vakalis - rt for prostate cancer
TRANSCRIPT
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Ε. ΑΝΔΡΙΩΤΗΣ
ΚΑΡΚΙΝΟΣ ΠΡΟΣΤΑΤΗ
ΔΙΑΓΝΩΣΗΑΠΕΙΚΟΝΙΣΤΙΚΕΣ ΜΕΘΟΔΟΙ ΣΤΑΔΙΟΠΟΙΗΣΗΣ
Νεώτερα δεδομένα στην ακτινοθεραπεία του καρκίνου του προστάτη
2ο Συμπόσιο Κλινικής Ογκολογίας Ρόδου
Ακτινοθεραπευτής ΟγκολόγοςEuromedica – Αθήναιον Α & Ιατρικό Κέντρο Αθηνών
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Cancer Cases in 2013
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Cancer Deaths in 2013
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ΚΙΝΔΥΝΟΣ ΕΜΦΑΝΙΣΗΣ
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Male Cancer Mortality Rates 1930 to 2009
prostatecolorectal
stomach
lung
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CaPSURE: Risk Category at Diagnosis
0
20
40
60
80
100
1989 1990 1991 1992 1993 1994 1995 1996 1997 1999 2000 2001 2002
Pat
ient
s (%
)
High risk
Intermediate risk
Low risk
30.2%
37.3%
32.5%
25.1%
38.5%
36.4%
16.0%
37.2%
46.8%
36.6%
33.8%
29.5%
Reprinted with permission from Cooperberg MR et al. J Urol. 2003;170:S21
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Treating prostate cancer
Surgery?
Radiation?
Or Watchful Waiting?
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Κατευθύνσεις για την θεραπεία τοπικής νόσου
Ιατρικά προβλήματα ασθενούς Νοσηρότητα Ca προστάτου
Προσδόκιμο επιβίωσης (αναμενόμενη)
• Ενδοκαψική νόσος (Τ1/Τ2), Gleason score (< 7) & PSA(<10)
- Ριζική προστατεκτομή ή ακτινοθεραπεία ή παρακολούθηση
• Τοπικά προχωρημένη νόσος (Τ3/Τ4)– Ακτινοθεραπεία + Ορμονικός αποκλεισμός (LHRH ανάλογα)
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bRFS in pts with favorable tumors (T1-T2A, bGS< 6, iPSA< 10 ng/ml)
Kupelian PA, JCO 2002
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bRFS in pts with unfavorable tumors (T2b-T2c, bGS> 6, iPSA>10 ng/ml)
Kupelian PA, JCO 2002
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Long-Term Functional Outcomes after Treatment for Localized Prostate Cancer
The Prostate Cancer Outcomes Study (PCOS), comprised 1655 men in whom localized prostate cancer had been diagnosed between the ages of 55 and 74 years and who had undergone either surgery (1164 men) or radiotherapy (491 men).
Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis
• Urinary Incontinence: worse with surgery at 2 and 5 years but the same by 15 years
• Erectile Dysfunction: worse with surgery at 2 and 5 years but the same by 15 years
• Bowel Urgency: worse with radiation at 2 and 5 years' but by 15 years' the same
N Engl J Med 2013; 368:436-445
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Η ΑΚΘ ΒΕΛΤΙΩΝΕΙ ΤΗΝ ΕΠΙΒΙΩΣΗ;
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ΝΑΙ !
