Role of radiotherapy in prostate cancer.pptx

Role of Radiotherapy in management of prostate cancer
Various Guidelines included

1. Radiation Therapy in Prostate Cancer Dr Atul Gupta DM Resident Radiotherapy & Oncology AIIMS Jodhpur

2. Management Guidelines (Brief Overview) Radiation Therapy in Low Risk Disease RT in intermediate risk disease RT in high/very high risk disease Role of SBRT Role of Brachytherapy Radiation Technique & Specifications Topics to be discussed-

3. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guideline 2023

4. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guideline 2023

5. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guideline 2023

6. Radiation Therapy in low risk disease - *PSA < 10 ng/mL GS < 7 (ISUP grade 1) and cT1-2a*

7. In Low Risk Prostate Cancer – 3 Large RCTs done- PIVOT, SPCG-4 & ProtecT They reported cancer specific survival rate of 98-99% at 10 yrs for men on Active Surveillance Active Surveillance is safe in appropriately selected individuals who follow a specified surveillance protocol. Active Surveillance Watchful waiting Treatment intent Curative Palliative Follow-up Pre-defined schedule Patient-specific Assessment/markers used DRE, PSA, MRI at recruitment, re-biopsy Not pre-defined, but dependent on development of symptoms of progression Life expectancy > 10 years < 10 years Aim Minimize treatment-related toxicity without compromising survival Minimize treatment-related toxicity Eligible patients Mostly low-risk patients Can apply to patients with all stages

8. Radiation Therapy in intermediate risk disease - PSA 10–20 ng/mL or GS 7 (ISUP grade 2/3) Or cT2b

9. In Intermediate Risk Disease – Use of RT vs Surgery should not be driven by efficacy (Level 1 evidence of similar long term tumor control with either therapy)¹ If RT is used, it is recommended to be given as monotherapy in general (not to be used in combination with Brachy)¹ RTOG 0232 trial – Randomized patients to receive wither LDR brachy monotherapy or with supplemental EBRT Concluded that there was no difference in biochemical control between both arms Higher toxicities with addition of both EBRT & Brachy 1. Devita 12 th edition

10. Nodal Radiotherapy in Intermediate Risk Group- The use of nodal radiotherapy is allowed per national cancer consensus guidelines and is directed more specifically to UIR patients. However, there remains no evidence in intermediate-risk prostate cancer that nodal EBRT improves outcomes NRG/RTOG 0924 has completed accrual and primarily enrolled intermediate-risk patients, and the control arm (i.e., standard of care) is the use of prostate-only radiotherapy. Thus, the experimental arm is the addition of nodal EBRT given that there is no randomized evidence of benefit. -------  Results awaited

11. Radiation Therapy in High risk disease - Current Treatment Options- RT + long term ADT +/- Abiraterone/Prednisone Radical Prostatectomy +/- Adj RT +/- ADT PSA > 20 ng/mL or GS > 7 (ISUP grade 4/5) Or cT2c any PSA any GS (any ISUP grade) cT3-4* or cN +** (Locally Advanced)

12. Patients with T3-4, N0/ Nx , M0 prostate cancer or T1-2 disease with either prostate-specific antigen (PSA) of more than 40 g/L or PSA of 20 to 40 g/L plus Gleason score of 8 to 10 were randomly assigned to lifelong ADT alone or to ADTRT At a median follow-up time of 8 years, Overall survival was significantly improved in the patients allocated to ADTRT (hazard ratio [HR], 0.70; 95% CI, 0.57 to 0.85; P .001). Deaths from prostate cancer were significantly reduced by the addition of RT to ADT (HR, 0.46; 95% CI, 0.34 to 0.61; P .001). This study firmly establishes the role of RT in the treatment of men with locally advanced prostate cancer.

