Moderate and Extreme

Hypofractionationation in Prostate
Cancer with RapidArc

The Tata Medical Center experience

Indranil Mallick MD DNB

Tata Medical Center, Kolkata, India
International Oncology Summit, Turin, Italy
> Disclosures
Dr Indranil Mallick has received speakers
honoraria from Varian Medical Systems.

This presentation is sponsored by Varian Medical Systems.

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FOR HEALTH CARE PROFESSIONALS ONLY
> Tata Medical Center
Large tertiary care cancer hospital in Eastern
India 14,000 new registrations annually
Multidisciplinary evidence based care
Radiation Oncology Infrastructure
Two linear accelerators including a Novalis Tx,
Helical Tomotherapy
Novalis: RapidArc, CBCT, Real-time Position
Management (RPM)
~1500 treatments on Novalis annually
Image guided brachytherapy
Radiation Oncology Education
Only Indian center for UK FRCR examinations
Varian IGRT Clinical School
www.igrtonline.com largest online course on
IGRT
Radiation Oncology Research
More than 15 ongoing research protocols
Focus on modern techniques
> Hypofractionation in
Prostate Cancer
Several modern randomized controlled trials with moderate
hypofractionation
Trial Risk grp Hypofr schedule bPFS Toxicity
Arcangeli High risk 62Gy/20Fr/5 wks Better similar
(2010)
Fox chase Int and high risk 70.2Gy/26Fr/5 wks Equal ? worse GU
(2013)
RTOG 0415 Low risk 70Gy/28Fr/5.6 wks Non- similar
(2015 abstract) inferior
CHHiP (2015 Mainly int risk 60Gy/20Fr/4 weeks Non- similar
abstract) and 57Gy/19Fr/4weks inferior
HYPRO (2015) Int and high risk 64.6Gy/19Fr/6.5wks Equal ? worse GI
PROFIT (results Int risk 60Gy/20Fr/4wks (awaited) (awaited)
awaited)
> Why do it in India?
Patient
Less number of hospital visits
Less cost of stay and transport
Less cost of treatment
Hospital
Less use of resources
More patients can be treated using same
resources

Extremely relevant for a country like India

Experience at Tata Medical Center
with moderate hypofractionation
> Patient Demographics

187 patients
Moderate hypofractionation

First 18 patients Subsequently

65Gy/25Fr/5weeks 60Gy/20Fr/4weeks
(EQD2 = 76Gy) (EQD2=77.1Gy)

Mean age = 67.9 (95% CI 66.7 to 69.1 yrs)

Range 60 83 years
19.8% of patients were >=75 years
> Risk Stratification: PSA & Gleason
55.60%
PSA at diagnosis
60.00%

50.00%
Median = 23 ng/ml 40.00%
Range 1 to 274 ng/ml 30.00% 24.60%
19.80%
20.00%
10.2% of patients had PSA > 10.00%
100 ng/ml 0.00%

50%
<=10 10.1-20 >20
45%
43.20%
40% 36.80%
35%
30%
25% 20%
20%
15%
10% Gleason Score
5%
0%
Median = 7
6 7 8 to 10
> T/N stage and Risk groups
All patients had multiparametric MRI of the pelvis for locoregional staging.

T stage T4
2% Risk Group n %
T1/T2
33% Low (T1-T2a, Gleason 6, 4 (2.1%)
T3b PSA <=10ng/ml)
23% Intermediate (T2a/b, 23 (12.3%)
T3a Gleason 7, PSA 10-20
N stage 42% ng/ml)
High (T3/4), Gleason 8- 113 (60.4%)
N1 10, PSA > 20 ng/ml)
24% Node Positive (N1-M0) 43 (23.0%)
N0 Salvage/Oligomets 4 (2.1%)
76%
NCCN Very High risk (T3b/T4) = 25% of all patients
> Radiotherapy : Dose/Technique
Dose

N=18 N=169
65Gy/25Fr/5weeks 60Gy/20Fr/4weeks
(EQD2 = 76Gy) (EQD2=77.1Gy)