Η ΑΚΘ βελτιώνει την 10-ετή επιβίωση
Warde P et all Lancet 2011Widmark A et all Lancet 2009
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ΤΟΠΙΚΗ ΥΠΟΤΡΟΠΗ – ΔΟΣΗ ΑΚΤΙΝΟΘΕΡΑΠΕΙΑΣ
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Χαμηλή δόση
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το πρόβλημα λύνεται με
Αύξηση της δόσης
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Τυχαιοποιημένες μελέτες που δείχνουν το όφελος από την αύξηση της δόσης (χωρίς IMRT και ορμονοθεραπεία)
RCT N Comparison Result
Pollack(MDA)
2007 update
301 70Gy/35 vs. 78Gy/39 59% vs. 78% bPFS at 5 years
Zietman2005
393 70.2Gy vs. 79.2Gy (proton boost) 61% vs. 80% bPFS at 5 years
Peeters(Dutch)2006
664 68Gy/34 vs. 78Gy/39 54% vs. 64% FFF at 5 years
Dearnaley(RTO1)2007
843 64Gy/32 vs. 74Gy/37 60% vs. 71% bPFS at 5 years
Hoskin (Mt Vernon)
2007
220 55Gy/20 vs. 35.75Gy/13 + HDR 8.5Gy x 2 64% vs. 80% bPFS at 5 years
bPFS=biochemical progression free survival FFF= freedom from failure
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Low Risk
T1-2, GS ≤6, PSA ≤10
Memorial Sloan Kettering Cancer CenterIMRT Dose Escalation
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
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Intermediate Risk
Memorial Sloan Kettering Cancer CenterIMRT Dose Escalation
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
T1-2, GS 6, PSA > 10
T1-2, GS >6, PSA 10
T3, GS 6, PSA 10
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High Risk
GS >6, PSA >10
Memorial Sloan Kettering Cancer CenterIMRT Dose Escalation
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
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Improving the Results of Radiotherapy
Dose escalation– increasing the dose of
radiation by 10% can increase local control by 20% (level 1 evidence)
3D Conformal, IMRT, HDR Brachytherapy boost
Combination treatment with radiotherapy and androgen suppression
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Αύξηση της δόσης – Τοξικότητα
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Απώτερη Τοξικότητα στις μεγάλες μη-IMRT μελέτες αύξησης της δόσης
Γαστρεντερική Τοξικότητα Τοξικότητα από Ουροποιητικό
Grade 2 Grade 3 Grade 2 Grade 3
Κλασσική Δόση
8 – 23% 1 – 2% 6 – 28% 1 – 8%
Υψηλή Δόση(Μη-IMRT)
7 – 30% 1 -7% 10 – 30% 1 – 15 %
2 φορές μεγαλύτερος κίνδυνος σοβαρής τοξικότητας !
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Evolving Radiation
Technology
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ΤΕΧΝΙΚΕΣ ΑΚΤΙΝΟΘΕΡΑΠΕΙΑΣ
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J Urol 2001; 166: 876
≥ Grade 2 Απώτερη Τοξικότητα από Ορθό
3D-CRT: 14%
IMRT: 2%
p= 0.005
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Γαστρεντερική Τοξικότητα
Τοξικότητα Ουροποιητικού
Grade 2 Grade 3 Grade 2 Grade 3
Κλασσική Δόση
8 – 23% 1 – 2% 6 – 28% 1 – 8%
Υψηλή Δόση(Μη-IMRT)
7 – 30% 1 -7% 10 – 30% 1 – 15 %
Υψηλή Δόση(IMRT)
1 – 2% 0 – 3% 9 – 23% 0 – 6%
Απώτερη Τοξικότητα στις IMRT μελέτες αύξησης της δόσης
Κίνδυνος σοβαρής τοξικότηταςΧαμηλή δόση χωρίς IMRT = Υψηλή δόση με IMRT
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Μέτρια Υποκλασματοποίηση
8 εβδομάδες θεραπείας είναι απαραίτητες;
Οι κλινικές μελέτες
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• Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer
• Hypothesis: hypofractionated radiotherapy schedules for localised prostate cancer will improve the therapeutic ratio by either:
a) Improving tumour control
b) Reducing normal tissue side effects
CHHiP Trial
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T1B - T3A N0 M0 Estimated Risk of SV involvement ≤ 30% PSA ≤ 30ng/ml
Randomise
Group 1
74Gy / 37F 7.5 weeks (Standard)
Group 2
60Gy / 20F 4.0 weeks (Hypofractionation)
Group 3
57Gy / 19F 3.8 weeks (Hypofractionation)
Trial Schema
CHHiP Trial
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T1c-2aGS <7PSA <10
73.8 Gy/41 Fx
70 Gy/28 Fx
RTOG 0415 Schema
n=800Endpoint is 5 Year BFFF Non-inferiority margin 7% (Control 85%, Exp 78%)
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Cyberknife
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SBRT cheaper but more toxic than IMRT for Prostate Cancer
The study results were published online March 10 in theJournal of Clinical Oncology.
