1. N.N. Alexandrov National Cancer Centre
Chemotherapy in the Treatment of Locally Advanced Prostate Cancer (own experience).
Sergey Polyakov, MD, PhD
N.N. Alexandrov National Cancer Centre
Minsk, Belarus

2. The Role of Chemotherapy in PCa
DOCETAXEL×10-12
months
Localized PCa
Locally-Advanced PCa
mHormone-Naïve PCa
mCRPC
Historically the first evidence of CHEMO efficacy came from 2 trials
10-12 cycles of docetaxel provided survival benefit from 1.9 to 2.4 months compared to MITO
TAX 327 (Tannock et al, 2004)
SWOG (Petrylak et al, 2004)

3. The Role of Chemotherapy in PCa
DOCETAXEL×6
months
Localized PCa
Locally-Advanced PCa
mHormone-Naïve PCa
mCRPC
The next step was successful use of CHEMO in hormone naïve mPC
Earlier use was more beneficial comparing to mCRPC – only 6 cycles gave survival increase by 10 to 13 months
CAARTED (Sweeney et al, 2015)
STAMPEDE (James et al, 2016)

4. The Role of Chemotherapy in PCa
DOCETAXEL?
Localized PCa
Locally-Advanced PCa
mHormone-Naïve PCa
mCRPC
The question that has remained unsolved today is – could CHEMO be given even more earlier in nonmetastatic hormone naïve patients as adjuvant chemotherapy
As is used to be in breast or colorectal cancer
The theoretical benefit of earlier us
Possible synergism with primary hormones as it shown on mice model
Decreased resistance of PC cells earlier in the course of tumour development
And if the stem cell theory true this mean than earlier use of multimodal therapy may increase cure rate in high risk localised disease
Theoretical Benefit:
Possible synergism with primary hormones (Eigl et al. 2005)
Decreased resistance earlier in the course of PCa (Marín-Aguilera, 2014)
In line with stem cell theory

5. Questions
Safety
Efficacy
The questions that we have to answer are 2

6. Questions Safety Efficacy Combination with RTx Drug Mitoxantrone
AML
Estramustine 
Thromboembolism
Safety is important as most patients will survive up to 7 to 10 years long term morbidity for them unacceptable
Most issues in comb with radiotherapy as toxicities probably potentiate
Some drugs may be particularly dangerous:
For example SWOG 9921 trial assessing adjuvant mitoxantrone CHEMO after prostatectomy was closed prematurely after three cases of acute myelogenous leukemia (AML) were reported of a total of 487 patients in the mitoxantrone treatment arm.
Estramustin (EMCYTE) was shown to markedly increase thromboembolic complications

7. Vinblastin/doxorubucin/ ММС
Questions
Safety
Efficacy
Combination with RTx
Author
Year N
Scheme
No of cycles
G3-4 toxicity
Khil et al
1997 65
EMP/vinblastin
1/w × 16 5%
Ryan et al
2004 23
10 – 22%
Bagley et al
2002 25
Vinblastin/doxorubucin/ ММС
1/3w × 6
65-76% neutropenia
Swanson et al
2006 30
5-FU infusion
1/d × 8 w
30%
Kumar et al 22
docetaxel 5-25 mg/m2
1/w × 8
25 mg/m2 2/2 diarrhea
Perrotti et al
2008 20
docetaxel 20 mg/m2 no
Combination of CHEMO with concurrent radiotherapy and AA was assessed in a number of phase 2 trials
The toxicity was prominent
And in case of weekly docetaxel the optimal dose was 20 mg per meter squared

8. Questions Safety Efficacy TAX-3501 (Schweizer et al, 2015)
GETUG 12 (Fizazi et al, 2015)
RTOG 0521 (Sandler et al, ASCO 2015)
STAMPEDE (James et al, 2016)
As for efficacy
What we have is results of 4 trials which are
TAX-3501
GETUG 12 (french)
RTOG 0521
STAMPEDE (UK)

9. Studies with short follow up, low death numbers
All this trials were combined in meta-analysis which was recently published in the Lancet Oncology
As a result highly statistically significant benefit was shown for PFS, which translated in an 8% reduction in absolute failure rates at 4 years
HR for OS was 0.87 that translated to a potential absolute improvement of 2%;
however, the confidence intervals were wide, and the result were not statistically significant
However most trials had short follow up and low death numbers that made impossible to come to definite conclusions on OS
Lancet Oncol, 2016

