Radiation Therapy in Prostate Cancer Current Status and New Advances Mahdi Aghili MD,AFSA Cancer Institute -Department of Radiation Oncology Associated Professor of Tehran University of Medical Sciences 2/11/1390

HISTORY OF RADIATION THERAPY IN PROSTATE CANCER

Radiation Modalities External Beam → Involves the use of photons and electrons ←Brachytherapy “Close therapy” Radioactive sources placed within the prostate

History of RT in Prostate Cancer

Early Prostate Brachytherapy Prostate Implant (1917)

Recognized that a superior approach would be to insert radium needles directly into the prostate More of the prostate could be treated with less damage to the urethra Radiation Therapy and Prostate Cancer Prostate Brachytherapy Urology Textbook (1926)

Radiation Therapy in Prostate Cancer Enthusiasm for brachytherapy and RT in general decreased after World War II Many patients were not cured Mainstay of treatment became surgery Excitement also surrounded discovery of the hormonal therapy

Prostate Brachytherapy Newer techniques allow seeds to be better distributed throughout the prostate Interest decreased today with permanent seed implants due to urinary side effects and advances in external beam RT

Radiation Therapy in Prostate Cancer Interest returned in the 1960s Development of megavoltage (high energy machines) Highly penetrating beams which treat the prostate without excessive skin toxicity Malcolm Bagshaw Stanford University Demonstrated that prostate cancer is curable with external beam (megavoltage) RT

External Beam Treatment Machines 1920’s Low energy Poor penetration Unable to treat the prostate without skin toxicity 1950s Moderate Energy Improved penetration Less skin toxicity Today Computer controlled Linear accelerators Multiple high energy beams IMRT and IGRT

External Beam Treatment Advancing rapidly Better, more powerful machines New sophisticated approaches - Intensity Modulated RT (IMRT) -Image-Guided RT (IGRT) - Proton Therapy

RADIATION TECHNIQUES

External Radiotherapy ( Teletherapy ) The radiation source outside of body Fractionated Higher integral dose Conventional or newer technology (3D conformal,IMRT &proton beam) Gy depend to radiation technique

Conventional vs. IMRT

IMRT in Prostate Cancer Better focusing allows us to reduce risk of toxicity to rectum and bladder Also allows us to safely use higher doses to improve cure rates Also being used to potentially reduce risk of impotence by reducing irradiation of the penile bulb

IMRT MLC Segments Intensity Map

IGRT

Prostate Movement during 8 minutes One slice each 5 seconds

Image Guided RT (IGRT) Current interest focused on image guided RT (IGRT) Method to use imaging in the treatment room to improve the delivery of IMRT Not a replacement for IMRT IMRT focuses the radiation on the prostate while IGRT ensures that it is aimed correctly everyday

Small gold seeds implanted in prostate IGRT system used to match position everyday A more sophisticated method is to perform daily CT Used to ensure proper alignment of prostate

Tomotherapy RT is delivered slice-by-slice is a form of Computer Tomogeraphy (CT) guided Intensity Modulated RadioTherapy (IMRT)

Cyberknife Radiosurgery frameless robotic radiosurgery system Small linear accelerator and a robotic arm Total body radiosurgery Image guided Multiple shuts of RT beams 1-5 fractions

Modern Brachytherapy

I-125 seed

Quality of life after seed implants Morbidity Incidence Mean duration Difficulty urinating 80-95% 6-24 months Urinary retention 12% 2 weeks Urinary Incontinence <1-2% Rectal bleeding ? Impotency 30-40%

Seed Summary Convenient out patiant treatment for early postate cancer As effecting that removing the prostate Less side effects

Why HDR Seeds are permanent Needle tracks not straight Difficult to get adequate dose in periprostatic tissue

HDR Prostate Brachytherapy Practical advantage Physical advantage Biological advantage

HDR vs. LDR Practical advantage - No worries re : Seed Supply. - No worries re : Lost Seeds. - No worries re : Radiation Exposure. - No worries re : Seed Migration. - No worries re : Seed Emboli. - No worries re : Pre-Plan Matching. - No worries re : EPE. - No worries re : SVI - No worries re : Pubic Arch. - No worries re : Volume.

