IN RADIOTERAPIA BEST PAPERS. Direttore Unità Operativa Complessa Radioterapia Oncologica

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1 IN RADIOTERAPIA BEST PAPERS 2014 FILIPPO ALONGI Direttore Unità Operativa Complessa Radioterapia Oncologica

2 PROSTATE RT: WHERE WE ARE GOING? RT has evolved from radium(1911) to high Technology and high precision RT became one of the standard option for prostate cancer in treatment panorama. Ballance between advantages and sequele are differently reported by urologists and radiation oncologists in regard to the correct choice for each patient.

3 PROSTATE RT: IS DOSE ESCALATION EFFECTIVE? FEBRUARY 2014 Largest dose escalation trial PHASE III trial for 862 pts randomized to receive neoadv OT +: 64Gy in 32 fr vs 74Gy in 37 fr FUP 10 years: dose escalation improve bdfs but can increase acute and late toxicity. Yes doseescalationis escalation is effective, but could increase toxicity (with old technology) Furtherimprovements in radiotherapy ut e poe e ts ad ot e apy techniques have been shown to reduce the effect of dose escalation on side effects and should be used to maintain the reported advantages of dose escalation while minimising treatment sequelae

4 PROSTATE RT: OT & DOSE ESCALATION? 56 th ASTRO MEETING San Francisco intermediate andhig risk pts randomized to: High RT dose +STAD of 4 m vs High RTdose +LTAD of 2 years 57 months of FUP Median dose 78 Gy LTAD + High RT dose is superior than STAD + High RT dose Long OT seems to be better also with high RT doses

5 RADICAL RT: ISNEW TECHNOLOGY REALLY MORE EFFECTIVE? On pts, IMRT vs observation analysis documented an avantage for IMRT group. Advantage was high risk patients with younger age and lower comorbidities IMRT > SURVIVAL, BUT ONLY IN HIGH RISK PTS

6 RADICAL RT: ISNEW TECHNOLOGY REALLY MORE EFFECTIVE? COMMENTS: 1)The absence of any information about dose prescription, when IMRT is the key point of the data interpretation, makes impossible to discern whether improved outcomes are related to IMRT by itself 2) 52.6% of the IMRT population also received androgen deprivation therapy, but ADT was not considered as covariate in statistical evaluation. ADT has already showed a major impact on the overall survival ofintermediate and high riskpca

7 RADICAL RT: ARE WE READY FOR ROUTINE HYPOFRACTIONATION? AUGUST 2014 Current studies of moderate hypofractionation (20 30 fractions) have sufficient follow up to support the safety of moderate hypofractionation. However, long term efficacy data are still lacking because of the long natural history of PCa. Extreme hypofractionation (4 5 fractions) for low risk PCa in selected nonrandomized cohorts show good short term biochemical control comparable with current conventional fractionation, but reports of high grade urinary and rectal toxicity are concerning. MODERATE HYPO IS ALLOWED EXTREME EXTREMEPREFERABLY WITHIN PROTOCOLS

8 RADICAL RT: ARE WE READY FOR ROUTINE HYPOFRACTIONATION? MODERATE HYPO IS ALLOWED EXTREMEPREFERABLY WITHIN PROTOCOLS (CENTERS WITH EXPERIENCE AND TECHNOLOGY)

9 RADICAL RT: ARE WE READY FOR EXTREME HYPOFRACTIONATION? Extreme hypofractionation in 5 sessions (SBRT)is preferable within protocols. Nevertheless, at 7 years of FUP, results of biochemical control are excellent EXTREME HYPOFRACTIONATION (SBRT) IS A PROMISING APPROACH

10 RADICAL RT: WHAT IS THE BEST HIGH TECH APPROACH? SBRT seems to bemore related ltdto GU toxicity, even if costs are less than IMRT in conventional fractionation EXTREME HYPOFRACTIONATION (SBRT) IS A PROMISING APPROACH(LOW COSTS) SELECTION OF PATIENTS IS CRUCIAL TO REDUCE TOXICITY (GU)

