Maintenance/consolidation strategies in patients with advanced ovarian cancer

1
Mediterranean School of Oncology Highlights in
the management of ovarian cancer
Maintenance/consolidation strategies in patients
with advanced ovarian cancer Angiolo
Gadducci Department of Gynecology and Obstetrics,
Unit of Gynecologic Oncology, University of Pisa
Rome October 5-6 2007
2
Consolidation and maintenance therapy for
patients with advanced epithelial ovarian cancer
(EOC) in complete response after 1st-line
chemotherapy

• 1st-line CT is able to achieve a cCR rate of
  50, a pCR of 25-30, a median PFS of 15.522
  months, and a median OS of 31-44 months.
• Almost 75 of the pts who achieved a cCR and
  50 of those who obtained a pCR will relapse
  after a median time of 1824 months.
• G3 tumor and large RD after initial surgery are
  the strongest predictors of recurrence after the
  achievement of a CR.

3
Consolidation and maintenance therapy for pts
with advanced EOC in CR after 1st CT

• Pts with recurrent disease have a median OS from
  time of recurrence lt 2 years and a long-term OS
  (over 5 years) lt 10
• Attempts to improve the clinical outcome of EOC
  pts should be addressed to the identification of
• ?New 1st-line regimens able to obtain higher CR
  rates
• ?Effective treatments to consolidate or maintain
  the CR achieved by 1st-line CT

4
Consolidation and maintenance therapy for pts
with EOC in CR after 1st CT

• Whole abdomen radiation (WAR)
• Intraperitoneal (Ip) radioisotopes
• Radioimmunotherapy (RIT)
• Ip CT
• High dose CT (HD-CT)
• with haematopoietic support

• Prolonged administration of 1st-line CT
• Second-line single-agent CT (Epidx, topotecan,
  TAX)
• Biological agents

5
WAR as consolidation after CT in pts with
advanced EOC non- randomised studies
Authors pts 1st-line CT
consolidation clinical outcome

type Pts
Goldhirsch 45 in pCR
CDDPPAMHEXA WAR 24 3-y TTP 83
1988 No WAR 21 3-y TTP
49 Kuten 37 in pCR or DOX CDDP
WAR 5 pCR 2-y OS 100 1988 RD lt
2cm WAR 18 micro RD 5-y
OS 66
WAR 14 lt2cm RD 3-y OS
5 Shelley 27 in pCR or CTX CDDP WAR
12 pCR prog 4 33 1988
micro RD WAR 15 micro
prog 9 60 Kapp 46 in cCR
combination CT WAR whole series 5-y PFS
33 1999 (CDDP in 76) No RD
13 5-y PFS 62
MacGibbon 51 in pCR or CLB
CDDP- WAR 5-y OS 27 1999
RD lt 2cm based-CT 10-y
OS 10
6
WAR as consolidation after CT in pts with
advanced EOC randomised studies
Authors pts 1st-line CT
Consolidation Clinical outcome


Bruzzone 41 in pCR or CTXCDDPDOX
WAR prog 11 55 1990
lt2cm RD death 9
45 CTXCDDP prog 6 29
DOX x 3 death 3
14 Lambert 117 in pCR CBDCA WAR
No difference in OS 1999 RD lt 2cm
CBDCA
Pickel 64 in cCR
CBDCA-EPIDX- WAR 5-y OS 59 1990
based-CT observation 5-y OS
33 p 0.029
7
Is there a role for consolidation or salvage
radiotherapy after CT in advanced EOC
Reassessment of 700 advanced EOC pts enrolled in
28 trials Difficult to interpreter (uncontrolled
nature of the studies, inappropriate patient
selection) but generally disappointing Residual
disease OS No 76 Microscopic or
macroscopic lt 5 mm 49 Macroscopic gt 5 mm 17
RESULTS
Thomas Gynecol Oncol, 1993
8
Consolidation treatment of advanced EOC in
surgical CR after induction CT a randomised
trial comparing WAR, CT, and no further treatment
Surgery ? CDDP DOX/EPIDX for 4 cycles ? Second
Look
pPR74
pCR 98
r a n d o m i z e d
WAR CDDP DOX/ EPIDX x 6 cycles Observation
WAR CDDP DOX/ EPIDX x 6 cycles
Sorbe for Swedish-Norvegian Ovarian Cancer Study
Group, 2003
9
Consolidation treatment of advanced EOC in
surgical CR after induction CT a randomized
trial comparing WAR, CT, and no further treatment
5-y PFS 95 CI 5-y OS 95 CI WAR 56.3
39.1-73.4 68.8 52.7-84.8 CT
36.0 19.9-52.1 57.1 48.8-73.5
Observation 35.5
18.6-52.3 64.5 47.7-81.4

