| Tracks 1-22 |
| Track 1 |
PSA screening, pathologic stage migration and curability of prostate cancer |
| Track 2 |
Overall survival with treatment modalities for localized prostate cancer |
| Track 3 |
Potential advantages of radical prostatectomy for localized prostate cancer |
| Track 4 |
Risk of radiation-induced bowel
or bladder cancer and prostatorectal
fistulas |
| Track 5 |
Potential advantages of robotic and laparoscopic surgery |
| Track 6 |
Relationship between surgeon experience and rate of cure of prostate cancer |
| Track 7 |
Evolving clinical role of cryosurgery |
| Track 8 |
Opportunities for improvement in age-adjusted prostate cancer mortality |
| Track 9 |
Chemotherapy in metastatic and hormone-refractory prostate cancer |
| Track 10 |
Tolerability of and symptomatic relief with docetaxel in metastatic disease |
| Track 11 |
Treatment of PSA-only progression postprostatectomy |
| Track 12 |
Oral platinum satraplatin for hormone-refractory prostate cancer |
|
| Track 13 |
Survival associated with treatment versus watchful waiting |
| Track 14 |
Use of finasteride to enhance PSA screening |
| Track 15 |
Development of a clinical assay for prediction of recurrence risk of localized prostate cancer |
| Track 16 |
Epidemiologic evidence for prostate cancer as an infectious disease |
| Track 17 |
Single nucleotide polymorphism in HPC1, RNase L protein and viral susceptibility |
| Track 18 |
XMRV virus as a potential etiology for a subset of prostate cancer |
| Track 19 |
Update of SELECT: Selenium, vitamin E or the combination in the prevention of prostate cancer |
| Track 20 |
Inferior outcomes in African- American patients following localized therapy for prostate cancer |
| Track 21 |
Chromosomal translocations and gene fusion events and the development of aggressive prostate cancer |
| Track 22 |
Mechanism of androgen resistance in prostate cancer |
|
|
Select Excerpts from the Interview
Tracks 5-6
DR LOVE: Where are we right now with laparoscopic prostatectomy?
DR KLEIN: I believe the most important factor is the experience of the
surgeon rather than the surgical approach, because I don’t believe anybody
has demonstrated that laparoscopic or robotic approaches cure cancer more
frequently than open prostatectomy.
In fact, in some series the margin positivity rates are a lot higher, and they
probably cure it less frequently. Nor has anyone convincingly demonstrated
that return to regular activities is quicker using those approaches. As a regional
referral center with a busy practice, we see complications with all three
approaches.
Edson Pontes, Peter Scardino and I pooled our data and evaluated the likelihood
of cure based on biochemical failure after open prostatectomy based on
the number of prostatectomies performed by the surgeon (Bianco 2006).
We demonstrated that the learning curve for open prostatectomy is about
350 cases, but even surgeons who have done more than 1,700 prostatectomies
still have a learning curve, and the cure rate continues to go up based on the
experience of the surgeon.
More importantly, the data showed that surgeons who had handled more than
a thousand cases had approximately a 10 percent better cure rate than someone
who’d done fewer than that, controlling for clinical presentation parameters
(grade, stage and PSA) and pathologic parameters.
Experienced surgeons, who had performed more than a thousand prostatectomies,
had a 30 percent higher cure rate than individuals who had done 50 or
fewer prostatectomies. These are outstanding data.
If the patient has organ-confined disease with the cancer contained in the
prostate, it shouldn’t matter who operates on them in terms of cure rate. It
should be dictated by the biology of the disease, but our data clearly demonstrate
that more experienced surgeons are doing something — factors we
haven’t identified yet — that results in a higher cure rate.
DR LOVE: Could it be something related to the selection of patients?
DR KLEIN: We statistically controlled for the year the patient presented, the
prior experience of the surgeon, the grade, stage, and PSA at the time of
presentation and all the pathologic factors.
If the analysis is restricted to patients who pathologically after the fact had
cancer contained in the prostate, the cure rate is still higher for someone who’s
conducted more surgeries.
Track 8
DR LOVE: The widespread use of PSA screening has brought about a
significant stage migration in prostate cancer. What has been the effect on
the mortality rates?
