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Mediterranean School of Oncology (MSO) and Mediterranean Task force for Cancer Control (MTCC) Postgraduate Course

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Title: Mediterranean School of Oncology (MSO) and Mediterranean Task force for Cancer Control (MTCC) Postgraduate Course


1
Mediterranean School of Oncology
(MSO)and Mediterranean Task force for Cancer
Control (MTCC) Postgraduate Course Moroccan
Cancer SocietyCervical Cancer from
Epidemiology to Treatment Medical
TreatmentMarrakech, Saturday, 25 April 2009
  • Prof. Enrico Cortesi
  • Medical Oncology Dpt

2
Treatment options
  • Surgery
  • External beam Radiotherapy (adjuvant or exclusive
    )
  • /- Chemotherapy
  • /- Brachytherapy
  • Chemotherapy

3
Staging of cervical cancer
4
Treatment by stage
Earlier stage disease and smaller
lesions Clinical STAGES 1A - 1B1/ IIA (lt4 cm)
Surgery or pelvic RT and brachytherapy (in
1A2, 1B1 and IIA lt4 cm)
/- CRT if positive pelvic and/or para-aortic
nodes or if positive surgical margins
5
Treatment by stage
  • Selected Bulky IB2, IIA (gt4 cm),
  • IIB, IIIA , IIIB and IV A
  • Surgery Pelvic CRT and
  • brachytherapy
  • /- para-aortic CRT if positive nodes
  • Or
  • Pelvic CRT/ brachytherapy
  • /- Para-aortic CRT
  • if positive nodes

6
Treatment by stage
  • Surgery if feasible /- IORT or CRT
  • Local
  • recurrence
  • CRT if not done before

Chemotherapy alone /- palliative RT
BSC
IV B (distant M)
7
What is the role of Chemotherapy?
  • In association with RT
  • ? Concomitant
    standard
  • ? Neoadjuvant (NACT)
  • ? Adjuvant
  • Metastatic Disease

investigational
8
What is the role of Chemotherapy?
  • In association with RT
  • ? Concomitant
    standard
  • ? Neoadjuvant (NACT)
  • ? Adjuvant

investigational
9
Mechanisms of interaction between CHT and RT
  • Change in the slope of the RT sensitivity curve
    (CDDP, ADM, 5FU, MMC)
  • Inhibition of repair of sublethal damage (CDDP,
    BLM, HU)
  • Synchronization in a more radiosensitive cell
    cycle (HU)
  • Selective cytotoxicity and increase hypoxic cells
    radiosensitivity (CDDP, MMC)
  • Some activity on clones resistant to radiotherapy
    (TXL)

Perez CA et al. Semin Radiat Oncol 745-65, 1997
10
Rational of RT with concomitant CHT
  • Synergy between RT and cytotoxic drugs
  • Direct effect of CHT on primary tumor and on
    distant metastases
  • Activity on different cell populations

11
1996 - Consensus Conference on cervical
carcinoma sequential CH to RT
  • NA (CT ? RT) with cisplatin-containing regimens
    followed by radiotherapy has been studied in
    several randomized trial
  • Tumor response to NACT in more than 50 of
    patients, but no improvement in LC or in OS
  • In some large trial, NACT was inferior to
    standard pelvic RT in terms of LC and OS.
  • adjuvant (RT ? CHT) has small data, and no
    randomized trials have been reported