p0.032
p0.084
Pts in pCR 98
Pts in pPR 74
5-y PFS 95 CI 5-y OS 95 CI WAR 16.7
4.5-28.9 32.4 17.3-47.5 CT
25.3 11.0-39.5 40.5 24.7-56.4
pns pns
Sorbe for Swedish-Norvegian Ovarian Cancer Study
Group, 2003
10
Consolidation and maintenance therapy for pts
with advanced EOC in CR after 1st CT

• Whole abdomen radiation (WAR)
• Intraperitoneal (Ip) radioisotopes
• Radioimmunotherapy (RIT)
• Ip CT
• High dose CT (HD-CT)
• with haematopoietic support

• Prolonged administration of 1st-line CT
• Second-line single-agent CT (Epidx, topotecan,
  TAX)
• Biological agents

11
Intraperitoneal 32P as consolidation treatment of
advanced EOC pts in pCR after 1st CT non-
randomised studies
Authors pts Consolidation Clinical
outcome Varia 1988 57 32P 43 4-y OS
89 no32P 14 4-y OS 67 Spencer
1989 31 32P 14 0 recurrences no32P 17
4 (23.5) recurrences Peters 1992 34 32P
18 (53) recurrences Rogers 1993 69 32P 51
5-y PFS 86 5-y OS 90 no32P 18
5-y PFS 67 5-y OS 78 Spanos 1993 52
32P 23 pCR 5-y OS 75 submitted to
SL 32P 15 lt2cm 5-y OS 48 32P 14
gt2cm 5-y OS 32 Condra 1998 39
32P 39 5-y OS 81
12
Intraperitoneal 32P as consolidation treatment of
advanced EOC pts in pCR after 1st CT randomised
studies
Authors pts Consolidation Clinical
outcome Vergote 1993 50 32P No differences
in crude and DFS no32P 5-y PFS 5-y
OS Varia 2003 202 32P
42 67 no32P 36 63 p
ns p ns
13
Consolidation and maintenance therapy for pts
with advanced EOC in CR after 1st CT

• Whole abdomen radiation (WAR)
• Intraperitoneal (Ip) radioisotopes
• Radioimmunotherapy (RIT)
• Ip CT
• High dose CT (HD-CT)
• with haematopoietic support

• Prolonged administration of 1st-line CT
• Second-line single-agent CT (Epidx, topotecan,
  TAX)
• Biological agents

14
RIT as consolidation treatment after CT in pts
with advanced EOC
Authors pts Consolidation Clinical
outcome Stewart 28 with RD 131I-labelled
ab 1989 micro RD 5 CR 3
(60) RD lt 2cm 15 PR 2 (13) RD
gt 2 cm 8 CR PR 0 Mahe 6 with
131I-labelled ab 1999 minimal RD CR
PR 0 Nicholson 50 in
CR 90Y-labelled ab 25 5-y OS 80 1999
Matched controls 25 5-y OS
55 p 0.0035 Epenetos 21 in
CR 90Y-labelled ab 10-y OS 78 2000
15
Consolidation and maintenance therapy for pts
with advanced EOC in CR after 1st CT

• Whole abdomen radiation (WAR)
• Intraperitoneal (Ip) radioisotopes
• Radioimmunotherapy (RIT)
• Ip CT
• High dose CT (HD-CT)
• with haematopoietic support

• Prolonged administration of 1st-line CT
• Second-line single-agent CT (Epidx, topotecan,
  TAX)
• Biological agents

