for localized prostate cancer

Transurethral Hyperthermia in
Combination with short time Complete
Androgen Blockade (CAB) for localized
prostate cancer
XXXI Conference International Clinical Hyperthermia Society
Budapest, Hungary
12-14 October, 2012
Friedrich R. Douwes MD
Medical Director St. George Hospital, Bad Aibling
How frequent is prostate cancer
(PCa)?
• Most frequent cancer of men
• ca. 31.500 new cases per year.
Most important risk factor is age:
• Before 50 y. Pca is extremely rare and in most cases hereditary
• more than 90 % after 60 y & older
• Between 60 y & 70y 50 of 100.000 men per year positive for Pca are
expected.
• between 75 and 85 y. approx. 400.
Friedrich R. Douwes, MD
Friedrich R. Douwes, MD
Bill-Axelson A, Holmberg L, Ruutu M et al.
„Radical prostatectomy versus watchful waiting
in early prostate cancer.“ N Engl J Med 352:19771984
• After 10 years the survival advantage for pat. with prostatectomy is 6% better compared
to wait & watch. The question is should one operate 100 men to help 6, should one harm
94% with irreversible damage ?
Friedrich R. Douwes, MD
Why is this so ?
• between the initiatian of malignancy and the clinical manifestation
of a PCa lies a long latent phase
• more than 90% of the tumors grow either slowly or stop completely
to grow
• the majority don‘t creat any symptoms or metastasis during life time
• therefore most men die with their PCa and not of their PCa
Friedrich R. Douwes, MD
What is the best treatment?
Up today it is not decided!
• Surgery (radical prostatectomy)
• Radiation
• Kryotherapy
• HiFu
• wait & watch (active survaillance) or
• Hyperthermia ?
Friedrich R. Douwes, MD
Friedrich R. Douwes, MD
Radical Prostatectomy
in T1-T3 stage has no significant
advantage according to OS
• 695 men where randomized in two groups
• Prostatectomy & watchful waiting
• after an observation time 6,5 y. the OS was in both groups
similar
(L. Holmberg et al.NEJM 347: 781 – 789 (2002)
Friedrich R. Douwes, MD
Overall survival rate in
randomized studies:
Prostatectomie versus Placebo
Placebo (50) A, Prostatectomie (61) B
5 y survival rate 75% AB
10 y survival rate 55% AB
15 y survival rate 38%
Iversen, P. et. al. (1990): Radical Prostatectomy versus expectant primary
treatment in stages I and II. Prostatic Cancer, Urology 36: 493 - 498
Friedrich R. Douwes, MD
We are in a Treatment dilemma
• since aggressive prostatectomy in localized PCa could not
show significant advantage compared to „wait & watch“
• it is to be suspected, that many men get surgery
unneccessary
• since their PCa is not aggressive and life shortening
Friedrich R. Douwes, MD
Complicationen after
Prostatectomy
Mortality
1–3%
Incontinence
15 – 30 %
Impotence
80 – 100 %
Strictures
20 %
& Reoperation
Friedrich R. Douwes, MD
Should one offer surgery or
„wait & watch“?
• Exactly this dilemma we had in 1992, when we
developed the protocol to treat localized PCa with
transurethral hyperthermia & short term hormone
ablation
• Especially since many patients push for active
treatment!
• The consideration was, how can we kill the cancer in
the prostate or how can we eliminate it without
removing the organ from the body and without harming
the complicated function?
Friedrich R. Douwes, MD
Why hyperthermia?
• Hyperthermia can selectively destroy cancer tissue if our type of
electrohyperthermia is used.
• Hyperthermia induces apoptosis, caspase 9 activity, inhibits
angiogenesis, induces p53 etc
• Hyperthermia mobilizes the bodies own immunity.
• Hyperthermie preserves the healthy tissue and keeps it functional.
Cancer tissue can be eliminated totally so that the prostate is free
of cancer.
• Hyperthermia is not aggressive and not invasive
Friedrich R. Douwes, MD
Biopsy, MRI & Spectrography,
Cholin-PET, PSA-ratio PCa3Test
Transurethral Hyperthermia &
Prostate Health Program
Information about all
treatment options.