11 RADICAL RT: WHAT IS THE BEST HIGH TECH APPROACH? September2014 1)First, the authors did not report the scale and the grade of the toxicity. This represents a crucial bias. 2)Radiotherapy related toxicities are highly dependent on the radiation dose, fields used, and dose volume constraints. The lack of these data makes any considerations about toxicity rather speculative

12 RADICAL RT: HOW WE CAN IMPROVE OUTCOME IN HIGH RISK PATIENTS? The feasibility of weekly docetaxel associated to high dose RT + long term OT was confirmed High risk pts could deserve a multidisicplinary integration that seems to be feasible

13 RADICAL RT: IS USEFUL RT IN N+ PATIENTS? 56 th ASTRO MEETING San Francisco 2014 Observational Study 3682N+ pts 1/3 OT alone, ½ RT + OT. 5 y OS 71% in OT, 85% in Rt + OT RT+ OT approach in N+ is more effective than OT alone

14 RADICAL RT: WHAT ABOUT RELATED TOXICITIES? January pts evaluated Patients submitted to RT had higherincidence of complications However, patients submitted to RT had lower incidence of urological procedures during hospitalization. Limitations are the absence of specific type of RT (several patients treated with 2D RT) Complication after RT and prostatectomy could be frequent and depend on age, comorbidities and treatment procedure

15 RADICAL RT: WHAT ABOUT RELATED TOXICITIES?

16 RADICAL RT: WHAT ABOUT RELATED TOXICITIES? Biases of the study This study has generated much discussion because of several selection bias: retrospective comparisons selection biases patients given radiotherapy: were older, have more comorbidities, have more advanced disease. no differences between radiotherapy tecniques (EBRT, BRT) no clear definitions of toxicities

17 RADICAL RT: QUALITY OF LIFE? August 2014 Randomized trial 3994 pts: Surgery had the worst results in terms of sexual and urinary function Radiation has the worst results in terms of bowel function In both age influences after 3 years SURGERY AFFECTS MORE SEXUAL AND GU RT AFFECTS MORE INTESTINE AGE IS CRUCIAL

18 RADICAL RT: QUALITY OF LIFE? First randomized published trial for Sexual disfunction rehabilitation during RT: Sexual function could be improved by daily viagra during and after RT WE ARE LEARNING THAT SEXUAL ACTIVITY COULD BE IMPROVED FOR RT PATIENTS

19 POST OPERATIVE OPERATIVE RT: IS ADJUVANT EFFECTIVE? AUGUST pts randomized to receive RT or observation with 10 years FUP. compared with observation RT < 51% risk of biochemical relapse ART was safe RT is better than observation in pt3 and it is safe

20 POST OPERATIVE OPERATIVE RT: RANDOMIZED TRIALS Studio randomizzato Pazienti FUP mediano Outcome considerazioni RTOG 8794 (J Urology 2009) anni Metastasis free survival and overall survival a favore di RT Vantaggio di sopravvivenza solo a lungo termine EORTC (Lancet 2012) anni RT meglio di osservazione per PFS e LC a 5 anni, a 10 anni perso il vantaggio della RT vs osservazione. Margini positivi e età < 70 anni: unici forti fattori prognostici a favore di RT. No vantaggio sopravvivenza ARO anni RT meglio di osservazione per RT riduce il rischio di recidiva (European Urology 2014) PFS biochimica del 51%

21 POST OPERATIVE RT: POST OPERATIVE RT: WHO IS THE PERFECT CANDIDATE?

22 POST OPERATIVE OPERATIVE RT: WHO IS THE PERFECT CANDIDATE? November 2014 Endoresement of AUA/ASTRO GUIDELINES adding one qualifying statement: not all candidates for adjuvant or salvage RT have the same risk of recurrence or disease progression, and thus, risk benefit ratios are not the same for all men. highest risk for recurrence after radical prostatectomy include men with seminal vesicle invasion, i Gleason score 8 to 10, extensive positive ii margins, and detectable postoperative PSA. The decision to administer radiotherapy should be made by the patient and multidisciplinary treatment team, keeping in mind that not all men are at equal risk of recurrence or clinically meaningful disease progression. PERSONALIZED APPROACH BASED ON RISK FACTORS