16
Ip CT as consolidation for pts with advanced EOC
in pCR after 1st-line CT
Authors pts ip Consolidation Clinical
outcome De Gramont 13 CDDP cytarabine
1992 x 3 cycles median PFS 37
mos median OS 44 mos Tarrazza
56 CDDP x 3 cycles 41 10 (26)
recurrences 1993 Mitoxantrone x 3 15
4 (24) recurrences Dufour
50 Mitoxantrone x 6 cycles 5-y PFS 47.3 1994
5-y OS 59.8
17
Ip CT as consolidation for pts with advanced EOC
in pCR after 1st-line CT
Authors pts ip Consolidation Clinical
outcome Barakat 82 CDDP VP-16 36
median PFS not reached 1998 x 3 cycles
No consolidation 46 median PFS 28.5
mos p 0.03
Tournigand 68 CDDP VP-16
Mitoxantrone 5-y PFS 34 2003 x 3
cycles 5-y OS 58 Topuz
30 CDDP x 6 cycles 5-y OS 65 2004
4-y PFS 50
18
Ip CT as consolidation for pts with advanced EOC
in pCR after 1st-line CT results of EORTC 55875
153 pts with FIGO stage IIb-III EOC in pCR after
platinum-based CT
Randomization
CDDP x 4 cycles
8-y PFS 38 8-y OS 53
Observation
8-y PFS 37 8-y OS 48.5
p ns
Piccart 2003
19
Consolidation and maintenance therapy for pts
with advanced EOC in CR after 1st CT

• Whole abdomen radiation (WAR)
• Intraperitoneal (Ip) radioisotopes
• Radioimmunotherapy (RIT)
• Ip CT
• High dose CT (HD-CT)
• with haematopoietic support

• Prolonged administration of 1st-line CT
• Second-line single-agent CT (Epidx, topotecan,
  TAX)
• Biological agents

20
HD-CT as consolidation for advanced EOC pts
responsive to 1st-line CT

• Authors pts Consolidation Clinical
  outcome
• Legros 19 in pCR L-PAM or CBDCA CTX
  5-y PFS 32.8
• 1997 5-OS 74.2
• Cure 102 in pCR CBDCA CTX
  median PFS 22 mos
• or RD lt 2 cm Randomisation
• Conventional CBDCA CTX median
  PFS 11 mos
• p 0.03
• Cure Update results CBDCA CTX
  median PFS 18 mos
• 2004 Randomisation median OS 50
  mos
• Conventional CBDCA CTX median
  PFS 12 mos
• median OS 43 mos

21
Consolidation and maintenance therapy for pts
with advanced EOC in CR after 1st CT

• Prolonged administration of 1st-line CT
• Second-line single-agent CT (Epidx, topotecan,
  TAX)
• Biological agents

• Whole abdomen radiation (WAR)
• Intraperitoneal (Ip) radioisotopes
• Radioimmunotherapy (RIT)
• Ip CT
• High dose CT (HD-CT)
• with haematopoietic support

22
Randomised trials comparing qa different number
of cycles of 1st-line platinum-based CT in
advanced EOC pts
Authors pts 1st-line cycles Clinical
outcome Hakes 78 CDDP DOX CTX 5
pCR 34 4-y OS 29 1992 10 pCR
35 4-y OS 36 p ns p
ns Bertelsen 202 CDDP DOX CTX 6
pCR 23 3-y OS 29 1993 12 pCR
25 3-y OS 35 Lambert
225 CBDCA or CDDP 5 No difference in OS
1997 8 between the 2 arms
(median OS 24 months)
23
Consolidation and maintenance therapy for pts
with advanced EOC in CR after 1st CT

• Whole abdomen radiation (WAR)
• Intraperitoneal (Ip) radioisotopes
• Radioimmunotherapy (RIT)
• Ip CT
• High dose CT (HD-CT)
• with haematopoietic support

• Prolonged administration of 1st-line CT
• Second-line single-agent CT (Epidx, topotecan,
  TAX)
• Biological agents

