Jeffrey Tuan, FRCR Radiation Oncology National Cancer ...oncologypro.esmo.org/content/download/100792/... · Session 2: Localized prostate cancer Role of radiotherapy Jeffrey Tuan,

Session 2: Localized prostate cancer

Role of radiotherapy

Jeffrey Tuan, FRCR

Radiation Oncology

National Cancer Centre Singapore15 Dec 2016

Structure

• Modern treatment technique

• Dose escalation – Hypo fractionation; SBRT;

HDR

• Permanent seed implantation; LDR

• Combination with hormonal treatment (intermediate and high-risk)

• Side effects

15/12/2016 2016 ESMO Prostate Cancer Preceptorship 2

Mechanism of Action of RT

• Radiotherapy causes DNA Damage

• Ionizing the atoms making up DNA to cause double-stranded breaks

• Direct: Direct Ionizing damage to DNA

• Indirect: Indirectly ionizing via formation of free radicals (majority)

• Fate of irradiated cells:

• No effect

• Apoptosis (early)

• Cell senescence

• Mitotic catastrophe (late)


4 field technique of prostate and pelvic lymph nodesMoss and Cox, textbook of Radiation Oncology 1990


EBRT

• Cornerstone of curative management of localized

prostate cancer

– 25% for patients <65 years

– 50% patients >65 years

• 1990s: dose escalation 64-60>70-74>76-80Gy

– 5 year FFBF (L,I,H): >90%, 60-85%, 50-70%

– 10 year FFBF (L,I,H): 45-90%, 40-60%, 20-50%

– 5 year OS/DM/CSM: 82-97%/1-14%/0-8%

– RTOG late G3 <5% (depends on 3DCRT vs. IMRT)


Dose escalation

RCT show dose escalation >70Gy associated with improved bDFS

• If dose >75Gy use of IMRT with daily image guidance essential

– Low risk: 75.6-79.2Gy

– Intermediate to High risk: 75.6 -81.0Gy

• PTV whole prostate with 1cm margin all around except posterior 0.5-1cm

• Pelvic LN should be treated in all high risk patients or PLN risk >15% to dose of 45-48.6Gy

• Dose to Enlarged PLN 54-79.2Gy

Rectal bleeding (Laser-surgery, Transfusion) 3D-CRT

Peeters et al IJROBP 61:1019, 2005


Evolution of RT techniques

• 3DCRT to IMRT

– IGRT: portal imaging, kv

kv, fiducials, MVCT, CBCT,

intra-fraction, tracking

– VMAT

• Enable Dose escalation

• Decreased toxicities

(GI); GU similar


Intensity-modulated Radiation therapy, proton therapy, or conformal radiation

therapy and morbidity and disease control in localized prostate cancerSheets et al., JAMA 307, 2012

• IMRT lowers probability of new tumor treatment


Image guided RT (IGRT): in room 3D tools

Trans-perineal ultrasound systemUsed for image registration, set up and monitoring of intra-fractional movement


Improved outcome with IGRT

• N=376, TD 86.4Gy IMRT

• 186 with daily IGRT

• 190 without daily IGRT

• Med FU: 2.8 years

Zelefsky et al. , Int J Radiat Oncol. Biol. Phys. 2012


Dose escalationDearnaley at al, Lancet Oncol 15, 2014

• RT01 Dose escalation trial

• 843 patients– N=421: 64Gy -32Fx

– N=422: 74Gy -37Fx

– T1-T3a N0 M0

– PSA <50ng/ml

• Neo adjuvant ADT 6-9 mo

• Med FU 10 years

• OS no difference

• bNED:20% benefit


Biochemical failure at 10 yearsHou et al , J Cancer Res Clin Oncol, 2014


Overall survivalHou et al , J Cancer Res Clin Oncol, 2014


RT fractionation Arcangeli and Greco Nat Rev Urol 2016 Jul; 13(7):400-8


Dose and fractionation

• RT is delivered in fractions over several treatment sessions.

– Protects non-malignant tissues: • Repair of sub lethal damage

• Repopulation of cells in between fractions.

– Increases tumor damage: • Re oxygenation of hypoxic cells

during treatment, causing them to be more radiosensitive

• Redistribution of tumor cells into more radiosensitive phases of the cell cycle


Hypo fraction: what is α/β?

• α/β ratio: Suggests response of different tissues to ionizing radiation.– Dose where linear and quadratic

component cause the same amount of cell killing.

• Large ratio: Suggests early-responding tissues– More sensitive to radiation

– Less affected by fraction size

• Small α/β ratio: Suggests late-responding tissues– Less sensitive to radiation

– More affected by fraction size


Hypo fraction: what is α/β?

