Evidence based medicinefor HDR brachytherapy

prostate cancer

Prof. Roman Makarewicz

The Chair and Clinic of Oncology and Brachytherapy

Nicolaus Copernicus University

Ludwik Rydygier Collegium Medicum in Bydgoszcz

„Real-time image guided HDR brachytherapy for prostate”

21-22.11.2014 Otwock, Poland 1

Evidence-based medicine(Sackett et al. 1996)EBM is a self-styled paradigm. The explicit goal of evidence-based medicine is to make decision-makingmore rational: assessment of a new drug or a newtechnology, diagnosis, treatment

• To de-emphasize the authority of individuals

• A more effective use of available literature

• A shift away from „intuition, clinical experience and pathophysiological rationale”

• The traditional texts go out of date quickly

• The economical point of view

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Levels of evidence(Sackett et al. 2000)� 1A = Systematic Review of Randomized Controlled

Trials (RCTs)

◦ 1B = RCTs with Narrow Confidence Interval

◦ 1C = All or None Case Series

� 2A = Systematic Review Cohort Studies

◦ 2B = Cohort Study/Low Quality RCT

◦ 2C = Outocomes Research

� 3A = Systematic Review of Case-Controlled Studies

◦ 3B = Case-Controlled Study

� 4 = Case Series, Poor Cohort Case Controlled

� 5 = Expert Opinion

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Sackett et al.

Level Type of evidence

1a Evidence obtained from meta-analysis of randomized trials

1b Evidence obtained from at least one randomized trial

2a Evidence obtained from one well-designed controlled study withoutrandomization

2b Evidence obtained from at least one other type of well-designedquasi-experimental study

3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports

4 Evidence obtained from expert committee reports or opinions orclinical experience of respected authorities

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Grade of recommendationSackett et al.

Grade Nature of recommendations

A Based on clinical studies of good quality and consistency addressingthe specific recommendations and including at least one randomizedtrial

B Based on well-conducted clinical studies, but without randomizedclinical trials

C Made despite the absence of directly applicable clinical studies of good quality

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But …

� Evidence alone is never enough to guide clinicaldecision making

� Clinical expertise and experience of staff isstrongly required

� Preferences of patients

� Search for best external evidence for its validityand importance

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Searching and selectionof the required data

The traditional method of acquiring information has been the review of traditionaltextbooks. With the development of modern technology we have able to obtain current evidence.

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N = 708 pts

Surgery – 213

Radiotherapy – 495

Cohort 3 year BDFS p 5 year BDFS p

Whole cohortRPIMRT

83,591,7

0,00478,474,8

0,37

Favourable prognosis groupRPIMRT 95,1

97,3

0,4592,885,3

0,20

Intermediate prognosis groupRPIMRT 86,7

94,0

0,1386,782,2

0,46

Poor prognosis groupRPIMRT

53,885,8

< 0,00138,462,2

< 0,001

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The escalation EBRT dose from 68-70 Gy to 78-80 Gy resultsin a 10-15% decrease in riskof biochemical failure

� Local control ?� Risk of metastases ?� OS ?

The benefits:� Intermediate and high risk disease

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HDR brachytherapyas a monotherapy

�2000 – YoshiokaY, NoseT, Yoshida K. i wsp. „High-dose-rate interstitial brachytherapy as a monotherapy for localized prostate cancer: treatmentdescription and preliminary results of a phase I/II clinical trial” Int. J. Radiat. Oncol. Biol. Phys. 2000;48:675-681.

Dc = 48 – 54 Gy, Dfr = 6 Gy, 1 implant, czas leczenia 5 dni, 2 frakcje/dzień

�2001 – Martinez AA, Pataki I, Edmundson G. i wsp.

„Phase II prospective study of the use of conformal high-dose-rate brachytehrapy as monotherapy for the treatment of favourable stage prostate cancer: a feasibility report” , ibid., 2001;49:61-69.

Dc = 38 Gy, Dfr = 9,5 Gy, 1 implant, 4 frakcje/2 dni, bNED 93%

�2002 – Rodriguez RR, Demanes DJ, Altieri G. „California endocurietherapy cancer Center’s HDR monotherapy program for prostate cancer: earlyresults”, Abstract and Slide Compendium of the 11th International Brachytherapy Meeting, Santa Fe, New Mexico, 2002.

Dc = 38 Gy, Dfr = 9,5 Gy, 1 implant, 4 frakcje/2 dni, bNED 91%

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„The series included 298 early-stage prostate cancerpatients treated with HDR monotherapy and hada median follow-up time of 5.2 years. The groups weretreated with 7 Gy x 6 and 9.5 Gy x 4. 8-year biochemicalcontrol 95% with 3% Grade 3 GU and < 1% GI toxicity”.

