(frequently updated)
Focal ablation is the highly targeted destruction of
cancerous prostate tissue, usually with some kind of heat or cold (called
“thermal” ablation). There has been a lot of patient interest in focal
ablation, spurred on by doctors and institutions promoting it and media
reports. There has been much hype in the last year over focal ablation using
high frequency focused ultrasound (HIFU) focal laser ablation (FLA), and photodynamic
therapy (PDT). Cryoablation has been around for the longest time of any. There
have been pilot trials of radiofrequency and microwave ablation as well. Irreversible
Electroporation (IRE) may be the only form of ablation that is non-thermal, but
so far seems to share characteristics with thermal ablation therapies. The
promotional announcements for all of these therapies are often unbalanced, so
it behooves anyone interested in pursuing it to get an understanding of the
issues involved.
I am sincerely agnostic on this subject, and am very happy
to see a potential prostate cancer therapy explored in tightly circumscribed
clinical trials where patients are informed of the risks. I do believe that
until we have learned more, clinical trials with strict protocols should be the
only circumstances under which focal ablation is performed.
I. The Hope
Focal ablation has been touted as “the male lumpectomy.”
This is a term borrowed from breast cancer. Breast cancer sometimes starts as a
single tumor (called “unifocal”) that may be cured if it is removed with a
negative margin. Just as the breast is preserved by such excision, the hope is
that prostate function, and especially the function of nearby organs (bladder,
rectum, urethra, bladder neck, neurovascular bundles, erectile function, and
continence) can be fully preserved. Let’s understand why “lumpectomy” may be
very different for the prostate.
II. Multifocality
Prostate cancer is overwhelmingly a multifocal disease.
80-90% of prostatectomy specimens have separate tumors distributed throughout
the organ. Removing the largest, highest grade tumor (called “the index tumor”)
does not remove all the cancer from the prostate.
III. Hemiablation
One way to get around the multifocality issue is to ablate
half the prostate, either the right lobe or left lobe, but not both.This is called hemiablation. The hope
is that the damage to nearby organs will be significantly reduced in so doing. Prostate
cancer often appears to predominate in one lobe. But appearances are deceiving,
even when saturation biopsies have been used to determine that the cancer was
unilateral, it turned out to be bilateral in 3/4 of those cases (
see this link), and may be as high as 90% (
see this link). With traditional TRUS biopsies, unilateral cancer was
misidentified in about 80% of men (
see this link). Multiparametric MRI is not good at finding small tumors on the contralateral side.
Pompe et al. showed that it missed cancer on the contralateral side in 58% of patients. The main
issue is that it has not been proven that hemiablation is curative. In
a study of 55 men in
Belgium who received hemiablative HIFU, a quarter of the men relapsed and
required further treatment. In a
US study of 100 men receiving hemi-ablative HIFU, followed up with a biopsy after 2 years, a quarter had relapsed with Grade Group 2 or greater prostate cancer.
IV. Index Tumor Theory
Proponents of focal ablation argue that it doesn’t matter if
there are small amounts of prostate cancer that remain untreated. Prostate
cancer, they believe, spreads by cloning daughter cancer cells from a single “parent”
tumor within the prostate. This is called “Index Tumor Theory.” Under this
theory, if the index tumor is removed by ablation, the prostate cancer will not
spread further. In theory, the small untreated daughter foci of cancer are not
malignant and will cause no further problems. In theory, the index tumor is
identifiable as the largest, highest Gleason score tumor within the prostate.
Index tumor theory relies on the findings of two studies.
Liu et al. and
Mao et al. showed that
metastases arise as clones from a single parent cancer cell. The Liu et al.
study was based on cancers from 30 men who died of prostate cancer. The Mao et
al. study confirmed the earlier study in a sample of 16 men. While both studies
showed that metastases arose from a single prostatic parent cell, they did not
show that the parent cell was in an index tumor. In fact, a case report from
Johns Hopkins
showed that lethal metastases at least sometimes could arise from a small, low
grade tumor within the prostate, rather than from an index tumor. Adding to the
complexity,
Cheng et al. found that multiple tumors had independent origins. In 15/18
tumors, they found that they arose independently rather than from a parent
tumor within the prostate, and in only 3/18 tumors they arose through
intraglandular dissemination from an index lesion. Similarly,
Wei et al. looked at prostate tumors taken from 4 patients, and found there was
considerable genetic diversity within their index tumors as well as their other
cancer foci.
Ibeawuchi et al. discovered that a unifocal tumor could be as genetically diverse as
multifocal tumors.
Løvf et al. found that the various tumors in the same prostate only rarely shared genetic mutations, suggesting independent origins.