RADIOTHERAPY (INDICATIONS AND RESULTS)

Radiotherapy There are no randomized studies comparing radical prostatectomy (RP) with RT either EBRT or BT for localized prostate cancer External irradiation offers the same long- term survival results as surgery; moreover, EBRT provides a quality of life at least as good as that provided by surgery* *the National Institutes of Health (NIH)-1988

In daily practice, a minimum dose of > 74 Gy is recommended with short-term androgen deprivation therapy (ADT) is recommended (based on the results of a phase III RCT) Higher Dose RT provide a significant increase in 5-year freedom from clinical or biochemical failure for patients in an intermediate-risk group -Dutch Trial :68 Gy with 78 Gy -MRC RT01 study: 64 Gy with 74 Gy -MD Anderson study specially in high risk group

Dose Escalation for HR Pca Dose escalation protocols showed that better BRFI and local control specially in high risk group - Dose radiation by 10% can increase local control by 20% - 3D Conformal, IMRT, HDR Brachytherapy boost Higher dose fractions may improve disease specific survival HDR has lower margin of healthy organ than IMRT and 3D-CRT

Result of dose escalation in HR and LR groups

Dose Escalation In cases of intermediate- or high-risk localised PCa, brachytherapy in combination with supplemental external irradiation or neoadjuvant hormonal treatment may be considered Compared to EBRT alone, the combination of EBRT and HDR brachytherapy showed a significant improvement in biochemical relapse free survival (p = 0.03)

Late effects the prospective EORTC randomised trial ( ) : -≤ 70 Gy with older RT techniques 90% of patients were diagnosed as stage T3-4 91% evaluated for urinary or intestinal complications or leg oedema 19% grade 2, 3.8% grade3 and 1% death Newer techniques (3D-CR & IMRT ) Recent data from MSKCC: grade 2 or more GI toxicity was 5% with IMRT, compared with 13% with 3D-CR and for late GU toxicity was 20% in patients treated with 81 Gy, compared with 12% in patients treated with lower doses

Incidence of late toxicity by RTOG grade Toxicity (from EORTC trial 22863)

Impotency Radiotherapy affects erectile function to a lesser degree than RP according to retrospective surveys of patients A recent meta-analysis has shown that the 1 and 2 year rate of probability for maintaining erectile function: -brachytherapy :0.76 and ERT+ BT:0.60 and External irradiation:0.55 and nerve-sparing RP:0.34 and Standard RP:0.25 and 0.25

ADJUVANT OR SALVAGE RT

Adjuvant RT Immediate post-operative for pT3 3 RCT have assessed the role of immediate post-operative radiotherapy -EORTC trial (1005 pts): pT3 pN0 with risk factors R1 and pT2R1 after RP immediate post op 60 Gy or 70 Gy after PSA rising: improves 5-year clinical or biological survival: 72.2% vs 51.8% (p < ), and 3% survival benefit after 10 yrs,risk of grade 3-4 GU toxcisitiy <3.5% ARO trial 96-02(385 pts): improvement in BFS of 72% versus 54% respectively (p = )

SWOG 8794 trial(425pts):in pT3 patients with median follow-up of more than 12 years ; adjuvant radiation significantly improved metastasis-free survival, with a 10-year metastasis-free survival of 71% versus 61% (median: 1.8 years prolongation, p = 0.016) 10-year overall survival of 74% versus 66% (median: 1.9 years prolongation, p = 0.023)

Adjuvant RT Patients with pT3 pN0 have a high risk of local failure after RP due to positive margins (highest impact), capsule rupture, and/or invasion of the seminal vesicles, who present even if with a PSA level of < 0.1 ng/mL two options can be offered to pT3 - Either an immediate radiotherapy to the surgical bed upon recovery of urinary function; or clinical and biological monitoring followed by salvage radiotherapy when the PSA exceeds 0.5 ng/ml so providing patients with the chance of about 80% being Progression free 5 years late r

Salvage treatment 1) After Radical Prostatectmy -Usually define by PSA rising -RT may curable in 50% of patients specially if PSA<1.5 ng/ml -ERT Gy to prostate bed -Hormon therapy ?? 2)After External RT -PSA rising in absent of regional or distant mets -Should be confirmed by biopsy or MRI-MRS -Hormontherapy, Brachytherapy(seed or HDR), Surgery, Cryotherapy or HIFU

Salvage treatment after Radiotherapy BRFS( 5 yrs) Complications Salvage Surgery 44-65% Incontinence 40% Stricture 25% Cryotherapy 58% Incontinence 15% fistula 10% rectal and perineal pain35% HIFU 10-50% Stricture 11%, rectal fistula up to66% Brachytherapy % (LDR) Incontinence 6%,GU (G3-4)17% 89% (2 yrs for HDR) GI 7%

Conclusion Radiotherapy is a good option as surgery in early stage prostate cancer with acceptable long term results and complications Newer techniques 3D-CRT, IMRT, IGRT, SBRT, Brachytherapy improved local control and reduced complications