13. Duration of ADT ? Short Term vs Long term ADT

14. RTOG 9910 RT Prolonged neoadjuvant ADT does not improve outcomes ICORG 97-01 RT Prolonged neoadjuvant ADT does not improve outcomes RTOG 9202 RT 28 months superior to 4 months of ADT EORTC 22961 RT 36 months superior to 6 months of ADT DART/GICOR RT 28 months superior to 4 months of ADT with dose-escalated RT TROG RADAR RT 18 months superior to 6 months of ADT PCSIV RT 36 months not superior to 18 months of ADT Trial Name Radical Therapy Outcome

15. The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Long-term ADT significantly improved OS (HR, 0.85; 95% CI, 0.78 to 0.94) with a 12-year absolute benefit of 6.3% (2.3% to 10.4%) over short-term ADT. Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended. *P rolongation of total ADT duration in the adjuvant setting from 4–6 months to 18–36 months In UIR – short term ADT (4-6 months) recommended In High Risk/Locally advanced- long term ADT (1.5-3 yrs ) recommended

16. Abiraterone in High Risk Non-Metastatic Prostate Cancer ?

17. Non-metastatic patients randomized to receive radiotherapy + ADT versus radiotherapy + ADT + abi raterone or abiraterone plus enzalutamide . Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. 2 years of abiraterone and prednisolone added to ADT and, if indicated, radiotherapy should be considered a new standard treatment for non-metastatic prostate cancer with high-risk features. Thus , abiraterone is commonly reserved for patients with multiple high-risk features and a significantly elevated PSA . (cT3-T4, GG>4, PSA>40)

18. Docetaxel with ADT/RT in high risk non-metastatic prostate cancer ?

19. Multiple trials have evaluated the benefit of docetaxel chemotherapy in addition to radiotherapy and ADT. In general, most of these trials were negative for benefit from the addition of docetaxel, especially with long-term follow-up. D’Amico et al (JCO 2021)- A randomized trial of 350 men who were treated with radiotherapy, 6 months of ADT, and neoadjuvant and concurrent docetaxel. After a median follow-up of 10.2 years, there were no significant differences in OS between arms (HR, 0.99; 95% CI, 0.65 to 1.51; P = 0.98) NRG/RTOG 0521- A total of 563 men were randomized to radiotherapy plus 2 years of ADT +/– six cycles of docetaxel. After a median follow-up of 10.4 years, the 10-year OS rates were 64% and 69% for the control and experimental arms, respectively (HR, 0.89; 90% CI, 0.7 to 1.13; 1-sided P = 0.22). Thus, Docetaxel chemotherapy should at this time not be recommended for patients with high-risk localized prostate cancer.

20. Prophylactic Nodal Irradiation in High Risk NM Prostate Cancer ?

21. This phase III, single center, randomized controlled trial enrolled eligible patients undergoing radical radiotherapy for node-negative prostate adenocarcinoma, with estimated nodal risk ≥ 20%. Randomization was 1:1 to PORT (68 Gy /25# to prostate) or whole-pelvic radiotherapy (WPRT, 68 Gy /25# to prostate, 50 Gy /25# to pelvic nodes, including common iliac). All patients received image-guided, intensity-modulated radiotherapy and minimum 2 years of androgen deprivation therapy.  Prophylactic pelvic irradiation for high-risk, locally advanced prostate cancer improved BFFS and DFS as compared with PORT, but OS did not appear to differ. Nodal radiotherapy is commonly recommended in men with high-risk disease. This is based primarily on the fact that most high-risk trials mandated the use of nodal radiotherapy rather than a clear demonstrable benefit from nodal radiotherapy

22. Immediate Adj RT post Radical Prostatectomy

23. Study N Inclusion Criteria Randomisation Definition of BCR PSA Median FU Biochemical PFS OS SWOG 8794 2009 431 pT3 cN0 ± involved SM 60-64 Gy vs. observation >0.4 152 10 yr.: 53% vs. 30% (p < 0.05) 10 yr.: 74% vs. 66% Median time: 15.2 vs. 13.3 yr., p = 0.023 EORTC 22911 2012 1005 pT3 ± involved SM pN0 pT2 involved SM pN0 60 Gy vs. observation >0.2 127 10 yr.: 60.6% vs. 41% (p < 0.001) 81% vs. 77% n.s. ARO 96-02 2014 388 pT3 (± involved SM) pN0 PSA post-RP undetectable 60 Gy vs. observation >0.05 112 10 yr.: 56% vs. 35% (p = 0.0001) 10 yr.: 82% vs. 86% n.s . FinnProstate Group 2019 250 pT2,R1/ pT3a 66.6 Gy vs. observation (+ SRT) > 0.4 (in 2 successive measurements) 112 vs. 103 (patients alive 10 yr.: 82% vs. 61% p < 0.001 10 yr.: 92% vs. 87% n.s .