Informed consent
• Watchful waiting
•Transurethral hyperthermia plus 6-9 month
androgen depriviation
• Radiotherapy- Cyberknife +/Hormone depriviation
•Transurtral Hyperthermia
+Androgendepriation
•Radiotherapie
•Whole Body Hyperthermia
•Complementary
•Cancer Treatment
•IPT
Symptoms
mHRPCa
Chemotherapy & IPT
Hyperthermia
Radiotherapy
Treatment protocol
• All patients receive after the application of the treatment catheter a
3 hours lasting hyperthermia
• During this time we achieve a temperature of 50-52°C
• The treatment is repeated twice one to days apart
• Treatment is carried out with local anaesthesia
• Coverage with antibiotics.
• CAB is started before the transurethral hyperthermia (TU-RF-P)
Friedrich R. Douwes, MD
Catheter Application in Transurethral
Hyperthermia (TU-RF-P)
Balloonn
Friedrich R. Douwes, MD
Friedrich R. Douwes, MD
Since Hyperthermia is mainly
oncolytic but not oncostatic!
Therefore the consideration was to add to
the oncolytic component of hyperthermia an
oncostatic component through a time limited
complete androgen blockade (CAB).
Friedrich R. Douwes, MD
Why this additional
hormone blockade?
• PCa is hormone dependant
• Androgens stimulate proliferation
• Complete androgen blockade inhibits proliferation
and causes apoptosis.
• Even in cancer cell outside the prostate e.g in the
bone marrow
Friedrich R. Douwes, MD
What is complete
androgen blockade (CAB)?
• LHRH-blocker like buserelin, goserelin, leuprorelin etc.
• 5-Alpha-Reduktase-inhibitor like Finasterid, Dutasterid
(Proscar, Avodart) and
• Androgenreceptor blocker like Bicalutamid (Casodex) or
Flutamid
Friedrich R. Douwes, MD
How is the CAB applied ?
• Trenantone (leuprorelin) every three months for six
month
• Casodex (Biculutamid) 150 mg daily for six months
• Proscar (Finasterid) 5 mg daily for six months
Friedrich R. Douwes, MD
Friedrich R. Douwes, MD
Friedrich R. Douwes, MD
Materials and Methods
• 115 Patienten, treated between January1999 and December
2000 in our biomedical Prostate Center.
• Are evaluated retrospectively
• All patients had a prostate cancer verified by biopsy
• Clinical stages were between T1 – T3.
• All patients with verfied metastases were excluded
• None of the patients had surgery or radiotherapy.
• All had denied surgery or radiotherapy and confirmed this by
their signature.
Friedrich R. Douwes, MD
Friedrich R. Douwes, MD
When did patients receive CAB ?
• All patients who qualified for the treatment
received the CAB
• one to two weeks or
• directly before or during TU-RF-P
Friedrich R. Douwes, MD
How was the follow up ?
• PSA-values after 6 weeks & 3, 6 and 12 months
• then twice per year
• Time was registered to PSA relapse.
• Clinical symptoms, side effects, the disease specifics and
overall survival were registered
Friedrich R. Douwes, MD
Patients (1)
Included: 115 Patients, who where treated
1999/2000 in Bad Aibling
Age of patients between
44 - 81 years (Mean: 64 ± 8 y)
Tumor size between T1 and
T3
Friedrich R. Douwes, MD
Tumorgrading G1 bis G3
98,3% with PSA values > 4 ng/ml
53,1% with PSA values > 10 ng/ml
Friedrich R. Douwes, MD
Time since diagnosis: 3 weeks
to10½ years (mean: 21 ± 26 months)
Friedrich R. Douwes, MD
Course of PSA from
1. Treatment over 8-10 years
Friedrich R. Douwes, MD
Patients who had a
PSA > 4 ng/ml
Friedrich R. Douwes, MD
Development of the prostate
volume during the first 3 years
after treatment with TU-RF-P
Friedrich R. Douwes, MD
Events during observation time
For 24 of 115 patients (22,9%) a PSA relapse was documented
In 12 Patients it was caused by cancer(10,4%)
All 24 patients (22,9%) had again a transurethral hyperthermia
plus hormone therapy (CAB)
for 8 patients (7,0%) with micturation problems during the
observation time, a resection was necessary, in no case PCa was
documented.