Tattersall MH. J Natl Cancer Inst Monogr.
21101-3 1996
12
1996 - Consensus Conference on cervical
carcinoma Concomitant CH/RT
There is no evidence that hydroxyurea or
any other concomitant chemotherapy agent
should be incorporated into standard practice
Optimal management of locally advanced cervical
carcinoma radiation therapy is the mainstay of
treatment
Tattersall MH. J Natl Cancer Inst Monogr.
21101-3 1996
Keys H, Gibbons SK. J Natl Cancer Inst Monogr.
21 1996
13
Randomized Trials on CRT
14
Five clinical Trials on concomitant CRT
STUDY FIGO stage Control Group Comparison Group
KEYS et al. (GOG 123) IB2 Radiotherapy Radiotherapy Weekly Cisplatin
ROSE, BUNDY, WATKINS et al. (GOG 120) IIB-IVA Radiotherapy Hydroxyurea Radiotherapy Weekly Cisplatin Or Radiotherapy Cisplatin, 5-FU, Hydroxyurea
MORRIS et al (RTOG 9001) IB2-IVA Extended field Radiotherapy Radiotherapy Cisplatin and 5-FU
WHITNEY et al. (GOG 85) IIB-IVA Radiotherapy Hydroxyurea Radiotherapy Cisplatin and 5-FU
PETERS et al. (SWOG-8797) IB or IIA(selected Postoperatively) Radiotherapy Radiotherapy Cisplatin and 5-FU
15
1999 - Something changed...The NCI Clinical
Announcement
Strong consideration should be given to the
incorporation of concomitant cisplatin based
chemotherapy in women who require radiation
therapy for treatment of cervical cancer
16
SWOG -8797 trial (Adjuv)
268 patients
PFS
OS
p 0,03
p 0,07
  • The addition of concurrent cisplatin based CT to
    RT significantly improves progression-free and
    overall survival for high-risk, early-stage
    patients who undergo radical hysterectomy and
    pelvic lymphadenectomy for carcinoma of the
    cervix.

Peters et AL Journal of Clinical Oncology, Vol
18, No 8 (April), 2000 pp 1606-1613
17
RTOG 9001 Trial (Exclusive)
430 patients
PFS
p 0,04
OS
p lt 0,01
  • The addition of chemotherapy with fluorouracil
    and cisplatin to treatment with external-beam and
    intracavitary radiation significantly improved
    survival among women with locally advanced
    cervical cancer.

Morris et Al NEJM, 1999 340, 1137-1143
Eifel, et al. J Clin Oncol. 200422872-880
18
GOG 123 trial (Neoadjuv)
374 patients
PFS
plt 0,001
p 0,008
OS
  • Adding weekly infusions of cisplatin to pelvic
    radiotherapy followed by hysterectomy
    significantly reduced the risk of disease
    recurrence and death in women with bulky stage IB
    cervical cancers.

Keys et Al, NEJM, 1999 340 1154-1161
19
GOG 120 trial (Exclusive)
526 patients
OS
Stage IIB
Stage III
Overall survival by treatment and number of
patients at risk (for death) at 60 and 120 months
Rose, P. G. et al. J Clin Oncol 252804-2810 2007
20
2001 meta-analysis on Concomitant CRT
Significative Advantage (plt0.0001) OS (gt
12) DFS (gt 16) Local Control Reduction of
Distant metastases Better results in gt I-II
stages and with CDDP based CH
19 randomized trials 12 based on CDDP (/- BLM,
VCR, 5FU) 7 non CDDP (MMC, 5FU, BLM,
EADM) 4580 pz
Green JA et al., Lancet 358781, 2001
21
  • Suggested treatment
  • . application to less developed countries
    requires the regimen to be cheap and easy to
    administer .
  • .. cisplatin once a week fits this criteria.

Green JA et al., Lancet 358781, 2001
22
2001 - CHT RT in cervical cancer
  • Standard Treatment is
  • Concomitant Chemoradiotherapy
  • Platinum based
  • Optimal Radiotherapy

23
Only CDDP?
The study was closed prematurely when a planned
interim futility analysis indicated that PVI
FU/RT had a higher treatment failure rate (35
higher) and would, most likely, not result in an
improvement in progression-free survival compared
with weekly cisplatin/RT.
PVI FU does not show improved outcome over weekly
cisplatin
Lanciano R et al, JCO 238289, 2005
24
Only CDDP ?
5FU 225mg/m2 X5/w po Carbo Carbo 100mg/m2 /week
(IIB 67-IIIB 33) 234 235
Follow UP m 12.6 11.8
CR _at_ 3 m 73 72
PFS 1 y 75 76
OS 1y 93 94
No differences in terms of tumor response rate
or treatment toxicity
Veerasarn V et al, Gynecol Oncol 10415, 2007
25
2006 The COCHRANE Review
  • 24 Randomized Trials
  • 15 Platin based
  • 8 without platin (MMC, 5FU, BLM, EADM..)
  • 4921 pz