24
2nd line single-agent CT as maintenance therapy
in advanced EOC pts
Authors pts maintenance Clinical
outcome Rothenberg 97 in cCR Altretamine x 6
cycles 2-y OS 2001 whole series 97
75 RD lt 1 cm 61 82
RD gt 1 cm 36 64
Scarfone 163 in pCR EPIDX x 4 cycles
2006 Randomisation No difference in
OS Observation
25
2nd line single-agent CT as maintenance therapy
in advanced EOC pts
Authors pts maintenance Clinical
outcome TAX CBDCA? topotecan x 4
cycles Pfisterer 1308 IIb-IV
Randomisation 2003 TAX CBDCA?
Observation No difference in
PFS Topotecan x 4 cycles median PFS
18.2 mos De Placido 273 in cCR (87)
Randomisation 2004 or PR (13) Observation
median PFS 28.4 mos p ns
26
Phase III randomized trial of 12 vs 3 months of
maintenance TAX in advanced EOC after CR to
TAX/platinum-based CT a SWOG and GOG trial
Markman et al 2003
12- cycles TAX 3 cycles TAX Grade 2-3
neuropathy 23 7.5 median PFS
28 months 21 months p
0.0023 At Cox model the HR of 3-cycle arm for
progression was 2.31 (99 CI, 1.08-4.94)
27
(No Transcript)
28
Phase III randomized trial of 12 vs 3 months of
maintenance TAX in advanced EOC after CR to
TAX/platinum-based CT a SWOG and GOG trial

• The Data Safety Monitoring Board of the SWOG
  early closed the study because of the PFS
  advantage.
• This study has been criticized for the premature
  and inappropriate closure and for having no
  quality-of-life component

Markman et al 2003
29
Protocol AFTER SIX
CBDCA or TAX or CDDP TAX Every 3 weeks x 6
cycles
CR PR
AFTER SIX 3
AFTER SIX 2
AFTER SIX 1
macro-PR
micro-PR
CR
MAINTENANCE (arm A) TAX 60 mg/m2 weekly)
OBSERVATION (arm A) (intensive follow-up)
MAINTENANCE (Phase II) (TAX 60 mg/m2 weekly x
21 weeks)
up to PD or excessive toxicity
VS
VS
Any kind of 2nd line-CT (arm B) (topotecan-anthrac
yclines-gemcitabine
MAINTENANCE (arm B) TAX 175 mg/m2 3-h every 3
weeks x 6 cycles
up to PD or excessive toxicity
30
Giuseppe Favalliaugust 3rd ,1954 - sept
28th, 2005
31
After 6
Protocol AFTER SIX 1Study details

• patients planned 250
• participating Institutions 23
• accrual 03/99- 05/06
• randomized patients 200
• (68 of pts entered from 4 institutions)
• As of March 30, 2007
• pts with PD 107 (53)
• deaths 48 (24)

Conte, Favalli, Gadducci et al., ASCO Meeting
2007
32
 
Protocol AFTER SIX 1 Patient characteristics
Overall 200 () TAX 101 () Control 99 ()
Median age (range) 59 (19-78) 59 (19-78) 58 (35-76)
PS (ECOG) () 0 ?1 Unknown 75.0 13.0 12.0 72.4 13.3 14.3 76.3 13.4 10.3
Histology Serous Endometroid Undifferentiated Clear cell Mucinous Other 72.0 13.0 6.5 2.0 1.5 5.0 70.0 11.9 6.9 1.0 2.0 7.9 73.0 14.4 6.0 3.0 1.0 2.0
Grade 1 2 3 Not specified 4.0 22.5 63.5 10.0 3.0 22.8 63.4 10.8 5.1 22.4 64.3 8.2
Stage IIb IIc IIIa IIIb IIIc IV 5.5 9 7 9 62.5 6 5.0 9.9 5.9 9.9 62.4 5.9 6.1 8.1 8.1 8.1 62.5 6.1

33
Protocol AFTER SIX 1 Patient characteristics
Overall TAX Control
Residual disease after 1st surgery No macroscopic disease 1 cm 1.1-2 cm gt 2 cm Not specified 52.5 9.5 10.5 20.0 7.5 52.5 8.9 10.9 21.8 5.9 52.0 10.2 10.2 18.4 9.2
First-line Chemotherapy CBDCA TAX CBDCA TAX EPI/DOX CDDP TAX EPI/DOX 91.0 4.5 4.5 92.0 3.0 5.0 89.9 6.1 4.0
Response pCR cCR 52.5 47.5 53.5 46.5 51.5 48.5
Conte, Favalli, Gadducci et al., ASCO Meeting
2007

