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Advanced and Relapsed Cervix Cancer ESGO Teaching Course Yerevan Armenia September 2010. Nick Reed Beatson Oncology Centre GLASGOW. Relapsed Cervix Cancer. Follow up of Cervix Cancer Careful Monitoring Clinical exam Symptoms Is there any role for routine imaging?

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advanced and relapsed cervix cancer esgo teaching course yerevan armenia september 2010

Advanced and Relapsed Cervix CancerESGO Teaching Course Yerevan Armenia September 2010

Nick Reed

Beatson Oncology Centre

GLASGOW

relapsed cervix cancer
Relapsed Cervix Cancer
  • Follow up of Cervix Cancer
  • Careful Monitoring
  • Clinical exam
  • Symptoms
  • Is there any role for routine imaging?
  • Imaging, CT MRI (PET)
  • Role of Pap smears
problems of diagnosing relapse
Problems of Diagnosing Relapse
  • Post Radiation Effects
  • Difficulty in Interpretation
  • Need for Histological confirmation
  • Wait 3 months after treatment
prediction of relapse
Prediction of Relapse
  • Traditional data indicate about 35% of patients will relapse
  • Stage 1B ) 10-20%
  • Stage 2A )
  • Stage 3B )
  • Stage 4A ) 60-70%
  • Stage 4B )
typical symptoms of relapse
Typical Symptoms of Relapse
  • Weight loss, Leg Oedema
  • Pelvic and/or thigh/buttock pain
  • Back ache
  • Bloody vaginal discharge
  • Supraclavicular Lymph Nodes
  • Cough, SOB, Haemoptysis
  • Chest pain
sites of metastatic disease
Sites of metastatic disease

Metastatic sites treated patients

Henriksen E: Am J Obst &Gyn 1949

Metastatic sites untreated patients

Henriksen E: Am J Obst & Gyn 1949

relapsed cervix cancer1
Relapsed Cervix Cancer

Following RT

  • 27% relapses in Cervix / Uterus or upper vagina
  • 6% Lower vagina
  • 43% Parametrium
  • 16% Distant
  • 8% Unknown

Following RHND

  • 25% local recurrences at vault/upper vagina
relapsed cervix cancer2
Relapsed Cervix Cancer
  • Triad of:
  • Weight Loss + Pelvic Pain + Oedema Legs
  • Ureteric obstruction
  • Back ache from Hydronephrosis
relapsed cervix cancer3
Relapsed Cervix Cancer
  • Traditionally most deaths within 1st year
  • 50% of deaths within 12 months
  • 25% in second year
  • 15% during third year
  • Newer CCRT may delay this pattern
chemotherapy for relapse
Chemotherapy for Relapse
  • Predictors of Response
  • Site of disease following RT
  • Intra Field vs Outwith RT field
  • e.g. Para-aortics
  • Chest, Lung mets only
  • Other sites
management of relapse
Localised Disease

Surgery (Exenteration)

Radiation

Chemo-radiation

Metastatic disease

Chemotherapy

Hyperthermia

Chemo-radiation

New Drugs

Novel approaches

Management of Relapse
response rates
Response Rates
  • Response with Isolated Relapses
  • Response in lungs : CR 53% OR 73%
  • Response in pelvis : CR 0% OR 21%

(Potter M : Cancer 1989)

  • Highlights Issues of vascular access
  • Hypoxia
  • Most studies differentiate prior RT
chemotherapy for relapsed disease
Chemotherapy for Relapsed disease
  • Wasserman & Carter 1977 Review
  • Limited drugs available
  • No differences allowed for site or prior therapy
  • Pre Platinum era
chemotherapy for cervix
Chemotherapy for Cervix
  • Post 1977
  • Recognition of influencing factors
  • Chemo naïve vs prior therapy
  • Previous EBRT
  • Advent of cisplatin
  • Major Impact!!
platinum
Platinum
  • Initial data used cisplatin @ 50 mg/m2
  • Given every 3 weeks
  • GOG 43 : 20-31% RR
ifosfamide
Ifosfamide

Phase 2 studies

  • Coleman R 16-40% RR

incl. 20% CR and median response of 26 mo

  • Sutton GOG : 15.7% RR
  • Cervellino 1995 : 50 RR%
  • Cis vs Cis Ifos GOG
other drugs in cervix cancer
Mitolactol 28-29%