Technique
All patients were treated with IMRT (no exceptions)
RapidArc for patients treated on Novalis

Androgen Deprivation
Low risk: No ADT (n=4); Int risk: 6 months; High risk and N+= 2-3 yrs
GnRH analogues: 101 (56%); Orchidectomy 82 (44%)
> Radiotherapy: Targets
Low risk: Prostate only
Int Risk: Prostate + SV
High Risk: Prostate + SV
+ elective pelvic nodes
PTV: 7mm around
prostate + SV; 5mm
around elective nodal
volume
2 arcs starting at Planning technique
220 and 160 Ring structures
around the PTV

Anterior and
posterior body
dummies Overlapping
rectum and
bladder structures
> Dosimetry
QUANTEC guidelines were adapted to determine equivalent
doses at 3Gy/Fr (using a/b=3 for bladder and rectum)
TMC constraints were made stricter than QUANTEC
constraints
Plans were approved when criteria were met.

EQD2 QUANTEC TMC Mean Novalis

Organ Dose
(3Gy) Constraint Constraint dose (all) RapidArc
RECTUM V59Gy 70Gy <20% <7% 6.70% 6.71%
V56Gy 65Gy <25% <15% 13.80% 12.46%
V53Gy 60Gy <35% <20% 18.10% 15.78%
V47Gy 50Gy <50% <35% 27.70% 22.83%

BLADDER V59Gy 70Gy <35% <10% 6.20% 4.5%

V56Gy 65Gy <50% <20% 9.80% 6.4%
> Dosimetry in high risk
> Node Positive Disease
> Image Guidance

If no imaging or offline
corrections are used, the
random variations in AP
direction require large
PTV margins
All patients are treated
with daily volumetric
image guidance
> Acute Toxicity
RTOG score
GU n % Lower GI n %
Grade 0 67 (35.8%) Grade 0 62 (33.2%)
Grade 1 104 (55.6%) Grade 1 94 (50.3%)
Grade 2 15 (8%) Grade 2 31 (16.6%)
Grade 3 1 (0.5%) Grade 3 0 (0%)

NCI-CTC score Diarrhea n %

Grade 0 164 (87.7%)
Grade 1 16 (8.6%)
Grade 2 7 (3.7%)
Grade 3 0 (0%)
> Relative or Absolute doses?
Significanc
Toxicity Dosimetric correlates
e
Relative Rectal V70 (7.7% vs 8.1%) p=0.714
Relative Rectal V65 (15.9% vs 14.1%) p=0.192
GI toxicity, Relative Rectal V60 (21.2% vs 18.1%) p=0.038
Relative Rectal V50 (33.5% vs 28%) p=0.020
Grade 2 or
Absolute Rectal V70 (4.5 cc vs 4.5 cc) p=0.835
more Absolute Rectal V65 (9.9cc vs 7.9cc) p=0.038
Absolute Rectal V60 (13.1cc vs 10.1cc) p=0.013
Absolute Rectal V50 (20.8cc vs 15.5cc) p=0.007
GU Relative Bladder V70 (8.2% vs 6.8%) p=0.403
toxicity, Relative Bladder V65 (11.2% vs 10.3% p=0.712
Grade 2 or Absolute Bladder V70 (33.6cc vs 18.3cc) p=0.000
more
Absolute Bladder V65 (46.1cc vs 28.8cc) p=0.001

ASTRO 2014: Arunsingh/Mallick et al

> Which doses matter the most?
Absolute dose cutoffs from ROC
curves

Grade 2 proctitis
V EQD2 60Gy > 9.7 cc
V EQD2 50Gy > 17.1 cc.
For Grade 2 GU symptoms
V EQD2 70Gy > 23.6cc
V EQD2 65Gy > 38.1cc.