26
Cochrane Review
  • Significative advantage for CRT ? OS (10), DFS
    (13) and LC
  • Advantage for metastases not significant
  • Advantages not limited to platinum based CRT
  • gt advantages with adjuvant CT
  • Correlation with stage (I-II vs III-IV)
  • gt G3-4 acute toxicities with CRT
  • Late toxicities not comparable

27
Capecitabine and radiotherapy ASCO 2008 phase
II study
  • Background
  • Role of Capecitabine as radiosensistizer in
    rectal cancer
  • Thymidine phosphorilase highly concentrated in
    cervical cancer tissue compared with healthy
    tissue
  • Encouraging activity as radiosensitizer in
    cervical cancer in phase I and II studies

Dunst J et Al, JCO , 2002 203983-3991
Miwa M. et Al, Eur. J. Cancer, 1998
1274-1281 Torecillas L.et Al, Eur. J. Cancer
Suppl. 2003 52 Padilla et Al, Eur J. Cancer
Suppl 2005, 257
28
Capecitabine and radiotherapy ASCO 2008 phase
II study
Adjuvant capecitabine 1000 mg/mq bid, 1-14, q
21 X 6 cylcle
8 weeks Radiotherapy (EBRT Brachytherapy)
Capecitabine 825 mg/mq bid on RT days
60 patients with stage IIB- IIIB cancer of the
cervix
Primary end point ORR
Secondary endpoint TTP, PFS, OS, Safety,
disease control rates
29
(No Transcript)
30
Key Conclusions
  • High efficacy of this non-platinum based regimen
    in locally advanced cervical cancer
  • PFS compares favourably with cisplatin based
    chemoradiotherapy
  • This is the first study to evaluate adjuvant
    capecitabine in this setting
  • Capecitabine raised no safety concerns and may
    play a role in prolonging TTP
  • Long term follow up is ongoing.

31
What is the role of Chemotherapy?
  • In association with RT
  • ? Concomitant
    standard
  • ? Neoadjuvant (NACT)
  • ? Adjuvant

investigational
32
Neoadjuvant chemotherapy a possible role
  • Tumor size reduction ? to facilitate local
    therapy
  • Inoperable tumors ? Radically resectable tumors
  • Increase of radiosensitivity and decrease of
    hypoxic cell fraction
  • Action on micrometastases
  • Response to NACT can be considered as a
    prognostic factor

33
Phase II studies on NACT
REF. N.of pt Stage CHT RR (CR) Resecability (pCR)
Duenas-Gonzalez 2002 41 IB2-IIIB CDDP 100mg/mq g1 GEM 1000 mg/mq g1,8 q 21 x3 cycles 95 (7,5) 77 (14)
Park 2004 43 IB2-IIB TAX 60 mg/mq CDDP 60 mg/mq q 10 x 3 cylces 90 (39) 100 (11)
Duenas-Gonzalez 2003 43 IB2-IIIB TAX 175 mg/mq CBDCA AUC6 q21 x3 cylces 95 ( 9) 95 (17)
DAgostino 2002 42 IB2-IVA TAX 175 mg/mq EPI 100 mg/mqCDDP 100 mg/mq q21 x 3 cycles 78 (19) 76 (19)
Zanetta 1998 38 IB2-IIIB TAX 175 mg/mqIFX 5 ggCDDP 50 mg/mqq21 x 3 cycles 84 (28) 89 (16)
Di Vagno 2003 58 gtIB2 CDDP 80 mg/mq VNB 25 mg/mq 1,8 q21 x3 cyles Not reported 81 (20)
Gonzalez-Martin A. et Al.Gynecol Oncol. 2008
Sep110(3 Suppl 2)S36-40.
34
NACT? Surgery
  • 872 patients
  • Dose of CDDP between 100 to 300 mg/mg in 10- to
    21-Day cycles
  • Patients population with less advanced disease (
    1/3 stage IB 2/3 Stage II )
  • RESULTS? highly significant effect of NACT ,
    which translates into an absolute gain in 5-year
    OS of 14 (from 50 to 64)