24. Early Salvage vs Adjuvant RT ?

25. Study n Inclusion criteria Randomisation Definition of BCR PSA (ng/mL) Median FU ( yr ) BPFS OS or MFS Side effects RAVES TROG 08.03/ ANZUP 2020 333 target was 470 early closed pT3a/pT3b ,any T , SM+ PSA post-RP: < 0.1 ng/mL 64 Gy ART PSA: < 0.1 ng/mL vs. 64 Gy early SRT at PSA > 0.2 ng/mL med > 0.4 post RT 6.1 5 yr.: 86% vs. 87% (p > 0.05) N.R LT grade > GU: 70% vs. 54% (p = 0.002) RADICALS RT 2020 1396 pT3a/ pT3b/pT4, PSA > 10 ng/mL, pre-RP any T, SM+ ,Gleason 7-10 PSA post-RP: < 0.2 ng/mL 52.5 Gy (20 Fx ) or 66 Gy (33 Fx ) ART early SRT identical at PSA > 0.1 med .pre-SRT: 0.2 ng/mL > 0.4 or 2 at any time 4.9 5 yr.: 85% vs. 88% (p = 0.56) N.R SR urinary incontinence 1 yr : 4.8 vs. 4 (p = 0.023) urethral stricture grade 3/4 2 yr : 6% vs. 4% (p = 0.02) GETUG-AFU 17 2020 424 target was 718 early closed pT3a/pT3b/ pT4a and SM + ,PSA post-RP: < 0.1 ng/mL 66 Gy (ART) vs. 66 Gy early SRT at PSA 0.1 both groups: 6 mo. LHRH-A med. pre-SRT 0.24 > 0.4 6.25 5 yr : 92% vs. 90% (p = 0.42) N.R LT grade > 2 GU 27% vs. 7% (p < 0.001) ED: 28% vs. 8% (p < 0.001) ARTISTIC Meta-analysis 2020 2153 see above see above see above 4.5 5 yr.: 89% vs. 88% p = 0.7 N.R N.R Early Salvage RT after RP on biochemical failure should be SOC Spares ~50% patients from pelvic radiation Acceptable option a/w lower GU toxicity

26. Radiation Dose Escalation ?

27. Local control is a critical issue for the outcome of RT of PCa . It has been shown that local failure due to insufficient total dose is prognostic for death from PCa as a second wave of metastases is seen 5 to 10 years later on. Several RCTs have shown that dose escalation (range 74–80 Gy ) has a significant impact on 10-year biochemical relapse as well as metastases and disease-specific mortality.

28. Trial n Inclusion Criteria Radiotherapy Dose Follow-up (median Outcome Results MD Anderson study 2011 301 T1-T3, N0, M0, PSA < 10 ng/mL PSA 10-20 ng/mL PSA > 20 ng/mL 70 vs.78 Gy 15 yr. DM, DSM, FFF All patients: 18.9% FFF at 70 Gy 12% FFF at 78 Gy (p = 0.042) 3.4% DM at 70 Gy 1.1% DM at 78 Gy (p = 0.018) 6.2% DSM at 70 Gy 3.2% DSM at 78 Gy (p = 0.043) No difference in OS (p > 0.05) Dutch randomized phase III trial 2014 664 T1b-T4 143 pts. with (neo) adjuvant HT 68 vs. 78 Gy 110 mo Freedom biochemical and/or clinical failure at 10 yr 43% FFF at 68 Gy 49% FFF at 78 Gy (p = 0.045) RTOG 0126 2018 1532 T1b-T2b ISUP grade 1 + PSA 10-20 ng/mL or ISUP grade 2/3 + PSA < 15 ng/mL 70.2 vs. 79.2 Gy 100 mo OS, DM, BCF (ASTRO) 75% OS at 70.2 Gy 76% OS at 79.2 Gy 6% DM at 70.2 Gy 4% DM at 79.2 Gy (p = 0.05) 47% BCF at 70.2 Gy 31% BCF at 79.2 Gy (p < 0.001; Phoenix, p < 0.001) FLAME Trial 571 EAU risk classification: Intermediate risk (15%) High risk (84%) 77 Gy (35 fx . 2.2 Gy ) vs. 77 Gy (35 Fx .) + focal boost (up to 18 Gy ) ADT (65% both arms – duration unknown) 72 mo. BFS (5 yr.) DSM (5 yr.) BFS: 92% at 77 Gy + boost 85% at 77 Gy (p < 0.001, HR: 0.45) DSM: p = 0.49 Focal boost in favour of: Local control (HR: 0.33) Distant MFS (HR: 0.58)