34
Protocol AFTER SIX 1 Compliance
Never Started 6
Toxicity 9
Discontinued 17
PD/death 3
Completed 77
Refusal 3
Other 2
3 pts 1 course 4 pts 2 courses 4 pts 3
courses 4 pts 4 courses 2 pts 5
courses Observation Arm 14 pts randomized to
observation received maintenance TAX
35
After 6 Protocol 1 Compliance II(total
courses 525)
Dose delays 29 5.5
Toxicity other 16 13 3.0 2.5
Dose reduction 33 6.3
Toxicity other 25 8 4.8 1.5
36
Protocol AFTER SIX 1 Toxicity
per Cycle per Cycle per Cycle per Patient per Patient per Patient
G2 G3 G4 G2 G3 G4
Leukopenia 9.7 1.1 - 27.0 4.5 -
Neutropenia 8.4 8.4 1.0 29.2 21.3 3.4
Anemia 1.5 0.2 - 5.6 1.1 -
Neuropathy, Motor 1.9 0.6 - 7.9 3.4 -
Neuropathy, Sensory 5.9 1.3 - 21.3 6.7 -
Arthromyalgia 1.7 0.2 - 4.5 1.1 -
Nausea/Vomiting 1.3 - - 4.5 - -
Other toxicities (thrombocytopenia, stomatitis,
renal, liver) were reported in less than 2 of
patients
37
Protocol AFTER SIX 1 Progression-free
survival-ITT
N Events Median PFS (months) PFS at months PFS at months PFS at months
N Events Median PFS (months) 12 24 36
Maintenance 101 56 34 79 59 49
Control 99 51 30 70 54 43
Logrank 0.2 (1), p 0.68 Logrank 0.2 (1), p 0.68 Logrank 0.2 (1), p 0.68 Logrank 0.2 (1), p 0.68 Logrank 0.2 (1), p 0.68 Logrank 0.2 (1), p 0.68
38
Protocol AFTER SIX 1 Overall survival-ITT
N Events Median OS (months) OS at months OS at months OS at months
N Events Median OS (months) 12 24 36
Maintenance 101 30 77 97 87 78
Control 99 18 Inf 98 90 86
Logrank 2.3 (1), p 0.13 Logrank 2.3 (1), p 0.13 Logrank 2.3 (1), p 0.13 Logrank 2.3 (1), p 0.13 Logrank 2.3 (1), p 0.13 Logrank 2.3 (1), p 0.13
39
Treatment role on PFS in subgroups
Maintenance better
Control better
HR 95CI
1.24 (0.67-2.31)
0.78 (0.47-1.29)
0.80 (0.37-1.62)
0.96 (0.60-1.54)
2.19 (0.43-11.31)
1.46 (0.47-4.51)
0.76 (0.5-1.17)
0.939 (0.54-1.64)
0.95 (0.56-1.60)
40
Protocol AFTER SIX 1 Cox Model
Arm HR 95 CI
control 1.00 -
maintenance 0.94 0.62 - 1.41
Grading
1 2 1.00 -
3 1.07 0.68 - 1.70
Second look
no (cCR) 1.00 -
yes (pCR) 0.79 0.52 - 1.19
Stage
IIb IIc 1.00 -
IIIa IIIb 1.06 0.56 - 1.99
IIIc IV 3.10 1.13 - 8.48
Tumor residual
no macroscopic 1.00 -
macroscopic 1.91 1.21 - 3.03
Conte, Favalli, Gadducci et al., ASCO Meeting
2007
41
Protocol AFTER SIX 1 PFS by risk group
At Risk Failed Median
49 15 Inf
75 37 32
71 54 18 P lt 0.0001
42
Protocol AFTER SIX 1 Conclusions

• Compliance to maintenance TAX was good (77 of
  pts completed the treatment)
• 2-yr PFS on control arm was as expected (observed
  54 vs expected 50)
• Stage (IIIc IV vs others) and RD (macroscopic
  vs none) were independent prognostic parameters
  for PFS
• No differences in PFS and OS were observed
  between the 2 arms
• The results from this trial do not support the
  administration of maintenance TAX (175 mg/m2 q 3
  wks) to pts with carefully defined clinical or
  pathological CR