Kneppers et al. found among 30 men with lymph node metastases that for 23%, their metastases were not clonally derived from the index tumor.
All of the above-mentioned genetic studies have been
conducted in small numbers of patients. Genetic studies are tremendously
difficult to conduct and interpret. Genetic breakdown is a characteristic of
cancer, which complicates the subjective determination of what constitutes a
clone from the index tumor.
None of this disproves index lesion theory entirely. In fact,
there must be some truth to it or focal ablation would never be effective.
Focal ablation trials with 5 years of follow-up demonstrate that focal ablation
seems to halt progression in most men. However, because the studies have not
been randomized, we cannot rule out that those mostly low risk patients were
caught early and would not have progressed appreciably in that time frame
anyway. We also know from long-term active surveillance trials that about half
of all men with confirmed low-risk tumors will eventually progress – the
smaller Gleason 6 tumors must be monitored. The most likely scenario is that
there are index tumors in some men but not others. Unfortunately, we have no
easy way of predicting which patients have index tumors and which have multiple
tumors that are capable of malignant spread.
V. Targeting the index
tumor
Assuming there is an index tumor, the next question becomes:
can we precisely locate the tumor for targeted ablation? Our best current tool for doing so is
using a multiparametric MRI (mpMRI) to target what seems to be the index tumor,
and to confirm the location with a biopsy (either ultrasound fusion or
in-bore). This poses special challenges.
Most patients who choose focal ablation are those who have
predominant Gleason pattern 3 (either Gleason score 3+3 or 3+4). mpMRI is not
at all sensitive at finding such low grade tumors if they are small; in fact,
it is no better than a standard TRUS biopsy. In
a study
of mpMRI and Ga-68-PSMA PET/CT, both imaging techniques missed more than half
the prostate tumors found after prostatectomy. Perhaps Color Doppler Ultrasound
or transperineal template mapping biopsy perform better (
see this link), but
they are seldom used. However, mpMRI is a good tool for finding larger and
higher grade tumors. In
a study at UCLA, 80% of “index tumors” were found using mpMRI. In
another UCLA study, mpMRI found that half of all men with intermediate or high-risk prostate cancer had satellite tumors in addition to their index tumor, but 2/3 of those same men were found to have satellite tumors when their prostates were surgically removed. Over half of the satellite tumors were Gleason score ≥ 3+4.
While mpMRI may detect index tumors, it is not a good tool for delineating even higher grade
tumors.
Priester et al. compared the dimensions of tumors found via mpMRI in 114 men to the
dimensions of their same tumors determined via post-prostatectomy pathology.
They found that the actual tumors were 3 times larger than their MRI estimates
– they missed 80% of the tumor’s volume by relying on the MRI. It is worth
noting too, that these MRIs were read by arguably the best radiologist in the
business, Daniel Margolis at UCLA. He literally wrote the book (PIRADS 2.0) for
interpreting mpMRIs.
In a study of 461 lesions in 441 men, the average size of tumors was only 1.6 cm on the mpMRIs but was 2.4 cm after prostatectomy. The correlation between MRI and actual size was poor (0.13- 0.65).
Pompe et al. found that mpMRI could not detect extracapsular invasion, and missed cancer in 58% of patients who had cancer in the contralateral lobe from the index tumor.
Brisbane et al. found that only 65% of biopsied clinically significant prostate cancer was within the MRI-defined region of interest.
Aker et al. found that neither MRI nor PSA were good indicators of recurrence after cryo.
If satellite tumors are to be ablated as well as the index
tumor, mpMRI performs even worse in finding them.
Hollmann et al. found that
satellite tumors were a median of 1 cm, and up to 4.4 cm, away from the index
lesion, so they would not be destroyed within the ablation zone of the index
lesion, and it would be difficult to locate them.
(Update 5/2019) Stabile et al found that mpMRI missed 30% of the significant (Gleason score≥3+4) cancer outside of the index lesion, and the missed tumors had a median length of 2.6 mm, which is smaller than anything an mpMRI can detect.
VI. Incomplete ablation
in the ablation zone
Now let’s assume you do indeed have an index tumor, and you
were able to accurately delineate it somehow, the next question becomes: Can
focal therapy be used to completely ablate the tumor? So far, the answer seems
to be – not completely. In some studies, treated patients had MRI-guided
biopsies of the ablation zone within 6 months of treatment. Cancer was found in
the ablation zone:
A. Focal Laser Ablation
(FLA):
(Update 5/2020) Feller et al. reported on the 10-year outcomes of 158 men and 248 cancer foci treated with MRI-guided FLA. All men had low or intermediate-risk prostate cancer. 122 had an MRI-targeted biopsy of their treatment sites after 6 months.