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Autor Liczba

chorychMediana

czasu obs. m-ce

Dawka bNED Powikłania

Demanes(2011)

298 62 7 Gy x 69,5 Gy x 4

97% (5 lat) 1% GI toks.3% G3 GU

Ghilizan (2011) 173 27 12 – 13,5 Gy x 2

Grills (2004) 248 58 9,5 Gy x 4 97%

Rogers (2012) 284 35 6,5 Gy x 6 94,4% GI > 1 (brak)

Yoshioka (2011) 112 65 6 Gy x 9 85% GS ≤ 693% GS = 7

3% G3,G,U,GI

Mark (2010) 301 100 7,5 Gy x 6 79% GS > 788% GS ≤ 7

Corner (2008) 110 24 10,5 Gy x 3 100% GS ≤ 7

Barkati (2012) 79 40 10 Gy x 310,5 Gy x 311 Gy x 3

11,5 Gy x 3

88% ns

Prostate cancer –monotherapy HDR

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Prada PJ, Jimenez I, Gonzalez-Suarez H. et al. High-dose-rate interstitial brachytherapy as monotherapyin one fraction and transperineal hyaluronic acid injectioninto the perirectal fat for the treatment of favorablestage prostate cancer: Treatment description and preliminary results. Brachytherapy 2012;11:105-110.

„40 consecutive patients who had favorable localizedprostate cancer were treated with 19 Gy in single fraction. Results showed no GU or GI toxicity of Grade 2 or greater with a median follow-up of 19 months”.

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227 sequentially enrolled

Allocated to BT 26 Gy/2 fr. Allocated to BT 31.5 Gy/3 fr.

n=113 n = 107

bNED 3 ys - 93% bNED 3 ys - 97%

Median follow-up 47 months

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Liczba chorych

Dawka Średni czas obserwacji

96 m-cy

OS bNED GI≤G2 GU G3≥

HDR+IMRT 109 45 Gy IMRT16,5 – 20 Gy/3 fr. HDR

82% 87% 15,6% 2,9%

HDR 301 45 Gy/2 implanty/6 fr. 84% 88% 2,3% 4,9%

Mark RJ, Anderson PJ, Akins RS et al. „InterstitialHDR Brachytherapy + IMRT vs HDR Monotherapyfor Early Stage Prostate Cancer: Long Term Follow –

up in 410 patients” Brachytherapy Journal, 2010;54:s.48.

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Rationale for high-dose-rate boost

� EBRT dose escalation up 78-80 Gy isrequired to optimize probability of prostatecancer control

� HDR allows an unequalled degree of doseconformity to target and sparing of OAR

� The postulated low α/β ratio of prostatecancer provides radiobiological rationale for hypofractionation or HDR

� A wealth of clinical data supports its use

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No of pts 129 with intermediate and high group riskEBRT 45 Gy/25 fr., HDR 19 Gy/2 fr. Median follow-up 30 msGrade 3≥ GU and GI - 2,56%eNED – 85% at 5 years

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220 randomized

Allocated to EBRT 55 Gy/20 fr. Allocated to EBRT + BT 37.75 Gy + 17 Gy/2 n=111 n = 109

The mean bNED 4,3 years The mean bNED 5,1 years

Median follow-up 30 months (range 3-91)

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870 consecutive patients with intermediate risk

IMRT to 86,4 Gy IMRT 50,4 Gy

+ boost (BT)

bNED-81% bNED-92%

DMFS-93% DMFS-97%

DMFS – distant metastases free survival20

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Patients with intermediate risk group

� IMRT - 37,5 Gy/15 fr

� HDR 15 Gy/1 fr

Median follow-up 6,2 years

� bNED - 97%

� Clinical efficacy and toxicity are similar to their previous protocols IMRT

45 Gy/25 fr + HDR 20 Gy/2 fr23

Radiation dose to normal tissuesincluding rectal and bladder wall was significantly lower with brachytherapy(HDR or LDR) comapred to most advanced external techniques� VMAT� Cyberknife� IMPT or IMRT

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Author Isotope Dose N bNED (%)

3 years 5 years

Grado (1999) I125 160 Gy 49 pts 48 34

Pd103 120 Gy

Beyer (1999) I125 120 Gy 30 pts. - 53

Pd103 90 Gy

Lee (2008) Pd103 90 Gy 21 pts. 94 38

Tharp (2008) HDR 70 pts. 71% 3 years

Lee (2007) HDR 36 Gy/6fr. 21 pts 89% 2 years

Tena (2006) HDR 27-33 Gy/6fr. 88% 2 years

Salvage brachytherapy in patients afterEBRT

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The findings of the study suggest that:

� in terms of bNED BT approaches provide superior outcome in patients with low risk disease

� for intermediate risk disease EBRT + BT appear equivalentto BT alone and appear superior to EBRT or surgery

� for high risk combination RBRT + BT + ADT appearsuperior to more localized treatments (seeds, surgery, orEBRT alone)

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Despite significant variability in dose and fractionation usedreported bNED is high

� 95% for low risk

� 91% for intermediate risk

� 82% for high risk

Treatment is well tolerated� GI toxicity is rare

� GU toxicity 1-14% (most commonlystricture)

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For the time being there are no completedrandozmized trials comparing outcome HDR boostwith modern dose escalation image-guided EBRTOngoing trial of National Cancer Institute of Canada

Randomized trial (intermediate risk prostate cancer)

EBRT 37,5 Gy/15 fr EBRT 78 Gy/39 fr EBRT 60 Gy/20 fr

+ HDR 15 Gy/1 fr

The available data strongly suggest that HDR boost results in a higher DFS

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Conclusions

� HDR brachytherapy combined with EBRT is anexcellent option for the definitive treatment of localized prostate cancer in any risk category.

� HDR monotherapy has been playing a growningrole as a tretment’s option of low risk group of patients.

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