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CT scan is obtained at the time of the Simulation
Fiducials may be inserted before this step. CT images are then imported into the treatment planning computer
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bladder
Radiation zone
prostate
rectum
Goal = radiation zone precisely around the prostate cancer with small margin
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IMRT (intensity modulated radiation therapy)
using 7 different beams to target the prostate
The computer can determine the optimal number of beams to deliver the radiation dose to hit the target and avoid other structures
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Prostate
Seminal Vesicles
Courtesy: Chester Ramsey
Prostate
Seminal Vesicles
Alignment on markers Alignment on mid gland prostateΚίνηση του προστάτη
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AP 4.15 mm
SI 3.14 mm
RL 1.92 mm
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There is significant movement of the prostate gland based on daily gas in rectum
Planned target
Rectal gas
No Rectal gas
Planned target, missed badly if rectal gas pushes the prostate forward
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Rectal balloon
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After IMRT was established then IGRT (image guided) was introduced
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Lower Risk of Side Effects with Image Guided IMRT compared to IMRT
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Is there ever a need for radiation after a man has already had his prostate removed
PostOp Radiation (Adjuvant Therapy) if the pathology report from the surgery raises the concern: “was the cancer completely removed?”
Salvage Radiation
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Ορισμοί
• Άμεσα μετεγχειρητική (adjuvant) – Μη ανιχνεύσιμο PSA μετεγχειρητικά– Α/θ σε 3-12 μήνες (αφού βελτιωθεί η ακράτεια)
• Ακτινοθεραπεία διάσωσης (salvage)– Ανιχνεύσιμο PSA μετεγχειρητικά– ↑ του PSA αφού πρώτα μηδενιστεί
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NCCN Advice on PostOp Radiation
RP (radical prostatectomy) PLND (pelvic lymph node dissection) RT (radiation therapy) ADT (androgen deprivation therapy e.g. Lupron)
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Adverse Features
1.Positive Surgical Margins2.Invasion into the Seminal Vesicles3.Extracapsular Extension4.Detectable PSA (after surgery the PSA
should fall to undetectable by a few weeks)
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Impact of Path Reporting Positive Surgical Margins
Risk Group + Margins - Margins
Low risk 5.1% 0.4%Intermediate 17% 6.5%High 43% 21.5%
Odds of a PSA Relapse
J Urol. 2010;183(1):145.
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PostOp Radiation…does it work?
SWOG 8794 Trial path (425 men) = extraprostatic extension after surgery
10 Year PSA Cure Rate (seminal vesicle)
Surgery Only 12%Surgery Plus Radiation 36%
EORTC (1005 men)
5 Year Cure Rate if Positive Margins
Surgery Only 49%Surgery Plus Radiation 78%
German Study (Wiegel, 268 men)
5 Year Cure Rate all T3
Surgery Only 54%Surgery Plus Radiation 72%
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Survival Benefits from PostOp Radiation for High Risk Patients
RT RTRT
No RT No RTNo RT
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Άμεσα μετεγχειρητική ή α/θ διάσωσης;
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Is it Better to Treat PostOp for High Risk Features or to Wait and Treat later if the PSA starts rising (salvage)?
8 Year Specific Survival by Group and Therapy
Immediate RT DelayedPositive Margins 91% 67%Extra-capsular Spread 92% 75%Gleason 7 88% 72%Node Metastases 88% 68%
Role of postoperative radiotherapy after pelvic lymphadenectomy and radical retropubic prostatectomy: a single institute experience of 415 patients
Cozzarini. IJROBP 2004;59:674
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Χρόνος έναρξης της άμεσης α/θ
≥ 3 επεισόδια ακράτειας : στους 6 μήνες: 33%, στους 12 μήνες: 18%, στους 24-60 μήνες: 15%
Στα περισσότερα κέντρα 3-12 μήνες μετεγχ/κά αφού αποκατασταθεί η εγκράτεια• Δεν φαίνεται να επηρεάζει την νόσο• Η πολύ πρώιμη έναρξη → ↑ του % απώτερης
τοξικότητας από το ουροποιητικό
Feng et al, IJROBP, 2005
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Salvage Radiation: if months or years after surgery the PSA blood tests starts rising again
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Salvage Radiation…does it work?