Friedrich R. Douwes, MD
Telephone
interview
• 85 patients were interviewed between 2007 and 2009 on how satiesfied they
were with the treatment:
Friedrich R. Douwes, MD
Survival time analysis (1)
Number of patient survival: 3 years: 97%,
5 years: 93%, 8 years: 87% None of the patients died of PCa
Friedrich R. Douwes, MD
Results of long term
observation: in 123 Pca patients
between 1999 - 2008
• 18/115 died that is 15.6% of the entire group.
Thereoff
• 7/18 with cardio-vascular and central problems (38,8%)
• 11/18 with cancer (61,1% )
(colon, pancreas, lung, brain)
but none from prostate cancer!
Friedrich R. Douwes, MD
Case report from PC study
TUR-RF plus CAB
• Ho. He., DOB. 1936
• March 2002
PC
verified by biopsy
Histology: Adenocarcinoma
Stage: pT2a, pN0, M0
Initial PSA: 7,13 ng/ml
• Patient rejects surgery & radiation
Friedrich R. Douwes, MD
Ho. He.
• 02/02 two transurethral thermotherapies at 48°C
& CAB
• 08/02
End of Hormontherapy
• Treatment continued with natural substances like Saw
palmetto, ß-Sitosterin, MCP, pomegranate, Indol-3-Carbinol,
Green Tea, naturally Vit. E and Vit D3.
• Hormonal restauration.
Ho. He.
Remission until today
• Last PSA 1,90 ng/ml 22.09.2011
Friedrich R. Douwes, MD
Average PSA Course
8
7
6
5
4
3
2
1
0
Initialer
Friedrich R. Douwes, MD
2002
2003
2004
2005
2006
2007
Average Testosteron Course
6
5
4
3
2
1
0
2002
Friedrich R. Douwes, MD
2003
2004
2005
2006
He. Ach.
DOB 24.11.1929
March 1990: prostate carcinoma diagnosed
Histology: pT2, Nx, Mx, G2
Initial PSA: 21,30 ng/ml
No operation, but a hormone ablation was started
Hormone therapy for about 6 years, then discontinued due to hormone
resistance
• PSA increase to 15,6
• Signs of active local cancer growth
•
•
•
•
•
•
Friedrich R. Douwes, MD
He. Ach.
• 4/96: Initial consultation at Klinik St. Georg
• 2 transurethral thermotherapies plus KAB
• 11/96: Ablative hormone therapy and androgen blockade with LHRH-Blocker Profact was discontinued, Finasterin and Bicalutamid
was continued for another 6 months.
• PSA values returned to normal
Friedrich R. Douwes, MD
He. Ach.
• Non specific immune stimulation with mistletoe lectins
• Remission until today
• Last PSA: 2,65 ng/ml (see PSA course)
Friedrich R. Douwes, MD
Average PSA Course
Friedrich R. Douwes, MD
Conclusion
• Transurethral thermotherapy is a gentle non invasive treatment,
which selectively can eliminate cancer tissue from the prostate.
• Through a concomitant CAB, this process can be supported so
that we get excellent long term results.
• The androgen blockade (CAB) lasted only six month to maximum
one year and was then finished.
Friedrich R. Douwes, MD
Conclusion
• This treatment approach shows that after 8 years 87 % of our
patients are still without a relapse.
• If these results should be verified in randomized studies, this then
could lead to a paradigm change in the treatment of PCa.
Friedrich R. Douwes, MD
Thank you for your attention.