EJC 392470, 2003
35
Neoadjuvant chemotherapy meta-analysis MRC - 2003
Comparison 1
Comparison 2
  • 18 trials CHT?RT vs RT
  • 2074 pt
  • Stages IIB-IVA
  • 5 trials CHT?CH /- RT vs RT
  • 872 pt
  • Stages IB-II

EJC 392470, 2003
36
EJC 392470, 2003
37
Why NACT is not so used today?
  • Meta-analysis did not support the administration
    of NACT before RT alone
  • Meta-analysis suggested an advantage of NACT
    before surgery, when compared with RT alone (but
    this control arm is evidently inferior)
  • Radiotherapy was given only to a part of the
    population analysed in comparison
  • No Phase III study to select the best drug to use
    in Neoadjuvant setting
  • NACT is still considered investigational, new
    studies are required

Gonzalez-Martin A. et Al.Gynecol Oncol. 2008
Sep110(3 Suppl 2)S36-40.
38
EORTC 55995 trial is ongoing
NACT?Surgery CDDP total dose 225 mg/mq Dose
intensity at least of 25 mg/mq/week For a maximum
of 8 weeks
Stage IB2-IIB cervical cancer
CRT CDDP 40 mg/mq/week x 6 weeks External beam
RT 45-50 Gy
From 2002, planned accrual 686 patients
Inclusion criteria age 18-75, stages IB2-IIB,
PSlt2
Waiting for the results
Gonzalez-Martin A. et Al.Gynecol Oncol. 2008
Sep110(3 Suppl 2)S36-40.
39
CRT conclusions
  • standard
  • Concomitant CRT (gt platinum)
  • Locally advanced disease (? IB2)
  • Positive nodes
  • options
  • NACT ? RT maybe, with the right schedule and
    high DI
  • NACT ? Surgery waiting for results from Ph III
    Trials
  • Adjuvant CHT after RT more studies are required
  • Optimal RT

40
What is the role of Chemotherapy?
  • In association with RT
  • ? Concomitant
    standard
  • ? Neoadjuvant (NACT)
  • ? Adjuvant
  • Metastatic Disease

investigational
41
Metastatic disease
  • Prognosis is poor for patients with advanced
    cervical cancer, who are no longer amenable for
    surgical resection or radiotherapy ? 1 year
    survival is less than 20
  • For several years cisplatin alone has been
    considered the most active drug in this setting
  • Single-agent cisplatin showed 20 to 30 ORR, 7
    months of PFS 7.1 months of OS.
  • A number of studies have been conducted to
    identify other active agents to be used alone or
    in combination with CDDP

Long HJ, et al. J Clin Oncol. 2005234626-4633.
Moore DH et Al, JCO 2004 22 3113-3119
42
Metastatic disease
  • First line drugs
  • Carboplatin
  • Cisplatin
  • Paclitaxel
  • Gemcitabine (?)
  • Topotecan (?)
  • First line
  • combination therapies
  • Cisplatin/ Paclitaxel
  • Carboplatin/ Paclitaxel
  • Cisplatin/ Topotecan
  • Cisplatin /Gemcitabine (?)

43
Cisplatin Plus Paclitaxel Improves Response
Rates and Progression-Free Survival in Women With
Stage IV B, Persistent, or Recurrent SquamousCell
Cervical Carcinoma Compared With Cisplatin Alone,
PHASE III study
Cisplatin Paclitaxel vs Cisplatin Alone
  • ? Phase 2 data showed an objective response rate
    (RR) 46 with paclitaxel/cisplatin vs 17 with
    cisplatin alone