- 26% were positive with clinically significant cancer
- 15% were positive with clinically insignificant cancer
- 59% were negative
(Update 5/2021) Mehrahlivand et al. reported that 3 years after MRI-guided FLA of 15 low and favorable intermediate-risk patients, almost half had residual cancer in, adjacent to, or in close proximity to the treatment area.
(Update 5/2019) Chao et al found that 8/32 (25%) had an mpMRI suspicious for cancer in the ablation zone within 2 years after FLA (Median time to positive mpMRI in the ablation zone was 6 months). All were confirmed by biopsy. Only one of those patients had low volume GS 6. 24/32 (75%) had an unsuspicious mpMRI, but biopsy at 2 years after FLA was nevertheless positive in 9 of the 14 men (64%) who had a biopsy. So 17/22 men (77%) had a positive biopsy in the ablation zone after 2 years. Change in PSA did not predict a positive or negative mpMRI or a positive or negative biopsy.
In this study, MRI-detected cancer was found in 10/27 patients after 12 months, with cancer found in the ablation zone via biopsy in 3 patients. Cancer was found in the ablation zone in 2/9 patients (22%) in
this study,
7/10 (70%) patients in
this study that used a targeted biopsy, and 4/12 (33%) in
this study.
In one study,
2/13 (15%) had residual cancer within the ablation zone, but only 13 of 23
patients had a targeted biopsy.
Knull et al. compared the pre-operative mpMRI images with MRIs obtained immediately after FLA in 23 lesions. They found that FLA did
not completely overlap the intended ablation zone in about half of the lesions, and those tumors extended a median of 0.9 mm past the edge of the ablation zone.
B. High Intensity
Focused Ultrasound (HIFU):
Cancer was found in the ablation zone in 36% of
the patients who had biopsies for cause in
this study. In a hemi-ablation
study,
28% had biochemical recurrence and 3/8 biopsied patients (38%) had cancer in
the treated lobe. In another hemiablation
study,
16% had cancer in the ablated lobe. In a large
study
of whole gland HIFU, 29% were given a repeat treatment. Cancer was found in 42% of high-risk men in the ablation zone
in this study - 10% were given a repeat treatment. In a
US hemiablation study, 17% had Grade Group 2 or greater cancer in the treated lobe.
(Update 3/2020)
Klotz et al. reported the 1-year outcomes of an MRI-guided and MRI-thermometry HIFU-ablated kind of thermal ablation called TULSA-PRO. The favorable risk men were all biopsied a year after whole gland treatment. Cancer was found in 35% of the treated men even though they barely had a prostate left (3 ccs.) and their PSA was very low (0.5 ng/ml).
Full article here.
(Update June 2022)
Ehdaie et al. reported on 2-year biopsies of 101 intermediate risk men treated with MRI-based HIFU. 20% still had cancer in the ablation zone, 12% GS≥3+4. 60% still had cancer in the prostate, 40% GS≥3+4.
(Update 6/21/20)
Lumiani et al. reported the 16-month outcomes of 52 consecutive TULSA-PRO patients, mostly focal. 27% were positive for recurrence on follow-up MRI, and the recurrence was confirmed by biopsy in all those who had a biopsy. Recurrence rates were similar for focal and whole-gland.
(Update 3/16/23)
Duwe et al. reported the 2-year outcomes of 29 favorable risk men
treated with focal (38%) or hemi-ablation (62%) at a single center in Mainz, Germany. After 2 years, 38% had biopsy-proven recurrence, a third of those with cancer in the ablation zone, and one with numerous pelvic lymph node metastases. The trial was stopped early because of the high failure rate.
C. Photodynamic Therapy
(PDT) /TOOKAD:
In a hemiablation
study,
11/21 men (52%)had a positive biopsy in the treated lobe.
D. Cryo:
In a
whole-gland
study of
cryoablation, 37% had residual cancer in the ablated prostate. In
a study of focal cryoablation, 23/50 (46%) of patients undergoing re-biopsy were positive for PCa.
Baskin et al. reported that neither MRI or PSA were adequate indicators of progression. On biopsy, 10% of patients had residual GS≥7 cancer on the treated side, and 10% had GS≥7 cancer on the untreated side.
Aker et al. reported that on biopsy 18 months post-treatment, 35% still had clinically significant prostate cancer (only 46% had no prostate cancer), and that neither MRI nor PSA were good indicators.