Friedrich R. Douwes, MD
Journal of the National
Cancer Institute
2010; 102 (13)
• Outcomes in Localized Prostate Cancer:
National Prostate Cancer Register of
Sweden Follow-up Study
Pär Stattin; Erik Holmberg; Jan-Erik
Johansson; Lars Holmberg; Jan
Adolfsson; Jonas Hugosson
Friedrich R. Douwes, MD
Methods:
In the National Prostate Cancer Register of Sweden
Follow-up Study, a nationwide cohort was studied
with 6849 patients aged 70 years or younger
Inclusion criteria were:
• diagnosis with local clinical stage T1–2 prostate cancer from January 1,
1997, through December 31, 2002, a
• Gleason score of 7 or less, a
• serum PSA level of less than 20 ng/mL, and
• treatment with surveillance (including active surveillance and watchful
waiting, n = 2021) or curative intent (including radical prostatectomy, n =
3399, and radiation therapy, n = 1429).
• Among the 6849 patients, 2686 had low-risk prostate cancer (ie, clinical
stage T1, Gleason score 2–6, and serum
• PSA level of <10 ng/mL).
• The study cohort was linked to the Cause of Death Register, and
• cumulative incidence of death from prostate cancer and competing
causes was calculated.
Friedrich R. Douwes, MD
Results
• For the combination of low- and intermediate-risk prostate cancers,
calculated cumulative
• 10-year prostate cancer-specific mortality was 3.6% (95%
confidence interval [CI] = 2.7% to 4.8%) in the surveillance group
and
• 2.7% (95% CI = 2.1% to 3.45) in the curative intent group.
• For those with low-risk disease, the corresponding values were 2.4%
(95% CI = 1.2% to 4.1%) among the 1085 patients in the surveillance
group and
• 0.7% (95% CI = 0.3% to 1.4%) among the 1601 patients in the curative
intent group.
• The 10-year risk of dying from competing causes was 19.2% (95% CI
= 17.2% to 21.3%) in the surveillance group and 10.2% (95% CI = 9.0%
to 11.4%) in the curative intent group.
Friedrich R. Douwes, MD
Conclusion
• A 10-year prostate cancer–specific
mortality of 2.4% among patients with
low-risk prostate cancer in the
surveillance group indicates that
surveillance may be a suitable
treatment option for many patients with
low-risk disease
Friedrich R. Douwes, MD
Niedrigrisiko-Prostatakarzinom Progress
lässt sich verzögern
5-aReduktase-lnhibitor Dutasterid
randomisiert untersucht
• Das Problem von Screeningprogrammen für das Prostatakarzinom ist
bekannt:
• Es werden sehr viele Tumoren entdeckt, bei denen unklar ist, ob sie
dem Patienten zu Lebzeiten jemals Probleme bereiten würden.
• Andererseits fühlen sich viele Patienten unwohl bei dem Gedanken,
mit einem malignen Tumor im Körper zu leben.
• Kanadische und US-amerikanische Urologen konzipierten eine PhaseIll-Studie mit dem 5a-Reduktase-lnhibitor Dutasterid als eine nicht
invasive Option.
Friedrich R. Douwes, MD
Is their a difference in survival between
prostatectomy and watchfull waiting?
Holmberg et. (NEJM 346 (2002)781-786)
• Ca. 695 pts. with PCa T1-T2 were randomized in two groups.
• One group received no treatment only “wait & watch)
• The other group received a radical prostatectomy.
• Result: No difference in the OS after 7 years.
(NEJM 346 (2002)781-786)
• In the operated group died only 16 of PCa, in the placebo
group 31, this was counted as a 50% success of surgery over
wait& watch. But in the operated group died more of other
diseases, so that their was no difference in the overall survival
rate after 7 y.
Friedrich R. Douwes, MD
5a-Reduktase-Inhibitoren
• 5a-Reduktase-Inhibitoren blockieren die Umwandlung von
Testosteron in Dihydrotestosteron und führen dadurch zu einer
Reduktion des Prostatavolumens und einer Abnahme der
Konzentration an Prostata-spezifischem Antigen.
• Deshalb werden 5a-Reduktase-Inhibitoren, wie z.B. Dutasterid,
zur Behandlung der symptomatischen BPH eingesetzt.
• Dutasterid ist der einzige dieser Inhibitoren, der beide Isoformen
der a-Reductase hemmt.