Epirubicin 27%

Mitomycin C 12%

Vindesine 0-30%

Vinorelbine 13-21%

Newer Drugs

Topotecan

Gemcitabine

Taxol 17%

Irinotecan 20%

Other Drugs in Cervix Cancer
combinations
Combinations
  • Non cisplatin containing
  • Cisplatin containing
  • Bleomycin added
  • Vogl reported Cis/ Bleo/ Mtx
c ifx bleo vs c ifx gog 149
C Ifx Bleo vs. C Ifx : GOG # 149

32% vs. 31% PFS and OS =

Bloss (JCO 2002 15: 165-171)

relapsed cervix cancer4
Relapsed Cervix Cancer
  • SWOG : Comparative studies
  • Cis 33% 17 mo
  • Cis + MMC 25% 7 mo
  • Cis+ MMC + Bleo +V 22% 6.9 mo

Alberts D ; JCO 1987: 5:1791-5

relapsed cervix cancer5
Relapsed Cervix Cancer
  • Cis + Epi > Cis + Dox, ? Why difference
  • BIP : 69-74% RR
  • GOG study # 110
  • Cis 17% RR 3.2 mo PFS
  • Cis + Ifos 31% RR 4.6 mo PFS
  • Cis + Mitolactol 21% RR 3.3 mo PFS
eortc studies
EORTC Studies
  • 55802 Phase 2 VCR/Bleo/MMC/Cis (VBMP)
  • 55811 Phase 2 Vindesine
  • 55832 Phase 2 MMC/ Cis
  • 55835 Phase 2 Bromocriptine
  • 55883 Phase 2 Vinorelbine
  • 55842 Phase 2 Epirubicin
  • 55863 Phase 3 P vs BEMP
eortc vbmp 55802
EORTC VBMP : 55802
  • Group A Distant mets
  • 26 pts
  • 54% RR -31% CR
  • Median TTP 20 wk
  • Median Survival 42 wk
  • Group B Pelvic mets
  • 24 pts (23 prior RT)
  • 25% RR - all PR
  • Median TTP 15 wk
  • Median Survival 32 wk

Vermorken JB et al, Int J Gyn Cancer 2000,10: 358-65

eortc 55832 phase 2 mmc cis
EORTC55832 Phase 2 MMC/ Cis
  • Mitomycin C 6 mg/m2 d1
  • Cisplatin 50 mg/m 2 d1
  • 33pts All bar 1 had prior Sx/RT
  • 25 distant mets only , 8 local
  • OR 42%
  • 5 CR 9 PR duration 7.9 mo
  • Median Overall Survival 11.2 mo

Wagenaar HC et al Eur J Cancer 37 1624-1628, 2001

eortc 55863 p vs bemp
EORTC 55863 P vs BEMP
  • Cisplatin 50 mg/m2
  • Bleomycin 15 mg/ m2 d2-4
  • Eldisine 3 mg/ m2 d1
  • Mitomycin C 8mg/m2 d1 alt cycles
  • Cisplatin 50 mg/m2 d1
    • Q 3/52 x4 then Q 4/52 sine Bleo
eortc 55863 p vs bemp1
EORTC 55863 P vs BEMP

BEMP 35% RR (CR 9%)

P 20% RR (CR 6%)

bemp vs p
BEMP RR

All pts 35%

Eligible 42%

Evaluable 54%

CR 11%

Med Duration 9.2 mo

CISPLATIN RR

All pts 20%

Eligible 25%

Evaluable 27%

CR 7%

Med Duration 7 mo

BEMP vs P
future directions
Future Directions

Outside clinical trials the use of Cisplatin alone is still the gold standard if chemotherapy is used for palliation.

The use of more aggressive regimes seems to bring additional toxicity.

