they reported a better response, including increased survival, but with higher
toxicity with increased dose. As with Radium-223, PSA response may not be the
best measure of its efficacy. They also noted large declines in circulating
tumor cells (CTCs). There was better response among patients who had better
anti-PSMA uptake. Based on this, they suggested the following additional
• Improved patient selection using
PSMA-based imaging and circulating tumor cell (CTC) analysis
• Escalated cumulative doses using
• Concurrent use with docetaxel to
• Earlier use as soon as
biochemical recurrence is identified after initial therapy
At the 2015 Genitourinary Conference there were early
reports on some of those studies. Batra et al.
reported on a small Phase II clinical trial of Lu-177-anti-PSMA used with or
without docetaxel, and with fractionated dosing. The group that received both
docetaxel and the higher cumulative dosing with fractionated dosing had the
best response, with 81% having a reduction in PSA of over 30%, although their
overall survival did not seem significantly improved compared to the low dose
group. The group that received the highest fractionated dose, but without
docetaxel, had an overall survival three times longer (43 months) than the
group that received a low dose. Myelosuppression was reversible after
treatment. Karir et al.
reported on CTC counts of patients in the same study. Over 90% of those
with an unfavorable CTC count (>5) had a favorable CTC count (<5)
following treatment. Interestingly, they found that anti-PSMA alone, without
the added Lu-177, had a favorable effect in a small subset they tested.
Agarwal et al.
used Lu-177-EDTMP in 44 patients with metastatic castrate resistant
prostate cancer or breast cancer with skeletal metastases to see if it provided
significant pain palliation. Complete alleviation of pain was observed in 13%,
a partial response in 48%, and a minimal response in 25%.
The results so far look promising, and certainly warrant
expanded clinical trials.
For those interested, there is an open clinical trial (NCT00859781
) at 10
locations around the U.S., testing Lu-177-anti-PSMA plus ketoconazole and
hydrocortisone in patients with biochemical progression after primary RP or RT
and castrate-resistance, but who have no detectable distant metastases.