DR KLEIN: The age-adjusted mortality rate for prostate cancer has decreased
by approximately 10 percent since 1987 (Jemal 2007). Although I’m not a
statistician, based on my clinical sense, that’s less than what I would have
expected.
DR LOVE: At this point, what opportunities do we have to further make an
impact on prostate cancer mortality?
DR KLEIN: I believe the greatest opportunity will be to develop biologic- or
image-based methods — most likely biologic-based — to identify which
patients have potentially lethal tumors at diagnosis or to identify when tumors
switch from indolent to potentially lethal. That will allow us to better select
treatment. We need correlative translational studies to identify markers that
tell us which patients need treatment.
Then we need to expand the established multimodality approach and develop
neoadjuvant chemotherapy regimens for patients with locally advanced or
high-risk disease, similar to what’s being done in breast and colon cancer.
Attempts to do so in a number of trials in prostate cancer have been disappointing.
However, a couple of adjuvant trials are now being conducted with
chemotherapy, and some are in the works with new biologic agents, which is
where we’re headed.
Track 11
DR LOVE: What is your clinical approach for the patient who has PSA-only
progression after prostatectomy?
DR KLEIN: Initially I consider the age and general medical condition of the
patient, and then I pay a great deal of attention to PSA doubling time, which
I believe is a highly useful clinical tool. D’Amico’s published data relating
PSA doubling time to the risk of dying of prostate cancer showed that if the
PSA doubling time was short — three months or less — the patients’ median
survival was about five years (D’Amico 2004). If the PSA doubling time was
longer than 12 months, their median survival was longer than 10 years.
I treat patients who have a PSA doubling time of three months or less with
hormone therapy and either add chemotherapy as part of a protocol or enroll
them on another study.
If the PSA doubling time is longer than 12 months, I tend to follow patients
without treatment. I counsel them that their condition is not a life-threatening
event at this point and that they can live many years with a slow PSA doubling
time.
I put the patient who has a PSA doubling time between three and six months
on hormones. If the PSA doubling time is between six and 12 months,
I recommend dietary and lifestyle interventions or a clinical trial with a
relatively nontoxic agent.
Track 22
DR LOVE: What do we know about the mechanism of androgen resistance
in prostate cancer?
DR KLEIN: We once believed that resistance to antiandrogen therapy was the
result of mutations in the androgen receptor that made them no longer sensitive
to our treatments. It turns out that prostate cancer cells that are “androgen
independent” are not resistant to androgens, but rather they are exquisitely
sensitive to even the most minute amount of androgen in the cell. That comes
about through a variety of mechanisms, including mutations and amplification
of the androgen receptor.
Thus, Labie’s belief in combined androgen blockade and the need for cellular
androgen levels to be down close to zero has a biologic basis (Labrie 2005). I
believe a major breakthrough will be the development of a new class of agents
that directly target the androgen receptor and prevent it from binding with
even the most minute amounts of androgen.
I would bet that even in men with androgen-independent disease, such agents
would add substantially to longevity, and they might also be useful as adjuvant
therapy for men with high-risk disease. I believe the problem with our current
therapies is that, although they reduce the androgen level, they probably can’t
take it all the way down to zero, and their toxicity is a little high.
Tracks 9-10
DR LOVE: Where are we right now in terms of clinical research in
adjuvant chemotherapy?
DR KLEIN: I believe more and more patients are now being treated with
docetaxel and are benefiting from it. An industry-sponsored adjuvant trial
(XRP6976J/3501) is comparing early therapy to late therapy in patients with
high-risk disease and undetectable PSA after surgery. The therapeutic intervention
is hormones with or without docetaxel (1.1).
DR LOVE: In your experience, how well is docetaxel tolerated by patients?
DR KLEIN: It depends on the cohort of patients. In the neoadjuvant setting,
the patients are usually younger men who are otherwise healthy, and they
can tolerate receiving it every week for six to eight weeks reasonably well.
The likelihood of a Grade III or IV toxicity is pretty low. I don’t have much
experience with docetaxel in the adjuvant setting, but I expect it would be
similar.
In the metastatic setting, tolerability depends on the state of the patient.
A patient who is healthy and asymptomatic will complain about the side
effects, despite the benefit. However, a patient who feels poorly, has a lower
performance status, is experiencing pain and is significantly palliated by the
docetaxel will be happy to have it and won’t complain about the side effects.
Select Publications