23 POST OPERATIVE OPERATIVE RT MOST SIGNIFICANT RISK FACTORS? September 2014 COMMENTS: In conclusion, the beneficial impact of art on survivalin in patients pn1 can depend on individualized tumor characteristics. Specifically, patients who benefited from art were those with: low volume LNI ( two PLNs) in the presence of intermediate to high grade non specimen confined disease intermediate volume LNI (3 to 4 PLNs), regardless of other tumor characteristics. Conversely, all other patients with LNI did not seem to benefit significantly from art art is effective for pn1 up to 4 positive LN

24 ADJUVANT RT: HOW WE CAN IMPROVE OUTCOME IN HIGH RISK PATIENTS? RT after RP in case of PSA >0.2, GS>7 8,pT3 ADT+RT(66.6Gy)+6 6Gy)+6 Docetaxel 56 th ASTRO MEETING San Francisco 2014 RESULTS: 70% 3 years FFP vs 50 % of Hystorical data. Intentification of adiuvant approach in very high risk is feasible and seems to be effective

25 POST OPERATIVE OPERATIVE RT SALVAGE TIME? SALVAGE RT FOR PSA RISE: WHAT IS THE CUT OFF???

26 POST OPERATIVE OPERATIVE RT SALVAGE TIME? A PSA value greater than 0.2 ng/ml is an appropriate cutpoint to define PSA recurrence after RRP Freedlan et al, Urology 61 : , 369, 2003

27 POST OPERATIVE RT EARLY SALVAGE OR ADJUVANT AT ALL? COMMENTS: Ultrasensitive serum PSA measurements plays in determining who will develop BCR after radical prostatectomy and, such as, be candidates for secondary treatment. Postoperative PSA levels achieved significant predictive accuracy already on day 30. PSA >0.073 ng/ml at day 30 increased significantly the risk of BCR The kinetics of postoperative PSA decline may allow better stratification of patients who would benefit from immediate RT. EARLY SALVAGE MAY REPLACE UPFRONT ADJUVANT AT ALL BY ULTRASENSIVE PSA

28 POST OPERATIVE OPERATIVE RT HAVE WE PREDICTORS FOR SALVAGE SUCCESS? COMMENTS: 7616 pts pt3/4n0/n1 Early RT reduced cancer specific mortality only in patients with a hig risk score due to Gleason score 8 10; pt3b/4, lymph node Invasion However, because of the lack of detailed data on PSA and clinical progression, these results should be interpreted with caution. EARLY SALVAGE MAY BE MORE USEFUL IN MORE AGGRESSIVE POSTOPERATIVE SETTING

29 OLIGOMETASTASES/RECURRENCES ROLE OF LOCAL THERAPY September 2014 COMMENTS: New imaging to detect early relapse(multiparametric MRI and Choline PET). Metastasis t directed d Treatment t(surgery OR RT) is a promising approach for oligometastatic PCa recurrence RT PROMISING TO DELAY RT PROMISING TO DELAY SISTEMIC TREATMENTS IN OLIGOMTS/OLIGORECURRENCE

30 OLIGOMETASTASES/RECURRENCES LOCAL THERAPY AND WHAT ABOUT RT? COMMENTS: Metastasis directed Treatment (SURGERY OR RT) is a promising approach for oligometastatic PCa recurrence This is the first randomized phase 2 trial that will asses the possibility of deferring palliative ADT and cancer progression with metastasis directed therapy by means of SBRT or surgery. RT PROMISING TO DELAY SISTEMIC TREATMENTS IN OLIGOMTS/OLIGORECURRENCE

31 GRAZIE