E. Irreversible
Electroporation/NanoKnife (IRE):
In a
study
of focal IRE, which is largely a
non-thermal form of ablation, 4/25 patients (16%) were found to have residual
cancer in the ablation zone. In
another study that used mpMRI to detect residual cancer up to one year after treatment, 9/30 patients (30%) were found to have residual cancer in the ablation zone.
Colletini et al reported in-field treatment failures by 18% of low and intermediate-risk patients detected via mpMRI-targeted biopsy after 6 months.
Valerio et al. reported that 6/34 patients (18%) had residual disease.
Guenther et al. reported that the recurrence rate at 5 years was 5.6% for Gleason 6, 14.6% for Gleason 7, and 39.5% for Gleason 8–10.
Gielchinsky and Lev-Cohain reported that 4/13 patients had biopsy-detected recurrence.
Zhang et al. reported that 6-months after focal IRE, 46% of low- and intermediate-risk cancer still had biopsy-detected cancer outside of the ablation zone and 17% still had cancer inside the ablation zone.
So we observe that ablation is sometimes incomplete within
the treated area. There are thermodynamic and biochemical reasons that may
explain those failures.
VII. Heat Sink Effect
Most kinds of ablation (e.g., FLA, HIFU, cryo & PDT) are
thermal, which means they rely on the local application of heat or cold to
ablate the tumor tissue. The second law of thermodynamics guarantees that heat
(or cold) will never stay exactly
where it is put. This is true for the thermal energy generated by laser beams,
by ultrasound, contact with cold, or by any kind of electromagnetic energy.
Water is a very good conductor of thermal energy, and prostate tissue is mostly
water. The thermal energy always flows away from where it is placed, leaving
the ablation zone with less ablative energy, and areas around it with more
ablative energy. This translates to sub-lethal killing of cancer cells within
the ablation zone, and killing of healthy tissue outside of the ablation zone.
VIII. Urethral Proximity
Because of the need to avoid damage to the urethra, tumor proximity to the urethra precludes use of focal ablation. A
study at UCLA found that 72% of candidates had tumors within 5 mm of the urethra on whole-mount pathology. An MRI correctly predicted proximity (positive predictive value) in 84%. This would screen out most patients. However, an MRI correctly predicted there were no tumors (negative predictive value) nearby in only 52%. This error in imaging can be a source of in-field recurrence.
IX. Biochemical Effects
Human cells, especially cancer cells, have self-preservation
mechanisms that may defeat efforts to ablate them. One such mechanism is “heat
shock protein (HSP).” Whenever cells are threatened with heat, they enlist HSPs
to protect themselves. (There are actually separate “cold shock proteins” that
have been identified.) HSPs play an important role in protecting cancer cells,
and scientists are developing HSP inhibitors that may one day help other
medicines to treat cancer. HSPs are known to play a special role acting as
chaperones in bringing the androgen receptor to a more protected place inside
the cell. They also encourage cells to enter a dormant phase where they are
less subject to destruction. Cell cycle dormancy may play a role in ablation
therapy. It is possible that in malignant cells that are not destroyed, cell
cycle arrest may delay cell replication for some time. Paradoxically,
activation of HSPs may turn cancer cells more aggressive. (See
this link and
this one). This has not been studied in regard to focal ablation, but should be.
We are coming to recognize the effects that cancer cells may
have on nearby “bystander” cells. In a recent
lab study, prostate cancer cells stressed by PDT released nitric oxide that
caused bystander cells to become more aggressive. The role of extracellular
vesicles/proteasomes in promoting malignancy in nearby cells under ablation
conditions has yet to be elucidated.
X. Organ-at-risk damage/toxicity
Because of the heat sink effect, there will always be some impact on surrounding healthy
tissues. Depending on where within the prostate the index tumor is, and how
large the ablation zone is, ablation may damage the urethra, the rectum, the
bladder neck, or neurovascular bundles. In most modern trials of focal
ablation, side effects have been low, but are not zero.
At the same time, there has been much progress made in
reducing the toxicity of radical (whole gland) radiation therapy. Take for
example,
a report
of HDR brachytherapy as a monotherapy for treating intermediate risk patients,
and compare it to the
recent report by the Ahmed/Emberton group of (mostly) intermediate risk patients
treated with focal HIFU in the UK, the largest study of focal HIFU. Both studies
had 5 years of follow-up.
|
HDR brachy
|
HIFU
|
Recurrence-free survival
|
94%
|
72%
|
Potency preservation
|
82%
|
84%
|
Percent pad-free
|
97.5%
|
97.6%
|
Serious rectal injury
|
none
|
2 patients
|
Oncological control was 30% better with HDR brachy and only
required a single treatment. Sexual, urinary, and rectal late-term side effects
were equivalent for both treatments. What is the advantage of focal ablation,
then?