• Die Substanz führt nicht nur zu einer mindest 90% und
hochsignifikanten Abnahme der Serumtiter von DHT, sondern
auch das Volumen von PCa wird reduziert
Friedrich R. Douwes, MD
Progressionsrisiko um 38 %
reduziert
• REDUCE-Studie konnte Dutasterid bei Hochrisikopatienten das
Auftreten von bioptisch nachweisbaren Tumoren mit einem
Gleason-Score von 5-6 um fast ein Viertel verringern (p < 0,001),
während bei Patienten mit höher gradigen Tumoren kein
Unterschied gefunden wurde.
• In 65 nordamerikanischen Universitätskliniken und Ambulanzen
wurde deshalb die REDEEM-Studie (REduction by DutastEride of
clinical progression in Expectant Management) gestartet:
• Aufgenommen wurden 302 Patienten im Alter zwischen 48 und
82 lahren mit kleinem Prostatca mit einem Gleason Score von 56, die sichcebo ein und unterzogen sich nach eineinhalb und
drei Jahren abermals einer 12-Stanzen-Biopsie.
• Primärer Endpunkt war eine Progression des Tumors, verifiziert
Friedrich R. Douwes, MD
entweder pathologisch in der Biopsie oder dadurch, dass eine
Patienten hatten weniger
Angstgefühle
• Insgesamt 289 der Patienten (96 %) erhielten nach Beginn der
Dutasterid-Behandlung mindestens eine Biopsie und wurden in
die Auswertung eingeschlossen. Innerhalb von drei Jahren
hatten 38 % der Männer in der Verum- und 48 % der Männer in
der Pla- cebogruppe eine Progression erfahren (Hazard Ratio
0,62; 95% CI 0,43-0,89; p = 0,009).
• Bezüglich der Nebenwirkungen fand sich kein dramatischer
Unterschied zwischen den beiden Studienarmen: 24 % der
Patienten in der Dutasterid- und 15 % der Männer in der
Placebogruppe berichteten entweder über sexuelle Dysfunktion
oder über eine Vergrößerung oder Empfindlichkeit der Brüste.
• Todesfälle oder metastasierte Erkrankungen. Stattdessen fanden
sich in der Verumgruppe häufiger Folgebiopsien, in denen kein
Tumor mehr zu entdecken war als im Kontrollarm.
Friedrich R. Douwes, MD
• Nach drei Jahren hatten auf Prostatakrebs bezogene
Ist Dutasterid schon eine
Behandlungsoption?
• REDEEM ist die erste randomisierte, placebokontrollierte Studie,
die eine medikamentöse Therapie als einzige Intervention in der
Nachsorge von Männern mit bioptisch festgestelltem
Niedrigrisiko- Prostatakarzinom untersuchte.
• Dutasterid kann die Progression dieser Tumoren verzögern und
bietet sich deshalb nach Ansicht der Autoren nicht nur als
Behandlungsoption für Patienten mit lokalisiertem Niedrig-RisikoProstatkarzinom an, sondern der 5a-Reduktasehemmer sollte in
künftigen Studien zur medikamentösen Therapie in dieser
Situation als Standard eingesetzt werden.
• Fleshner,NE et al. Lancet 2012;379:1103-1011
Friedrich R. Douwes, MD
Treatment for localized
prostate cancer therefore
remains controversial
• to our knowledge, there are no
outcome studies from contemporary
population-based cohorts that include
data
• on stage,
• Gleason score, and
• serum levels of prostate-specific antigen
(PSA)
Friedrich R. Douwes, MD
Friedrich R. Douwes, MD
Überlebenszeitanalyse (3)
• Verlauf des Anteils überlebender Patienten mit der Zeit in
Abhängigkeit vom PSA-Wert vor Therapie
Friedrich R. Douwes, MD
Überlebenszeitanalyse (2)
• Cox-Regression zur Untersuchung des Einflusses von Lebensalter,
Tumorgröße, Grading, PSA vor Therapie auf das Überleben
Einflussgröße
P-Wert
Cox-Regression
Alter
0,17
Tumorgröße
0,98
Grading
0,27
PSA vor Therapie
0,011
Friedrich R. Douwes, MD