Late results of the HyPro study (Hypofractionation in Prostate cancer patients) and clinical implications

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1 Late results of the HyPro study (Hypofractionation in Prostate cancer patients) and clinical implications Marjolein van Os, research technologist Erasmus MC Cancer Institute, Rotterdam, The Netherlands EORTC ROG RTT-meeting Prague, March Late results of the HyPro study Study design HyPro study in clinical practice; dose planning, imaging and scoring of toxicity Adjustments during trial Results: toxicity and survival Conclusion Now what? 1

2 Study design Randomized controlled trial for intermediate and high risk Prostate cancer patients 3 risk groups according to seminal vesicle involvement Gleason T1 - T3a T3b, T4 score PSA PSA PSA PSA < < Group 1 Group 1 Group 1 Group 2 Group 3 7 Group 1 Group 2 Group 2 Group 2 Group Group 2 Group 2 Group 2 Group 3 Group 3 Randomization between standard arm 39 x 2 Gy and hypofractionated scheme 19 x 3,4 Gy Scoring of toxicity by CRF and patient questionnaires; baseline, twice during treatment, at 3 and 6 months and then yearly (5 yrs) Aim of the study Relapse free survival: To detect an absolute reduction of 10% of the relapse rate at 5 years in the hypofractionation arm Toxicity: To demonstrate the non-inferiority of the hypo-fractionated schedule with respect to the incidence of grade 2 acute and late toxicity Highest score registered from both CRFs and patient questionnaires Health economics: The reduction in fractions means a step forward in patient s comfort and more efficient planning on the linacs. 2

3 Inclusion and Exclusion Criteria Histologically proven adenocarcinoma of the prostate No evidence of node / bone metastases WHO performance status 0-2 Intermediate and high risk PCa: T1b-T4, Gleason score 6, PSA 60 ug/l 3 risk groups according to seminal vesicle involvement Low risk excluded (T1c-2a and Gleason 3+3 and PSA 10 ug/l) Concomitant hormonal therapy was allowed Multi-centre trial 7 participating Dutch radiotherapy departments 3

4 QA and benchmarking Hypolder model for 7 institutes: Fiducials Delineation Margins 3-10mm CTV to PTV For the boost 0mm to the rectum and 3-5mm in other directions IMRT technique Finding dose constraints CKTO dose escalation study: "Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy. (Peeters ST, Int J Radiat Oncol Biol Phys Mar 15;61(4): ) 83% of the prescribed dose (=max. 64,7 / 53,6 Gy) to max 60% of the rectum volume After planning study for Elekta machines: 83% of prescribed dose to max 45% of rectal volume 4

5 Imaging protocol StereoGraphic Targeting (SGT): - fast online correction procedure - automated match on markers (Elekta XVI, TheraviewNT) 3D imaging from 2 orthogonal angles: crossfire MVI AP and kvi lateral Online position verification Automatic 3D markermatch (3 sec.) Visual check and approval (RTT) Automated remote table shift. 5

6 Describing work instructions Multiple work instructions: - Planning protocol / dose constraints, - Treatment protocol / logistics - Imaging protocol Management of PIF and toxicity forms: Scoring of acute genitourinary and gastrointestinal toxic effects according to RTOG-EORTC criteria from both case report forms and patients' self-assessment questionnaires; at baseline, twice during radiotherapy, and 3 months after completion of radiotherapy. May 2008: New planning software From 5 field to 7 field IMRT; faster, more conformal dose planning / longer treatment time XiO-plan pat 2 Monaco-plan pat 2 6