Moore DH et Al, JCO 2004 22 3113-3119
44
Summary of Study Design
Quality of life (QoL) and tumor measured after
each cycle
Cisplatin (50 mg/m2) Day 1 of a 21-day cycle 6
cycles total N 134
Patients with stage IVB, recurrent, or persistent
squamous cell cervical cancer (N 264)
Cisplatin (50 mg/m2)/Paclitaxel (135 mg/m2)
Day 1 on a Q3W schedule 6 cycles total N 130
N 264 for intent-to-treat analysis Paclitaxe
l given as a 24-hour infusion followed
immediately by cisplatin.
Moore DH et Al, JCO 2004 22 3113-3119
45
Main Findings
Clinical Outcomes Cisplatin (n 134) Cisplatin/ Paclitaxel (n 130) P Value
Complete response (CR), 6 15
Partial response (PR), 13 21
PR CR () 19 36 .002
Median progression-free survival, mos 2.8 4.8 lt .001
Median overall survival, mos 8.8 9.7 ns
Moore DH et Al, JCO 2004 22 3113-3119
46
Other Outcomes
Toxicity Cisplatin (n 130) Cisplatin (n 130) Cisplatin Paclitaxel (n 129) Cisplatin Paclitaxel (n 129)
Grade 3 Grade 4 Grade 3 Grade 4
Leukopenia 1.5 1.5 35.7 17.0
Neutropenia 2.3 0.8 20.9 45.7
Thrombocytopenia 1.5 0.8 1.6 2.3
Anemia 9.2 3.8 22.5 5.4
Nausea and vomiting 9.2 2.3 9.3 0.8
Moore DH et Al, JCO 2004 22 3113-3119
47
Key Conclusions
  • Cisplatin/paclitaxel significantly increased RR
    and PFS over cisplatin alone
  • Median OS and QoL were not significantly
    different between arms
  • Cisplatin/paclitaxel appropriate for palliative
    treatment of stage IVB cervical carcinoma

Moore DH et Al, JCO 2004 22 3113-3119
48
Cisplatin Topotecan vs Cisplatin alone
  • Randomized phase III trial of cisplatin with or
    without topotecan in carcinoma of the uterine
    cervix a Gynecologic Oncology Group
  • Topotecan/cisplatin and MVAC (methotrexate,
    vinblastine,
  • doxorubicin, cisplatin)
  • both superior to cisplatin in phase 2 trials

Long HJ et Al JCO 2005234626-4633.
49
Objectives
  • Gynecologic Oncology Group (GOG) Study 179
  • To compare efficacy and safety of
    topotecan/cisplatin vs MVAC vs cisplatin in
    patients with advanced cervical cancer
  • MVAC arm not included in analysis due to
    treatment-related deaths (this arm closed early)

Long HJ, et al. J Clin Oncol. 2005234626-4633.
50
Summary of Study Design
Topotecan 0.75 mg/m2 Days 1-3 Cisplatin 50
mg/m2 Day 1 every 3 weeks (n 147)
Patients with advanced (stage IVB) recurrent or
persistent cervical carcinoma (N 356)
Cisplatin 50 mg/m2 Day 1 every 3 weeks (n 146)
Maximum of 6 cycles for nonresponders
MVAC Methotrexate 30 mg/m2 Days 1, 15, and 22
Vinblastine 3 mg/m2 Days 2, 15, and 22
Doxorubicin 30 mg/m2 Day 2 Cisplatin 70 mg/m2
Day 2 every 4 weeks (n 63)
MVAC arm closed early because of
treatment-related deaths trial continued as
2-arm study. Patients achieving partial response
with acceptable toxicity could continue treatment
beyond 6 cycles.
Long HJ, et al. J Clin Oncol. 2005234626-4633.
51
Main Findings
  • OS longer in topotecan/cisplatin vs cisplatin arm
  • 9.4 vs 6.5 mos
  • HR, 0.76 (95 CI, 0.593-0.979) P .017
  • PFS longer in topotecan/cisplatin vs cisplatin
    arm
  • 4.6 vs 2.9 mos
  • HR, 0.76 (95 CI, 0.597-0.969) P .014

Long HJ, et al. J Clin Oncol. 2005234626-4633.
52
Main Findings
  • ?Cisplatin-naive vs cisplatin-experienced
    patients
  • Adding topotecan significantly extended PFS
  • PFS, 6.9 vs 3.2 mos HR, 0.50 vs 0.87 (P .03)
  • OS, 15.4 vs 8.8 mos HR, 0.63 vs 0.78 (P .42)
  • ?ORR significantly higher in topotecan/cisplatin
    arm