10. Trial Objective
To assess safety and efficacy of addition of combination docetaxel- based chemotherapy (docetaxel + vinorelbine) to standard local ± adjuvant therapy in patients with locally-advanced PCa
2 trials depending on type of local therapy:
Radiotherapy
chemo-hormono-radiotherapy
Surgery
adjuvant chemotherapy
At this point we would like to show results of our single center prospective RT
Which was designed to assess safety and efficacy of addition of combination docetaxel-based chemotherapy (docetaxel + vinorelbine) to standard local therapy with or without adjuvant AD in patients with locally-advanced PCa
2 trials were designed depending on type of local therapy:
The first assessed chemo-hormono-radiotherapy versus hormono-radiotherapy
And the second adjuvant chemotherapy after surgery

11. Radiotherapy Population: Study Design
PCa cT3-4 or N1 and M0 RPE
not indicated
Androgen deprivation + laparoscopic PLND ± TUR
RANDOMIZATION
Study arm
3D conformal EBRT
+ docetaxel AND vinorelbine × 4 - 1/2w
Control arm
3D conformal EBRT on prostate and lymph nodes
Primary:
bNED
Secondary: OS
CSS
PFS
Toxicity
In radiotherapy trial we included patients with locally advanced PCa without distant or bulky regional metastases in which RPe was not indicated
All the patients underwent surgical or medical castration with laparoscopic PLND and were randomized into 2 arms
In experimental arm 3D conformal EBRT was given with concurrent docetaxel AND vinorelbine combination chemotherapy In control arm standard 3D radiotherapy was administered
Primary end point was biochemical recurrence free survival and secondary: OS, CSS, PFS and Toxicity

12. Therapy in the Study Group
docetaxel 30/m2
+ vinorelbine 15/m2
Lap PLND + castration
2-3 months
Radiotherapy (3D CRT ):
on prostate 78.6 Gy
on lymph nodes 50.4 Gy
1.8 Gy per fraction
5 /w– 8.4 weeks
The treatment protocol is shown on this slide
Chemo was given every 2 weeks during course of radiotherapy
The radiotherapy was 78.6 Gy on prostate and 50.4 Gy on lymph nodes with standard fractionating

13. Radiotherapy Population: Patients Characteristics
Study arm, N (%)
Control arm, N (%)
Total, N (%)
Patients no.
46 (100)
92 (100)
Median age (min-max)
67 (51–76)
68 (50–84) cT
сТ3a-b
29 (63)
36 (78)
65 (71)
сТ4
17 (37)
10 (22)
27 (29)
Median PSA (min-max)
30.0 ( )
25.2 ( )
27.1 (0.3–147)
0 - 9,9 ng/ml
5 (11)
6 (13)
11 (12)
,9 mg/ml
14 (30)
11 (24)
25 (27)
≥ 20 ng/ml
26 (57)
28 (61)
54 (59)
Gleason score
2-6
23 (50)
49 (53) 7
16 (35)
24 (26)
8-10
7 (15)
17 (18)
pN1
20 (43)
37 (40)
A total of 92 patients were included with 46 in each arm
Median age 68
37-22% of T4
Median PSA 27
43-37% with lymph node metastases
There were no significant differences between groups

14. Radiotherapy Population: Efficacy Results
Median follow-up 7.5 years
Study arm
N (%)
Control arm
HR (95%CI)* p
BCR progression
8 (17)
16 (35)
0.40 ( )
0.038
Clinical progression
7 (15)
10 (22)
0.64 ( )
0.37
Died
13 (28)
20 (43)
0.58 ( )
0.13
Died from PCa
5 (11)
0.43 ( )
0.12
* Stratification depending on regional lymph nodes status
With median f-u of 7.5 years there were 16 vs 8 biochemical progressions
10 vs 7 clinical progressions
More parents died in the control group including from PCa

15. Radiotherapy Population: Efficacy Results
CCS
CSS N0
CSS N1
There was benefit of chemo-radio-hormono-therapy in all end points, but statistically only and in CSS in patients with lymph node metastasis
Biochemically no evidence of disease
p=0.06
p=0.4
p=0.04

16. Prostatectomy Population: Study Design
RADICAL PROSTA-TECTOMY
pT3-4 or pN+
RANDOMIZATION
CHEMO
ARM
DTX 70 mg/m2 + VRB 30 mg/m2  1 / 3 w × 4
Castration if N1
Salvage XRT if BCR
CONTROL ARM
Primary:
bNED
Secondary: OS
CSS
PFS
Toxicity
In surgery trial we included patients after radical prostatectomy with pathologically locally advanced or regionally metastatic disease
The patients were randomized into 2 arms
In control arm the patients underwent AA in case of lymph node metastases and were followed until biochemical recurrence
In chemotherapy arm the same treatment was administered together with 4 cycles of adjuvant chemotherapy with docetaxel and vinorelbine
Again primary end point was biochemical recurrence free survival and secondary: OS, CSS, PFS and Toxicity