• Radiobiological description (for radiation sensitivity)

• Estimated on the basis of experimental and clinical data

• Normal: is high (>8) for tumor

• For PCA: reported to be 1.5 +/-0.3 (Fowler at al, Acta Oncologica 44(3):265-276, 2001)

• Lower than rectum and bladder (~5)

• Suggest significant fractionation sensitivity

• Higher single doses (>2Gy) better


Hypo-fractionated radiotherapy for organ-confined

prostate cancer: is less more? Arcangeli and Greco Nat Rev Urol 2016 Jul; 13(7):400-8

• Conventional fractionated vs. hypo fractionated similar outcomes

• 50-66Gy in 2.1-3.5Gy/#

– 5 year FFBF (L,I,H risk): >90%, 60-85%, 50-70%

– 10 year FFBF: 45-90%, 40-60% 20-50

– Late GU and GI similar


Conventional versus hypo fractionated high dose radiotherapy for prostate cancer: 5-

year outcomes of the randomized, non-inferiority, phase 3 CHHiP trialDearnaley et al 17: 1047-60 Lancet Oncol 2016


Conventional versus hypo fractionated high dose radiotherapy for prostate cancer: 5-

year outcomes of the randomized, non-inferiority, phase 3 CHHiP trialDearnaley et al 17: 1047-60 Lancet Oncol 2016

• Biochemical failure-free rates: hypo

fractionation 60Gy/20# non-inferior

to conventional fractionation (HR

0.84, 90% CI 0.68-1.03, p=0.0018)

• Overall survival: no significant

difference between all groups


Clinical recommendation

• Can be recommended as an alternative to conventional fractionation for carefully selected patients

• Efficacy and toxicity are similar to conventional fractionated IMRT in most trials – at least at early time point (5yr follow up)

• Shorter fractions beneficial in improving health-related quality of life

– Shorter duration of treatment

– Fewer days off work

• Data mostly for primary treatment – insufficient data for hypo fractionation in adjuvant setting


SBRT

• Extreme hypo fractionation

• Taking advantage of low

α/β• Short follow up (~5years)

• 36.25Gy/5#

• 5 year FFBF: >85% for low

risk patients

• Seems to result in greater GI

toxicity


How is SBRT delivered?


EvidenceArcangeli and Greco Nat Rev Urol 2016 Jul; 13(7):400-8


• 8 institutions, 2003-2011

• 1110 pts. Localized PCA

• SBRT using Cyberknife system

• Med. Dose 36.25Gy, 4-5#

• Med. FU 36moKing et al, Radiother. Oncol. 2013


Katz et al Front Oncol. 2014 Oct 28;4:301


ASTRO SBRT model policy

• Consider cautiously as an alternative to conventional fractionated regimens.

• The evidence is not strong enough to justify widespread use

• Requires longer follow-up data (>10 years)

• Larger scale studies (multi-institution)

• But the current interim data suggest that it is at least as good as other types of RT for patients with equivalent risk levels.


HDR

• HDR after loader, planning

systems

– a/b of prostate cancer (~1.5)

• Iridium source

• Low risk: Monotherapy (short

follow up) 31.5-38Gy in 3-4#

• High risk: Boost (19-21gy 2#;

15gy/1#) with EBRT 45Gy


LDR: permanent implants

Permanent implants; 145Gy/125Gy

Iodine125 /palladium 103 (monotherapy for

low, low intermediate risk)

PSA<15, GS6-7, T1-2c

5 year FFBF: >85%, 69-97%, 63-80%

As boost: 5 year FFBF 85%

Similar OS DM CSM as EBRT

Contraindications: no rectum, large gland size,

pubic arch interference, large TURP, low peak

flow, fit for anesthesia

Toxicity: urinary stenosis

Advantages: less radiation exposure to bladder and

rectum, low risk of RT toxicity due to short range of

radiation, low rates of impotence

Disadvantages: anesthesia, radiation protection

issues, higher irritative and voiding problems


Multi-institutional analysis stage T1-2 with LDRZelefsky et al., Int. J. Radiat. Oncol. Biol. Phys. 67,2007

• I-125 dose >130Gy D90: 8 years bNED 93% vs. 76% (p<0.001)

• Quality of implantation important


Comparative analysis of prostate-specific antigen free survival outcomes for patients

with low, intermediate and high risk prostate cancer treatment by radical therapy

Results from the Prostate Cancer Results Study Group Grimm P et al BJU Int. 2012 Feb;109 Suppl 1:22-9


Neo-adjuvant HT + RT

• Reduction of prostate mass (20-30%)

• Reduce clonogenic tumor cells

• Reduce proportion of bladder/rectum: high dose level

• Reduce D95 bladder: 40-50%

• Reduce D95 rectum: 15-20%

• Conclusion:

– Dec. rate of late side effects

– Inc. tumor control rate

Zelefsky at al., Urology 1997

Pollack and Zagars, Sem. Radiat Oncol 1998


Neo-adjuvant HT + RTD’Amico et al., JAMA 299,2008

• Prospective Ph3 RCT

• 206 pts.