Outcome Topotecan Cisplatin (n 135), n () Cisplatin (n 139), n ()
CR 14 (10) 4 (3)
PR 22 (16) 14 (10)
ORR (CR PR) 36 (27) 18 (13)
Stable disease 61 (45) 70 (50)
Progressive disease 38 (28) 51 (37)
p 0,004
Long HJ, et al. J Clin Oncol. 2005234626-4633.
53
Key Conclusions
  • In patients with advanced cervical cancer,
    topotecan/cisplatin
  • Prolonged OS vs cisplatin alone
  • Improved median survival by approximately 3 mos
  • Improved PFS
  • Increased ORR
  • This combination was active in both
    cisplatin-naive and cisplatin- treated patients
  • High incidence of grade 3/4 neutropenia
    w/topotecan
  • Manageable toxicity did not impact quality of life

Long HJ, et al. J Clin Oncol. 2005234626-4633.
54
A randomized phase III trial of four cisplatin
(CIS) containing doublet combinations in stage
IVB, recurrent or persistent cervical carcinoma
a gynecologic oncology group (GOG) study.
  • Paclitaxel 135 mg/m2 over 24 hrs CIS 50 mg/m2
    day 2 every 3 wks (PC, Reference Arm)

Vinorelbine 30 mg/m2 day 1 and 8 CIS 50 mg/m2
day 1 every 3 wks (VC)
513 patients with recurrent or metastatic disease
Gemcitabine 1,000mg/m2 day 1 and 8 CIS 50 mg/m2
day 1 every 3 wks (GC)
Topotecan 0.75 mg/m2 days 1, 2, and 3 CIS 50
mg/m2 day 1, every 3 wks (TC
B. J. Monk, M. Sill, D. S. McMeekin, D. E. Cohn,
L. Ramondetta, C. H. Boardman, J. Benda
ASCO 2008 abstr LBA5504
55
  • In April 2007, a planned interim analysis
    recommended early closure since all experimental
    arms were unlikely to demonstrate a significant
    advantage compared to PC by the end of the study.
  • Conclusions VC, GC, and TC are not superior to
    PC in terms of OS.
  • Detailed results concerning OS, RR and PFS along
    with toxicity have to be presented.
  • Quality of life data will be important in
    defining optimal therapy in this setting.

B. J. Monk, M. Sill, D. S. McMeekin, D. E. Cohn,
L. Ramondetta, C. H. Boardman, J. Benda
ASCO 2008 abstr LBA5504
56
Potential II line treatments
  • Vinorelbine 1? RR 13,7
  • Irinotecan 2? RR 21, OS 6,4 mon.
  • Liposomial doxorubicin
  • Docetaxel ? Ongoing phase II study, GOG 0127S
  • Ifosfamide 3? RR 15
  • Premetrexed 4? RR 25, OS 7,4 mon, PFS 3,1 mon.
  • Mytomicin

1Muggia FM et al,Gynecol Oncol. 2004
Feb92(2)639-43.
2Verschraegen et al,J Clin Oncol. 1997
Feb15(2)625-31.
3 Sutton GP et al,Gynecol Oncol. 1993
Apr49(1)48-50.
4D.Scott Miller et al, Gynecologic Oncology,
2008,65-70
57
Treatment by stage
Earlier stage disease and smaller
lesions Clinical STAGES 1A - 1B1/ IIA (lt4 cm)
Surgery or pelvic RT and brachytherapy (in
1A2, 1B1 and IIA lt4 cm)
/- CRT if positive pelvic and/or para-aortic
nodes or if positive surgical margins
58
Treatment by stage
  • Selected Bulky IB2, IIA (gt4 cm),
  • IIB, IIIA , IIIB and IV A
  • Surgery Pelvic CRT and
  • brachytherapy
  • /- para-aortic CRT if positive nodes
  • Or
  • Pelvic CRT/ brachytherapy
  • /- Para-aortic CRT
  • if positive nodes

59
Treatment by stage
  • Surgery if feasible /- IORT or CRT
  • Local
  • recurrence
  • CRT if not done before

Chemotherapy alone /- palliative RT
BSC
IV B (distant M)
60
???? ????????? grazie 1000 !enrico.cortesi_at_
uniroma.it
61
Thanks for the attention!
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