GOG 169 and 179 bring fresh light.

gog studies
GOG studies
  • GOG 169
  • GOG 179
  • GOG 204
  • GOG 240
cisplatin taxol
Cisplatin + Taxol
  • Cisplatin & Paclitaxel
  • 47% RR (CR 14%, PR 33%) OS 9 mo Christos & Papadimitriou
  • GOG #169
  • Cisplatin (50 mg/m2) 19.4%
  • Cis + Paclitaxel (135 mg/m2 /24 hr) 36.2%
  • Cis CR 8% PR 18% OS 8.8 mo
  • Cis Tax CR 20% PR 27% OS 9.7 mo

Moore D, Proc ASCO 2001:20;201a

cisplatin p vs cisplatin plus paclitaxel pp phase iii study in sccuc gog 169
Cisplatin (P) vs Cisplatin plus Paclitaxel (PP)Phase III Study in SCCUC (GOG 169)

R

A

N

D

O

M

I

Z

E

Patients Cisplatin 50 mg/m²

Stage IV B q 3 wks x 6

Recurrent/persistent (n=134)

Measurable disease

PS 0-2

Cisplatin 50 mg/m² Paclitaxel 135 mg/m²/24h

Paclitaxel 135 mg/24 hrs

q 3 wks x 6

(n=130)

slide33

Cisplatin (C) vs Cisplatin plus Paclitaxel (CP)Phase III Study in SCCUC (GOG 169)

C CP

n=134 n=130 p-value

Response rate 19% 36% 0.002

CR rate 6% 15% < 0.05

Median PFS 2.8mo 4.8mo <0.001

Median survival 8.8mo 9.7mo ns

Neutropenia (G3+4) 31% 66.6%

Anemia (G3+4) 13% 27.9%

Quality of life no significant difference in scores

slide34

Cisplatin (C) vs Cisplatin plus Paclitaxel (CP)Phase III Study in SCCUC (GOG 169)Response rate according to previous platinum

chemoradiation radiation

C 2/40 ( 5%) 24/94 (26%)

C+P 10/31 (32%) 37/99 (37%)

gog 179
GOG 179
  • Cisplatin
  • MVAC**
  • Cisplatin Topotecan
  • ** Stopped early because of toxicity
gog 179 relapsed cervix overall survival
GOG 179 Relapsed CervixOverall survival

Long H et al JCO 2005 : 23; 4626-33

gog 204
GOG 204
  • Cisplatin paclitaxel
  • Cisplatin topotecan
  • Cisplatin vinorelbine
  • Cisplatin gemcitabine
  • No difference
relapsed cervix cancer non platinum agents
Relapsed Cervix CancerNon Platinum agents
  • Taxol 175 mg/m2 d 1
  • Topotecan 1 mg/m2 d 1-5
  • 54% RR ( 1CR and 6 PR) & 23% SD
  • PFS 3.7 mo OS 8.6 mo

Tiersten et al Gyn Onc 92,635-638: 2004

  • Phase 2 RCTs , only conclusion is that no added advantage to > 1 drug
gog 240
GOG 240
  • Cisplatin and paclitaxel
  • vs
  • Paclitaxel and topotecan
  • +/- Bevacizumab
newer directions
Newer Directions
  • SNAP 01
  • TIP vs IP
  • Neo-adjuvant schedules
  • Carboplatin and paclitaxel
  • Cisplatin plus other drugs
slide47
TIP
  • Taxol + Ifos + Cisplatin
  • OR 66% (CR 33%, PR 33%)
  • Survival in CR 13 mo+
  • Survival in PR 9 mo+
  • Survival in Non 6 mo

Zanetta, Mangioni et al

slide49

Anti-EGF Receptor Therapies

EGFR expression observed in 75-100 % of CC

Phase II study ZD1839 (500mg/d), no responses

Inhibition of angiogenesis a/o matrixmetalloproteinases. One complete response with TNP-470, an analogue of fumagillin, was seen in phase I.

Inhibition of COX-2 enhanced cytotoxicity in vitro of chemotherapy agents: potentiates tumor cell radiosensitivity in vivo

EGFR Tyrosine kinase inhibitors

Cetuximab (Erbitux)

Alone? Or Combined with radiation?

See H&N SCC data

slide50

VEGFR

  • Avastin for relapse 2nd or 3rd line
  • SGO abstract 2008
  • Reported 25% RR
  • How to integrate?
  • 1st line for hypoxic tumours?
  • Use of markers to predict, CAIX
  • Functional Imaging
other new agents
Other new agents
  • Cediranib
  • Pazopanib
  • Lapatinib
  • Single agent or in combination?
  • Carboplatin & Paclitaxel combination
  • All of the above under investigation
future directions1
Future Directions
  • Horizon Scanning
  • New drugs
  • Novel drugs
  • Novel schedules
  • Hypoxia