43
Consolidation and maintenance therapy for pts
with advanced EOC in CR after 1st CT

• Whole abdomen radiation (WAR)
• Intraperitoneal (Ip) radioisotopes
• Radioimmunotherapy (RIT)
• Ip CT
• High dose CT (HD-CT)
• with haematopoietic support

• Prolonged administration of 1st-line CT
• Second-line single-agent CT (Epidx, topotecan,
  TAX)
• Biological agents

44
Biological agents as maintenance therapy in
advanced EOC pts responsive to 1st-line
platinum-based CT
Authors pts maintenance Clinical
outcome median PFS median
OS Hirte 243 in CR or PR BAY 12-9566
10.4 mos 13.9 mos 2001 Randomisation
Placebo 9.2 mos 11.9 mos
TTR Berek 145
in cCR Oregovomab 13.3 mos 2004
randomised
Placebo 10.3 mos p ns

45
Maintenance Erlotinib following 1st-line
treatment with docetaxel CBDCA Erlotinib in
advanced EOC
Study population 48 pts with advanced EOC CT
regimen Docetaxel 75 mg/m2 CBDCA AUC 5 every
3 weeks x 6 cycles daily Erlotinib (50-100
mg) After 6 cycles, pts could receive erlotinib
alone (150 mg/die) until progression Results
27 (56) pts continued erlotinib for a median
of 8.6 months Grade 2 toxicity rash (18),
fatigue (15), alopecia (24) All pts Median
PFS 12.5 months Median OS 37.0 months Pts
receiving maintenance erlotinib Median PFS
14.8 months Median OS 37.0 months
Vasey, ASCO Meeting 2007
46
Maintenance Bevacizumab following first-line
treatment for advanced EOC a phase II trial
Study population 58 pts with advanced EOC CT
regimen - TAX 175 mg/m2 CBDCA AUC 5
bevacizumab 15 mg/kg every 3 weeks x 6-8
cycles. - Bevacizumab continued as single
agent for 1 year 50 pts completed CT, associated
with 2 GI perforations during the induction CT.
43 pts received 360 cycles of maintenance
therapy No grade 4 toxicity, 13 grade 3 toxicity
(muscolo-skeletal pain, dyspnea, hyperglicemia,
hypertension, thrombocytopenia,
proteinuria) Median PFS 11 months
Campos, ASCO Meeting 2007
47
Consolidation and maintenance treatment
Conclusions

• The majority of pts with advanced EOC experience
  OR to TAX/platinum-based CT, but the responses
  are generally of limited duration and long-term
  PFS is still unsatisfactory
• Efforts should be done to consolidate or maintain
  such responses as long as possible, especially
  for subset of pts with G3 and large RD after
  initial surgery who have the highest risk of
  relapse

48
Consolidation and maintenance treatment
Conclusions

• Clinical studies on consolidation with WAR, ip
  32P, RIT, ip CT and HD-CT have given conflicting,
  inconclusive and generally disappoint results.
• The administration of more than 6 cycles of
  1st-line platinum-based CT increases
  treatment-related toxicity without any clinical
  benefit when compared to a standard number of
  induction cycles.

49
Consolidation and maintenance treatment
Conclusions

• The maintenance treatment with 2nd-line agents
  such as epirubicin or topotecan does not appear
  to improve the clinical outcome of pts responsive
  to 1st-line TAX/platinum-based CT.
• The prolonged administration of single-agent TAX
  seemed to improve the PFS of complete responders
  to TAX/platinum-bases CT (SWOG/GOG trial)

50
Consolidation and maintenance treatment
Conclusions

• Italian After-6 trial has not confirmed SWOG-
  GOG trial
• Consolidation chemotherapy should be still
  considered as an experimental treatment that
  deserves to be tested in pts at high risk of
  relapse.

51
Consolidation and maintenance treatment
Conclusions

• Molecular targeted agents able to interfere with
  fundamental steps in tumor cell re-growth (i. e.
  neoangiogenesis and growth factor signaling
  pathways) should be investigated in this clinical
  setting.
• Finally, in the future a more precise definition
  of tumor biological behaviour by gene profiling
  might allow to identify subsets of pts to be
  treated with more tailored approaches.