17. Prostatectomy Population: Patient Characteristics
Variable
CONTROL arm, n (%)
CHEMO arm, n (%)
Total, n (%)
No of patients
64 (100)
52 (100)
116 (100)
Median age, years (range)
66 (51-76)
65 (44-78)
66 (44-78)
Median PSA, ng / ml (range)
18 ( )
16 (1.7-85)
17 ( )
PSA
< 10 ng / ml
16 (25)
16 (3)
32 (27)
10 – 20 ng / ml
17 (27)
13 (25)
30 (26)
> 20 ng / ml
31 (48)
23 (43)
54 (46)
Gleason`s score
≤ 6
38 (59)
27 (51)
65 (56) 7
15 (23)
16 (30)
31 (26)
≥ 8
10 (16)
9 (17)
19 (16)
pTN
pT3aN0
23 (36)
39 (33)
pT3bN0
20 (38)
43 (37)
pT2-4N1
18 (28)
17 (32)
35 (30)
A total of 116 patients were included with 64 in control and 52 in chemotherapy arm
Median age 66
Median PSA 17
Roughly 1/3 was pT3a
1/3 was pT3b
And 1/3 was N+ cases
Again there were no significant differences between groups

18. Prostatectomy Population: Efficacy Results
bNED
PFS
Median follow-up was 71 months
There was significant benefit of chemotherapy in biochemical RFS with HR of 0.51 (p=0.046)
And also not statistically significant benefit in PFS with HR of 0.59
Median follow-up 71 months
HR 0.51 (95%CI ) p=0.046
HR 0.59 (95%CI ) p=0.30

19. Subgroup analysis of BCR risk
Subgroup analysis of biochemical recurrence risk showed some improvement in efficacy in low grade cases and with higher PSA

20. Conclusions
Our results clearly indicate that the addition of docetaxel-based chemotherapy to standard treatment in locally advanced prostate cancer is associated with prolonged time to biochemical recurrence
There was also improvement in other end points:
OS and CSS in radiotherapy trial
PFS in surgery trial
The study is underpowered to assess survival
Multimodal therapy with the addition of docetaxel-based chemotherapy represents new promising concept demanding careful evaluation
Mature data from ongoing randomised studies is awaited
In conclusion

21. Conclusions
Our results clearly indicate that the addition of docetaxel-based chemotherapy to standard treatment in locally advanced prostate cancer is associated with prolonged time to biochemical recurrence
There was also improvement in other end points:
OS and CSS in radiotherapy trial
PFS in surgery trial
The study is underpowered to assess survival
Multimodal therapy with the addition of docetaxel-based chemotherapy represents new promising concept demanding careful evaluation
Mature data from ongoing randomised studies is awaited

22. Conclusions
Our results clearly indicate that the addition of docetaxel-based chemotherapy to standard treatment in locally advanced prostate cancer is associated with prolonged time to biochemical recurrence
There was also improvement in other end points:
OS and CSS in radiotherapy trial
PFS in surgery trial
The study is underpowered to assess survival
Multimodal therapy with the addition of docetaxel-based chemotherapy represents new promising concept demanding careful evaluation
Mature data from ongoing randomised studies is awaited

23. Conclusions
Our results clearly indicate that the addition of docetaxel-based chemotherapy to standard treatment in locally advanced prostate cancer is associated with prolonged time to biochemical recurrence
There was also improvement in other end points:
OS and CSS in radiotherapy trial
PFS in surgery trial
The study is underpowered to assess survival
Multimodal therapy with the addition of docetaxel-based chemotherapy represents new promising concept demanding careful evaluation
Mature data from ongoing randomised studies is awaited

24. Conclusions
Our results clearly indicate that the addition of docetaxel-based chemotherapy to standard treatment in locally advanced prostate cancer is associated with prolonged time to biochemical recurrence
There was also improvement in other end points:
OS and CSS in radiotherapy trial
PFS in surgery trial
The study is underpowered to assess survival
Multimodal therapy with the addition of docetaxel-based chemotherapy represents new promising concept demanding careful evaluation
Mature data from the ongoing randomised studies is awaited