• 70Gy vs 70Gy + 2+2+2

mo HT

• Randomization: 1995-

2001• Med. FU: 7.6yrs

• 5 year OS88% vs 78% (p<0.05)

• 7 yrs HR 1.8 (p=0.01)

• Low co-morbidity rate: HR 4.2


Increased mortality with ADTNguyuen at al., JAMA 306, 2011


Adjuvant RT

• High risk features: + margins, ECE, SV

involvement, persistent PSA elevation

• 3 RCT shows upfront adjuvant therapy

improves local control, risk of metastasis, OS

vs. observation

– Within 4 mo and PSA<1.5

– Adjuvant 64-66Gy; salvage 66-70.2-79.2Gy

– Early salvage vs. adjuvant not clear


Protons

• Excellent disease control

rates and a low side effect

profile in prospective series

• Good quality-of-life and

high patient satisfaction

rates

• Reduced risks of 2nd

radiation-associated

malignancies than other

external beam techniques

• More expensive

• Limited evidence

• Toxicity may not be

better


Randomized trial comparing conventional-dose with high dose conformal radiation

therapy in early-stage adenocarcinoma of the prostate: Long-term results from

Proton Radiation Oncology Group/American College of Radiology 95-09Zietman et al JCO 2010 Mar 128 (7) 1106-11

• At 10 years the phoenix BF rates were 30%

vs 17.4% for conventional vs. high dose

grps


• Results

• PSA-FFS– Low risk 99%, intermediate risk 99%

– High risk 76%• Late G3 GU ~5%

• Late G3 GI ~1%

• Patient reported QOL outcomes bowel and urinary scores relatively stable

• Some decline in sexual scores

Int J Radiation Oncol Biol Phys 88;2014


• A proton therapy plan and a 6-MV IMRT plan were constructed

• The risk of an SMN was estimated by use of risk models from the Committee on the Biological Effects of Ionizing Radiation.

Results:

• Proton therapy reduced the risk of an SMN by 26% to 39% compared with IMRT.


Toxicities

• GU: urine frequency, dysuria, hematuria

• GI: rectal bleeding, cramping, diarrhea

• Sexual: RT vs age related vs. ADT

• 2nd cancers


IMRT Results MSKCCZelefsky et al., J. Urol 176, 2006; Alikus et al., Cancer 2011

• MSKCC New York

• 1996-2000:561 pts

• 81Gy

• N=170

• Med. FU:99 mo

5 years 10 years

Erectile dysfunction (%) 51

GU-late side effects G2/3 (%) 9/3 11/5

GI-late side effects G2/3 (%) 2/0.1 2/1


Erectile dysfunction after RT

• 5 years after RT:30-60%

• 2 randomized trials

• Double blind, placebo-controlled

• 60 pts• Sildenafil and Tadalafil (20mg)

• 50-60% significant improvement

Oheshalom et al., J. Urol. 174, 2005

Incrocci et al., Int J. Radiat. Oncol. Biol. Phys. 66, 2006

Budaeus et al. Eur. Urol. 2012


Secondary cancers – Re-analysis of the SEER data

• What is the risk?

• Conclusion: patients choosing EBRT might be at a greater absolute risk of developing a second malignancy – not just from the RT per se, but possibly related to other factors such as longer follow up or older age, or more risk factors – an additional 207 cases of 100,000 patients or 0.2% can be expected. However the incidence of second cancers that could be possibly RT-induced (RTSPC) was shown to be 162 of 100,000 or 0.16% in the present study – although it might be actually be significantly lower …

Abdel-Wahab et al., Int. J. Radiat. Oncol. Biol. Phys. 72, 2008

Secondary tumors: 0.2% (207/100 000)

Real RT-induced tumors: 0.16% (162/100 00)


Conclusions

• RT, RP, LDR, and AS comparable for low risk PCA

• IMRT with IGRT standard, total doses 74-80Gy

• Intermediate risk: 4-6mo ADT, RT alone dose 76-78Gy

• High risk: selected cases 6 mo ADT, usually 2-3 years, RT 76-78Gy

• Severe side effects: GI>2%, GU more common,

erectile dysfunction


Thank you

New NCCS

4 gantry PTC + 17 RT

bunkers

Integrated labs

2021

[email protected]

4515/12/2016 2016 ESMO Prostate Cancer Preceptorship

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Jeffrey Tuan, FRCR Radiation Oncology National Cancer ...oncologypro.esmo.org/content/download/100792/... · Session 2: Localized prostate cancer Role of radiotherapy Jeffrey Tuan,