Depends…
Original Pathology What was the Gleason? Where the surgical margins clear? Did the cancer involve the seminal vesicles or lymph nodes? Was there extra-capsular spread?How long ago was the surgery?How fast is the PSA rising (doubling time)?How high the did PSA get before deciding to try radiation?How high a dose of radiation will be used?
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http://www.mskcc.org/cancer-care/adult/prostate/prediction-tools
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http://nomograms.mskcc.org/Prostate/SalvageRadiationTherapy.aspx
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http://nomograms.mskcc.org/Prostate/SalvageRadiationTherapy.aspx
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Does Salvage Radiation Improve Survival?
Mayo (2657) No improvement in 10 y mortality (70% versus 69%)
Hopkins (635) Improved cancer mortality at 10 years 86% versus 62%
Duke (519) All cause mortality at 11 years was reduced by 47%
J Urol. 2009;182(6):2708JAMA. 2008;299(23):2760.
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ΑΚΤΙΝΟΘΕΡΑΠΕΙΑ ΣΤΟΝ ΠΡΩΙΜΟ ΚΑΡΚΙΝΟ ΤΟΥ ΠΡΟΣΤΑΤΗ
• Εξωτερική ακτινοθεραπεία (EBRT)– Σύμμορφη τρισδιάστατη ακτινοθεραπεία (3 Dimensional Conformal Radiotherapy
– 3D CRT)– Τρισδιάστατη ακτινοθεραπεία διαμορφούμενης έντασης (Intensity Modulated
Radiation Therapy – IMRT/VMAT-IGRT)– Ακτινοθεραπεία με πρωτόνια (Proton Beam Radiation Therapy)– Στερεοτακτική ακτινοθεραπεία του προστάτη (Stereotactic Radiotherapy)
• Βραχυθεραπεία– Μόνιμα εμφυτεύματα χαμηλού ρυθμού δόσης(LDR) (seeds I-125 ή Pd-103)– Προσωρινά εμφυτεύματα υψηλού ρυθμού δόσης (HDR) (Iridium-192 sources)
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ΕΜΦΥΤΕΥΣΗ ΚΟΚΚΩΝ
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ΕΝΔΕΙΞΕΙΣ ΒΡΑΧΥΘΕΡΑΠΕΙΑΣ ΤΟΥ ΠΡΟΣΤΑΤΗ (LDR)
RECOMMENDED OPTIONAL INVESTIGATIONAL
Do well Fair Do poorly
PSA (ng/ml) <10 10-20 >20
Gleason Score 5-6 7 8-10
Stage T1c - T2a T2b - T2c T3
IPSS 0 - 8 9 - 19 >20
Prostate Volume (g) <40 40 - 60 >60
Q max mls/sec >15 15 - 10 <10
Residual Volume cc >200
TURP +/- +
ESTRO/EAU/EORTC recommendations on seed implantation for localized prostateCancer. Ash D et al. Radiother Oncol; 2000: 57, 315-321
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HDR brachytherapy
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88
HDR
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τελευταίες σκέψεις
Εξωτερική Ακτινοθεραπεία ασφαλής και δραστική• βελτιώνει την επιβίωση με αποδεκτή τοξικότητα σε υψηλού κινδύνου και τοπικά προχωρημένο Ca• αύξηση της δόσης προκαλεί καλύτερο έλεγχο (level 1 evidence)
Τεχνολογία που διατίθεται στην ΑΚΘ πολύ προχωρημένη • αυξάνει τη συνολική δόση• χορηγεί υψηλή δόση ανά συνεδρία• μειώνει τον συνολικό χρόνο θεραπείας• παρακολουθεί τη κίνηση του προστάτη κι εντοπίζει ακριβώς το στόχο
Είναι υπευθυνότητα των γιατρών να γνωρίζουν ποιες περιοχές να ακτινοβολήσουν, πώς να σχεδιάσουν τη θεραπεία και πότε πρέπει να ακτινοβολήσουν