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

2. PROSTATE RT: WHERE WE ARE GOING? Comments: 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? Comments: 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. Further improvements in radiotherapy 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 FEBRUARY 2014 Yes dose escalation is effective, but could increase toxicity (with old technology)

4. PROSTATE RT: OT & DOSE ESCALATION? Comments: 352 intermediate and hig 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 56 th ASTRO MEETING San Francisco 2014

5. RADICAL RT: IS NEW TECHNOLOGY REALLY MORE EFFECTIVE? Comments: On 42483 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: IS NEW 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 of intermediate and high risk PCa

7. RADICAL RT: ARE WE READY FOR ROUTINE HYPOFRACTIONATION? Comments: 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 PREFERABLY WITHIN PROTOCOLS AUGUST 2014

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

9. RADICAL RT: ARE WE READY FOR EXTREME HYPOFRACTIONATION? Comments: 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. Comments: SBRT seems to be more related to GU toxicity, even if costs are less than IMRT in conventional fractionation RADICAL RT: WHAT IS THE BEST HIGH TECH APPROACH? -EXTREME HYPOFRACTIONATION (SBRT) IS A PROMISING APPROACH(LOW COSTS) -SELECTION OF PATIENTS IS CRUCIAL TO REDUCE TOXICITY (GU)

11. Comments: 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 September2014 RADICAL RT: WHAT IS THE BEST HIGH TECH APPROACH?

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

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

14. Comments: -32465 pts evaluated -Patients submitted to RT had higher incidence 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) RADICAL RT: WHAT ABOUT RELATED TOXICITIES? Complication after RT and prostatectomy could be frequent and depend on age, comorbidities and treatment procedure January2014

15. WRONG STUDY ! RADICAL RT: WHAT ABOUT RELATED TOXICITIES?

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

17. Comments: 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 RADICAL RT: QUALITY OF LIFE? SURGERY AFFECTS MORE SEXUAL AND GU RT AFFECTS MORE INTESTINE AGE IS CRUCIAL August 2014

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

19. POST-OPERATIVE RT: IS ADJUVANT EFFECTIVE? Comments: -388 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 AUGUST 2014

20. Studio randomizzatoPazientiFUP medianoOutcomeconsiderazioni RTOG 8794 (J Urology 2009) 43112.7 anni Metastasis free survival and overall survival a favore di RT Vantaggio di sopravvivenza solo a lungo termine EORTC 22911 (Lancet 2012) 100510.6 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 9602 (European Urology 2014) 38810 anniRT meglio di osservazione per PFS RT riduce il rischio di recidiva biochimica del 51% POST-OPERATIVE RT: RANDOMIZED TRIALS

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

22. POST-OPERATIVE RT: WHO IS THE PERFECT CANDIDATE? November 2014 Comments: -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, Gleason score 8 to 10, extensive positive 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 RT MOST SIGNIFICANT RISK FACTORS? COMMENTS: In conclusion, the beneficial impact of aRT on survival 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 September 2014

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

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

26. “A PSA value greater than 0.2 ng/mL is an appropriate cutpoint to define PSA recurrence after RRP” Freedlan et al, Urology 61 : 365-369, 2003 POST-OPERATIVE RT SALVAGE TIME?

27. POST-OPERATIVE RT EARLY SALVAGE OR ADJUVANT AT ALL? EARLY SALVAGE MAY REPLACE UPFRONT ADJUVANT AT ALL BY ULTRASENSIVE PSA 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.

28. POST-OPERATIVE RT HAVE WE PREDICTORS FOR SALVAGE SUCCESS? EARLY SALVAGE MAY BE MORE USEFUL IN MORE AGGRESSIVE POSTOPERATIVE SETTING 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.

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

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