29. Role of Hypo-fractionated Radiotherapy ?

30. The study was based on five-year biochemical results from 14 168 patients treated with external beam radiotherapy. Treatment data from 11330 patients treated with conventional fractionation have been corrected for overall treatment time and fitted with a logit equation. The results have been used to determine the optimum α/β values that minimise differences in predictions from 2838 patients treated with hypo-fractionated schedules. The results indicate that the high fractionation sensitivity is an intrinsic property of prostate carcinomas and they support the use of hypofractionation to increase the therapeutic gain for these tumours .

31. Study/ Author n Risk, ISUP grade, or NCCN ADT RT Regimen BED, Gy Median FU, mo Outcome Lee, et al. 2016 550 542 LOW RISK NONE 70 Gy /28 fx 73.8 Gy /41 fx 80 69.6 70 5 yr. DFS 86.3% ( n.s .) 5 yr. DFS 85.3% Dearnaley , et al. CHHiP 2016 1,077/19 fx 1,074/20 fx 1,065/37 fx 15% low 73% intermediate 12% high 3-6 mo. before and during EBRT 57 Gy /19 fx 60 Gy /20 fx 74 Gy /37 fx 73.3 77.1 74 62 5 yr. BCDF( biochemical or clinical disease failure) 85.9% (19 fx ) 90.6% (20 fx ) 88.3% (37 fx ) De Vries, et al., 2020 HYPRO 403 392 30% ISUP grade 1 45% ISUP grade 2-3, 25% ISUP grade 4-5 NONE 64.6 Gy /19 fx 78 Gy /39 fx 90.4 78 89 8-yr. OS 80.8% vs. 77.6% (p = 0.17) 8 yr. TF 24.4% vs. 26.3% Catton, et al. 2017 608 598 intermediate risk 9% ISUP grade 1 63% ISUP grade 2 28% ISUP grade 3 NONE 60 Gy /20 fx 78 Gy /39 fx 77.1 78 72 5 yr. BCDF both arms 85% HR: 0.96 ( n.s )

32. To assess the effects of hypo-fractionated external beam radiation therapy compared to conventionally fractionated external beam radiation therapy for men with clinically localized prostate cancer.   The findings suggest that moderate hypofractionation (up to a fraction size of 3.4 Gy ) results in similar oncologic outcomes in terms of disease-specific, metastasis-free and overall survival. There appears to be little to no increase in both acute and late toxicity.

33. Role of Ultra-Hypo-fractionated Radiotherapy ?

34. Ultra-HFX has been defined as RT with > 3.4 Gy per fraction. It requires IGRT and (ideally) stereotactic body RT (SBRT). They included 38 studies with 6,116 patients who received RT with < 10 fractions and > 5 Gy per fraction. Five and 7-year biochemical recurrence-free survival (BRFS) rates were 95.3% and 93.7%, respectively, and estimated late grade > 3 GU and GI toxicity rates were 2.0% and 1.1%, respectively. The authors conclude that there is sufficient evidence to support SBRT as a standard treatment option for localised Pca .