ASTRO 2014: Arunsingh/Mallick et al

> Late side-effects
Data is not mature enough for a discussion on late
side-effects
GI
Grade 2 10 (6.3%)
Grade 3 5 (3.1%)
GU
Grade 2 8 (5%)
Grade 3 2 (1.3%)

Comparable to published cohorts treating high risk

patients.
> Disease-related Outcomes
Median Follow up of the whole cohort = 24 months
(from date of registration usually after diagnosis of
prostate cancer).
Biochemical Failure by the Phoenix definition: nadir +
2ng/ml
Biochemical Failure in the entire series:
in 13/187 patients
crude rate: 6.9%
actuarial rate at 36 months - 15.2 %
Type of failure:
12/13 patients failed with distant mets (bones/extrapelvic
nodes)
1 patient has biochemical failure without demonstrable
metastases or local disease
> Biochemical Failure (FFBF)
Median FU 24 mo.
3 year projected data:
Low risk: 100%
Int risk: 100%
High risk: 92.5%
Node +ve: 77.9%
Salvage: 0% (2 yr 50%)
(p<0.001)

RCT by Arcangeli et al (2010, IJROBP):

n=83 patients in Hypofractionated Arm High risk
Median FU 32 months. FFBF: 87%
 Our experience with
Extreme Hypofractionation
> Whats the evidence?
Pooled cohort of 1100 patients enrolled in more than 10 Phase
II studies.
Mainly on Cyberknife but also linac based IMRT/SBRT
Biochemical control: 95%, 84% and 81% for low-, intermediate- and high-
risk patients, respectively (p < 0.001).
No differences were observed with ADT (p = 0.71) or as a function of total
dose (p = 0.17).

King, CR. Radiother Oncol 2013.

> The SHORT study
Short-course Hypofractionated Once-Weekly Radiation Therapy
for localized prostate cancer
Trial No: CTRI/2016/02/006671
Phase I/II study safety and biochemical outcomes
Eligibility:
Localized prostate cancer.
All risk groups (PSA <60)
Treatment
35Gy/5Fr/once weekly with IMRT RapidArc
Elective nodal RT in high risk patients (25Gy/5Fr Simultaneously)
CBCT before and after treatment
Outcomes
Primary: Acute toxicity
Secondary: Biochemical control, Late toxicity, QoL
Planned accrual n=30 (completed in Feb 2016)
> Planning Techniques
> Excellent dose conformity
> Dosimetry
First 21 patients treated: Dosimetry with RapidArc
PTV coverage: minimum requirements
95% dose to 100%vol, 95% vol to get 100% dose

EQD2 QUANTEC Trial Mean

Organ Dose
(3Gy) Constraint Constraint dose
RECTUM V35Gy 70Gy <20% <10% 5.2%
V33.5Gy 65Gy <25% <15% 8.6%
V32Gy 60Gy <35% <20% 11.0%
V28.75Gy 50Gy <50% <35% 16.2%

BLADDER V35Gy 70Gy <35% <10% 2.9%

V33.5Gy 65Gy <50% <20% 4.3%
> Acute Toxicities
IPSS Scores
35

Grade Grade
Grade 1 Grade 2 30

0 3+
Acute 13 8 25
0 0
Proctitis(62%) (38%)
20
Acute 2 17 2
0
Cystitis (9.5%) (81%) (9.5%) 15
Acute
10
Small 0 0 0 10
(100%)
Bowel
Acute 10 5
0 0 0
Skin (100%)
0

Pre-treatment end of RT 3months

Late toxicities: 1 patient had a grade 3 GU toxicity

> Conclusions
Hypofractionated Radiotherapy
strong radiobiological basis.
Increasingly strong clinical evidence of safety and efficacy
Attractive prospect for most centers equipped with
3DCRT and IMRT
Systematic development of a moderate
hypofractionation protocol at Tata Medical Center with
toxicity and biochemical outcomes at par with
published results.
Extreme hypofractionation being explored in a clinical
trial.
RapidArc treatment planning achieves excellent
dosimetry in both settings
 Radiation Oncology Fellows
Dr Moses Arunsingh

Medical Physicists/Radiographers:
S Sriram Prasath/B Arun/ Pinaki Das

Radiation oncology colleagues

Thank You Dr Rimpa Achari
Dr Sanjoy Chatterjee
Dr Raj K Shrimali