7 Adjustment Hypro-technique Due to steeper dose gradient with Monaco IMRT: PTV definition PTV1 = prostate + 5 mm, 7mm caudal direction PTV2 = prostaat + 5/7 mm + VS + 8 mm (SIB-technique) PTV3 = PTV1 = prostate + 5/7 mm: no margin reduction towards rectum PTV4 = PTV2 = prostate + 5/7 mm + VS + 8 mm: no margin reduction towards rectum PTV1 PTV2 Prostaat + 5mm marge, 7mm naar caudaal Prostaat + 5/7mm, Ves. Sem + 8 mm Decrease of rectum dose constraint 35% of the rectum volume may receive 83% prescribed dose Imaging for 7 field treatment Treatment time up to 14 minutes: need for intrafractional corrections by 1 means of isgt-procedure in beam 3 and SGT isgt 7 2 7

8 Imaging for 7 field treatment The efficacy of isgt was evaluated by quantifying the residual 2D set-up errors of the prostate markers, as derived from lateral kv images, directly after applying the SGT correction and immediately after treatment. Cumulative frequency (%) Directly after SGT After treatment with isgt After treatment without isgt Time-average with isgt D sagital plane residue errors per fraction (mm) End of study Inclusion March 2007-December patients included 8

9 Follow up at 5 years 804 patients were evaluable, (median 71) years Median follow-up was 60 months 66% of the patients received androgen deprivation therapy (ADT) Acute toxicity published in Lancet Oncology Acute toxicity GI Gastro Intestinal: Hypofrationated more grade 2 tox., 2% grade 3 in both arms, not significant 9

10 Acute Toxicity GU Genito Urinary: Hypofrationated arm less grade 2, more grade 3, not significant. Late toxicity A 100 SF HF N 387 F Logrank P = B SF HF N 387 F Logrank P =0.26 Cumulative percentage GU HF SF Cumulative percentage GI HF SF mon. 60 SF HF At risk: mon. 60 SF HF At risk: Grade 2: 39% in SF vs 41% HF (p=0.16) Grade 2: 18% SF vs 22% HF (p=0.26) 10

11 Late toxicity No significant difference between arms for grade 2 for both GU and GI Predictive factors for late toxicity: Acute toxicity triples late toxicity probability (32% vs 12%; P =.000) Age > 70 yrs 50% of this age group showing late toxicity compared with 39% of younger patients (P =.002) Hormonal therapy Patients receiving HT were more likely to show late toxicity than those who were not receiving HT (47% vs 41%; P <.001). Relapse Free Survival at 5 yrs Cumulative percentage % Hypro Standard 77% Standard Hypro N Standard Hypro Logrank P =0.36 At risk: F mon

12 Overall Survival at 5 yrs Over all survival (OS) Cumulative percentage Standard Hypro 86% Standard Hypro N Standard Hypro Logrank P =0.92 At risk: F mon Conclusion Relapse Free Survival: Hypofractionated radiotherapy (19 fractions of 3.4 Gy) resulted in higher RFS rates, but the difference was not statistically significant Toxicity: Acute and late toxicity is comparable in both arms Health economics: Although the hypofractionated schedule shows no superiority over conventional treatment, reduction in fractions was appreciated with regard to patient s comfort. RT departments can treat twice as many patients in the same time Negative trial outcome! 12

13 Now what? RFS slightly (not significantly) better in Hypofractionated arm, Saving 20 fractions per treatment is very interesting Enough evidence that 19 x 3.4Gy is not worse than the standard scheme of 39 x 2Gy Meeting of National Platform for Radiation Urology (March 16) Implement as new standard, all groups Clinical practice 2016 Current clinical practice = 6 years later; New planning and treatment technique with VMAT 13

14 Planning study 16 Compose wishlist for Hypofractionated scheme with VMAT Check results, adapt constraints? Imaging VMAT takes less treatment time, isgt abandoned SGT online with kv s, prior to treatment 14

15 Future work Modification of work instructions for Hypofractionation with VMAT Elekta Still also have Varian machines, but no planning / treatment protocol >>? In 1,5 year move to Nieuwbouw, all Elekta Special thanks Physicians: Luca Incrocci, Shafak Aluwini, Ruud Wortel Physicists: Maarten Dirkx, Hans de Boer Technologists: Mascha van der Laar, Christa Timmermans 15