35. Fourteen trials with a total of 2,038 patients were included. Median follow-up was 37 months (range 6-55 months). Most patients had cT1-T2a, Gleason ≤7 disease with median pre-treatment PSAs of 5-10; 1,042 (51%) were low-risk, 744 (37%) were intermediate-risk, 158 (8%) were high-risk, and the remainder were unreported. Doses ranged from 33.5-50.0 Gy , most typically in 5 fractions. The pooled rate of FFBF was 98% [95% confidence interval, 97-98%]. The pooled rate of late grade ≥3 gastrointestinal and genitourinary toxicities were 1% [0-5%] and 2% [1-3%], respectively.  Despite the lack of long-term follow-up and heterogeneity of the available evidence, prostate SBRT affords appropriate biochemical control with few high-grade toxicities. These data have implications for ongoing worldwide utilization of prostate SBRT as well as ongoing prospective investigations.

36. Brachytherapy in Prostate Cancer

37. Difference between LDR & HDR Brachytherapy LDR Brachytherapy • Permanent seeds implanted • Uses Iodine-125 (I-125) (most common), Palladium-103 (103Pd-) or Cesium-131 isotopes • Radiation dose delivered over weeks and months • Acute side effects resolve over months • Radiation protection issues for patient and carers HDR Brachytherapy • Temporary implantation • Iridium-192 (IR-192) isotope introduced through implanted needles or catheters • Radiation dose delivered in minutes • Acute side effects resolve over weeks • No radiation protection issues for patient or carers

38. Role of LDR Brachytherapy- Low-dose rate (LDR) brachytherapy uses radioactive seeds permanently implanted into the prostate. LDR Brachytherapy in Low/Favorable Intermediate Risk Group- In patients declining or unsuitable for AS, LDR monotherapy can be offered to those with low-risk or NCCN favorable intermediate-risk and good urinary function defined as an International Prostatic Symptom Score (IPSS) < 12 and maximum flow rate > 15 mL/min on urinary flow tests . In addition, with due attention to dose distribution, patients having had a previous TURP can undergo brachytherapy without an increase in risk of urinary toxicity. A minimal channel TURP is recommended, leaving at least 1 cm rim of prostate tissue around the post-TURP urethral defect at the postero -lateral sides of the prostate and there should be at least a 3-month interval between TURP and brachytherapy to allow for adequate healing.¹ 1. Sylvester, J.E., et al. Fifteen-year biochemical relapse-free survival, cause-specific survival, and overall survival following I(125) prostate brachytherapy in clinically localized prostate cancer: Seattle experience. Int J Radiat Oncol Biol Phys, 2011. 81: 376

39. LDR Brachytherapy in Unfavorable Intermediate/High Risk Disease- ASCEND-RT trial- External beam RT (total dose of 78 Gy ) has been compared with EBRT (total dose 46 Gy ) followed by LDR brachytherapy boost (prescribed dose 115 Gy ) in intermediate-risk and high-risk patients with 12 months of ADT in both arms. The LDR boost resulted in 5- and 7-year PSA PFS increase (89% and 86%, respectively, compared to 84% and 75%). This improvement was achieved at a cost of increased late grade 3+ GU toxicity (18% compared to 8%). Toxicity resulted mainly in the development of urethral strictures and incontinence and great care should be taken during treatment planning.

40. Role of HDR Brachytherapy- High-dose rate (HDR) brachytherapy uses a radioactive source temporarily introduced into the prostate to deliver radiation. Fractionated HDR brachytherapy as monotherapy can be offered to patients with low- and intermediate-risk PCa , who should be informed that results are only available from limited series in very experienced centers. Five-year PSA control rates of 97.5% and 93.5% for low- and intermediate-risk PCa , respectively, are reported, with late grade 3+ GU toxicity rates < 5% and no, or very minimal, grade 3+ GI toxicity rates . Single fraction HDR monotherapy should not be used as it has inferior biochemical control rates compared to fractionated HDR monotherapy.