XI. Re-do rates
As we’ve seen, some recurrences occur within the ablation
zone, but most recurrences occur outside of the treated area. In the
above-cited report on HIFU, 28% of patients had a recurrence. This is typical
for focal ablation. An advantage often cited for focal ablation is that
patients who have a recurrence can be retreated with a second round of focal
ablation therapy. In the Ahmed/Emberton HIFU study, 25% of all patients were
treated with HIFU multiple times (others chose radical salvage therapy (7%) or permanent
hormone therapy (1%)).
In a
UCLA trial of focal ablation in 170 intermediate-risk men who were treated with partial gland cryo or HIFU, 22% had a recurrence within 2 years. Among those who were re-treated, half had a clinically significant recurrence.
“Re-do’s” incur extra costs and may increase morbidity of treatment.
There’s no guarantee that they will be effective. As we’ve seen, recurrences
are common even when the whole gland is ablated.
XII. Lack of long-term
data
The longest running studies of focal ablation, other than cryotherapy, have only 5
years of follow-up. While 5 years may be enough for therapies that are simply
an improvement over existing therapies, focal ablation requires longer
follow-up because of all the open questions that may affect long-term results.
Because many of the focal ablation patients so far have been low risk patients
who are likely to enjoy long progression-free times anyway, it is not at all
clear that the remissions are lasting ones. Both the
AUA nor the
EAU consider focal ablation to be experimental and unproven.
XIII. Tracking progression
after therapy
After radical prostatectomy, we hope that PSA will become
undetectable permanently. If it rises afterwards, we suspect recurrence. After
radical radiation therapy, PSA reaches a nadir, usually less than 0.5 ng/ml. If
it rises 2 or more points above that, we suspect recurrence. However, with
focal ablation, there is no reasonably expected PSA nadir, and there is no rise
in PSA we can label as a biochemical recurrence. The PSA changes will be
different for every patient. Because only the index tumor has been ablated, we
don’t expect PSA from small foci of cancer outside of the ablation zone to vanish,
nor PSA from BPH or prostatitis. The
Chao et al trial showed that change in PSA is not a good predictor of recurrence. Because PSA cannot be used to monitor remission, we have to use imaging
and periodic biopsies. Such imaging and biopsies requires experienced
radiologists and pathologists because ablated tissue is qualitatively different
from unablated tissue. Again, the
Chao et al trial showed that while a positive mpMRI always predicted a positive biopsy, a negative mpMRI led to a positive biopsy in most cases treated with FLA. If found to be true of other kinds of focal ablation, periodic biopsies will have to be part of routine follow-up.
XIV. Salvage after
ablation
If ablation doesn’t succeed and further ablation is either
futile or dangerous, what are the salvage options? Salvage prostatectomy is
complicated by the ablative tissue alterations, and may lead to increased
morbidity. There is no reliable data on whether or not salvage radiation is
effective after ablation failure. There are no experts in such salvage
therapies.
XV. Comparison to active
surveillance
Focal ablation is often put forward as a middle ground between
active surveillance and radical treatment. However, unlike active surveillance,
there is some risk of morbidity after focal ablation. There is no long-term
clinical evidence for the index tumor theory, and we have learned from
long-running active surveillance trials that up to half of all Gleason 6
cancers eventually progress. Because of this, the patient is actually on a lifelong
active surveillance protocol anyway: he must continue to have periodic imaging
and biopsies to track progression, but is disadvantaged by not being able to
use PSA to track progression.
Some focal ablation proponents, notably Ahmed and Emberton,
argue that focal ablation should only be offered to intermediate risk patients
and to those low risk patients who refuse active surveillance. This seems
reasonable.
XVI. Inexperienced
practitioners and practices
Focal ablation is still very new in the US, there are few
practitioners who have adequate experience, and the learning curve is steep.
There are no standard protocols. It may be years before there is consensus on
best practices.
XVII. Danger of procedures
Ablation often requires anesthesia, local or general. IRE,
for example, requires artificial paralysis and respiration throughout the
high-voltage process.
XVIII. Cost/Insurance
No form of ablation is covered by insurance or Medicare, and
out-of-pocket costs are typically in the $20,000 range. Because “re-do’s” are
often required, future costs are unpredictable. There will be ongoing costs of
periodic imaging (usually mpMRIs) and biopsies.
As with all new therapies, methods and outcomes will
undoubtedly improve over the years. This first wave of practitioners and brave
patients are taking risks that may eventually benefit many others. It is
important that patients understand those risks before making their treatment
decision.