41. EBRT Technique

42. Radiotherapy for the treatment of prostate cancer has evolved immensely over the past 40 years. High Surface dose, Low Conformality, Large Field size High Dose to normal tissues Rectal bleeding >30% More accurately defining the prostate and target volumes Smaller field sizes, Improved conformality Lower doses to normal tissues Enabled dose escalation to the prostate Rectal Bleeding 5-10% Inverse treatment planning Ideal dose to prostate and normal tissues Vast improvement in conformality Rectal Bleeding 2% CBCT scanning Continuous real-time tracking using orthogonal imaging Rectal Bleeding 1%

43. CT Simulation Technique- Prior to simulation, three fiducial markers can optionally be placed transperineally A hydrogel rectal spacer can also be inserted transperineally at time of fiducial marker placement, in order to provide temporary barrier to rectum. The spacer is reabsorbed within 6 months of placement, can significantly reduce rectal dose from EBRT. Patient Preparation- Maintaining a comfortably full bladder and empty rectum can reduce dose to normal OARs . Excessive rectal distension may be a/w worse outcomes due to geographic miss. Enema , Suppository and/or rectal tube to relieve gas distension may be considered. Immobilization- A body mould such as vaccum -locking immobilization bag (vac-loc) should be considered.

44. Simulation- CT scan from mid-abdomen to mid-femur CT should include L4-5 intervertebral disc level superiorly to below lesser trochanters inferiorly Contrast- i /v contrast- typically not required (but may be considered in selected cases where nodal anatomy may need more precise definition).

45. Adverse Effects post Radiotherapy

46. Acute Side Effects during RT – Inflammation related events – urethritis , cystitis, proctitis----  should be managed conservatively For patients with baseline obstructive symptoms/enlarged prostate It is possible to develop acute urinary obstruction requiring catheterization More common with Brachy due to acute severe reactions Patients with IPSS Score >15, should be medically optimized with alpha-blockers, potential cytoreduction with ADT , should be considered for HoLeP (Holmium Laser Enucleation of prostate) Late Urinary Toxicities- Chronic Urethritis , urethral strictures (Rare) Haemorragic cystitis (Rare) ----- managed with intra-vesicle formalin selective embolization of hypogastric arteries for refractory cases- Hyperbaric Oxygen Therapy

47. Late Rectal Toxicities- Typically manifests within first 3 yrs after RT (rare after 5 yrs ) Rectal bleeding , mucous discharge, incontinence of stool <1% patients- ulcer and fistula development Radiation induced proctitis management- Steroid Suppositories Sitz Bath Increased Dietary fibre Refractory Argon Beam Plasma Laser Coagulation Hyperbaric Oxygen Therapy Secondary Cancers After RT- Rare Occurrence Estimated to be <0.1% per decade Colonoscopy is indicated every 5-10 yearly Careful evaluation of patients presenting with hematuria to r/o possibility of secondary cancer

48. Erectile Dysfunction Rates after RT- For first 10 yrs after treatment, RT results in 10-20% more men who preserve erectile function than nerve sparing prostatectomy Other S/E- reduced/loss volume of ejaculate Short Term ADT------  most men recover testosterone within 6-12 months after completing ADT Long Term ADT------ more prolonged testosterone suppression and impact on libido and erectile function

49. Key Points regarding Radiotherapy in Prostate Cancer

50. Radiation Therapy – an integral part of management of prostate cancer irrespective of risk stratification Should be delievered with more conformal technique (preferably IGRT) In Intermediate Risk disease---  should be offered along with short term ADT (4-6 months) In High Risk Disease---should be offered along with long term ADT (18-36 months) Radiation Dose--- preferably hypo-fractionated RT (more convenient to patient without compromise in outcome) Ultra-hypo-fractionated RT(SBRT) also show good promise in management of ca prostate Brachytherapy---- can be offered as monotherapy in low grade/favorable intermediate risk group can be offered along with EBRT in unfavorable/high risk disease After Radical Prostatectomy---- Salvage RT is an acceptable option without compromise in long term outcome Prophylactic nodal irradiation---- indicated in high risk & intermediate risk disease Docetaxel-----negative results in non-metastatic prostate cancer Adverse effects with RT------ short term as cystitis, proctitis while long term as ED, urethral strictures but low incidence in era of more conformal RT and manageable