1. GCIG Cervix Committee November 14, 2008

2. GOG 240 Schema R A N D O M I Z E Regimen I
Paclitaxel 135 mg/m2 IV d1 (24h)
Cisplatin 50 mg/m2 IV d2
Q21d to progression/toxicity R A N D O M I Z E
Regimen II
Paclitaxel 135 mg/m2 IV d1 (24h)
Cisplatin 50 mg/m2 IV d2
Bevacizumab 15 mg/kg IV d2
Q21d to progression/toxicity
Eligibility:
1. Primary stage IVB or
Recurrent/persistent
carcinoma of the cervix
2. Measureable disease
3. GOG PS 0-1
Regimen III
Paclitaxel 175 mg/m2 IV d1 (3h)
Topotecan 0.75 mg/m2 d1-3 (30m)
Q21d to progression/toxicity
Regimen IV
Paclitaxel 175 mg/m2 IV d1 (3h)
Topotecan 0.75 mg/m2 d1-3 (30m)
Bevacizumab 15 mg/kg IV d1
Q21d to progression/toxicity

3. GOG 240 Primary & Secondary Endpoints
Primary Endpoints
1. Survival time from date of randomization
2. Frequency & severity of adverse events
CTCAE version 3.0
Secondary endpoints
1. PFS from date of randomization
2. Frequency of objective tumor response

4. GOG 240 Statistical Design
Randomized, phase III trial
2x2 factorial design (n=450)
Intent to treat principle
Random assignment to the four arms balanced for
Disease status
Performance status
Prior platinum therapy with pelvic RT
Reduction of hazard of death by 30% by addition of either bevacizumab or non-platinum doublet important to detect
Interim analysis to be conducted after 173 deaths

5. GOG 240 Toxicity monitoring
Topotecan-Paclitaxel-related toxicities – DSMB evaluation
(Myelosuppression and infection)
Stage
Cummulative Patients
Min # Events 1 50 19 2
100 30
Bevacizumab-related toxicities – DSMB evaluation
(Bowel perforation, hemorrhage, necrosis, fistula, PE)
Stage
Cummulative Patients
Min # Events 1 50 12 2
100 18

6. GOG 240 Exploratory Endpoints
Health-Related Quality of Life
FACT-Cx TOI
FACT-GOG/Ntx subscale (neuropathy symptoms)
BPI single item for pain
Prospective validation of prognostic markers
Smoking behavior
Prevalence of active smoking
Extent of nicotine dependence
Nicotine dependence with PFS & OS
Translational science

7. GOG 240 CellSearchTM Circulating Tumor Cell (CTC) Test
Number of CTCs - Correlation with PFS & OS Clearance of CTCs - Correlation with response - Correlation with OS & PFS

8. GOG 240 International Collaborators
Norway:
Gunn Kristensen MD
Germany:
Falk Clemens Thiel MD
South Korea:
Jong-Min Lee MD PhD
Spain:
Ana Oaknin Benzaquen

9. GOG 240 International Collaborators
NORWAY
Kristensen, Gunnar Department of Gynecologic Oncology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway Department of Medical Informatics, University of Oslo, Oslo, Norway
SPAIN
Dra. Ana Oaknin Benzaquen
Oncología Médica. División de Ginecología
Institut Català d´Oncologia. Hospital Duran i Reynals
Tel :
Fax:
KOREA
Jong-Min Lee, MD, PhD Associate Professor Department of Obstetrics and Gynecology East-West Neo Medical Center Kyung Hee University 149 Sangil-dong, Gangdong-gu, Seoul, , South Korea ; Office; Cell; Fax;
GERMANY
Falk Clemens Thiel, MD
Department of Gynecology University Hospital Erlangen
Universitätsstr. 21­ Erlangen Germany
Tel

10. GOG 240 Status
This protocol has received approval by the NCI and Central IRB and we anticipate activation within the upcoming 2-3 months.

11. John H. Farley MD
Associate Professor Obstetrics and Gynecology
Uniformed Services University of the Health Sciences
CVM0503

12. To determine if combining Cetuximab with cisplatin during radiation therapy increases overall survival (OS) when compared with weekly cisplatin and radiation therapy in patients with cervical cancer metastatic to high common and/or para-aortic lymph nodes.
Secondary Objective
To determine if the addition of Cetuximab to cisplatin and radiation therapy in this patient population improves progression-free survival (PFS).
To determine the relative toxicities of the addition of Cetuximab to cisplatin in this patient population.
CVM0503

13. Test the hypothesis that Cetuximab will be more effective in tumors that express low compared with high levels of the hypoxia marker Hypoxia Inducible Factor-1α (HIF-1α) and epidermal growth factor receptor (EGFR),
CVM0503

14. Concurrent Weekly Cisplatin + Cetuximab (preferably Monday)
Cisplatin 30mg/m2/week x 6 weeks
Cetuximab 400 mg/m2 initial loading dose week 1, then 250 mg/m2 x 5 weeks
VERSUS
In patients receiving extended field radiation therapy; pelvis and para-aortics.
4500 cGy in 29 fractions to the para-aortic nodes
(150 cGy/fraction)
4500 cGy in 25 fractions to the pelvis
(180 cGy/fraction)
CVM0503

15. Trial population
Cervical cancer patients with positive para-aortic and/or pelvic nodes :
Squamous Cell Carcinoma, Adenocarcinoma, Adenosquamous Carcinoma,
Clinical stages
IB, IIA, IIB, IIIA, IIIB, IV
Number of subjects: 328
CVM0503

16. GOG-0233/ACRIN-6671
UTILITY OF PREOPERATIVE FDG-PET/CT AND FERUMOXTRAN-10 MRI SCANNING PRIOR TO PRIMARY CHEMORADIATION THERAPY TO DETECT RETROPERITONEAL LYMPH NODE METASTASIS IN PATIENTS WITH LOCOREGIONALLY ADVANCED (IB2, IIA 4 CM, IIB-IVA) CARCINOMA OF THE CERVIX.
Has accrued 22/325 patients

17. GOG 219 October 23, 2008

18. GOG 219 ACCRUAL TO DATE = 301 PATIENTS
Enrollment primarily from U.S. sites
International participation increasing, specifically NCI Canada
Factors (pro)
Starting dose reduced after 1st toxicity evaluation
NCIC sites gaining experience with regimen
Factors (con)
Regulatory bodies in other countries
International shipment of drug
GOG-0219

19. ENROLLMENT BY QUARTER
GOG-0219

20. AMENDMENT
The Data Monitoring Committee (DMC) of the Gynecologic Oncology Group convened to review the interim safety analysis as outlined in section 11.5 of the study. In reviewing toxicity data, there was a higher than 20% incidence of Grade 3 or 4 toxicity in the form of leucopenia and metabolic toxicity. Median length of radiation therapy was similar in both arms and there were no deaths related to study participation. Based on their review in assessing the clinical impact of the toxicity, the DMC recommended decreasing the starting dose on regimen II to by one dose level rather than two dose levels as originally stipulated in section The starting dose on trial (now dose level I) is the previous dose level -1 from former versions (prior to NCI Version Date 10/03/2007).
GOG-0219

21. AMENDMENT
Regimen II: Concurrent Cisplatin and TPZ and Radiation Therapy (10/23/2007)
Cisplatin 60mg/m2 (max = 105 mg) administered IV over minutes days 1, 15 and 29 with radiation therapy
TPZ 220mg/m2 (max = 385 mg) IV administered over two hours prior to Cisplatin on days 1, 15 and 29
TPZ 220mg/m2 (max = 385 mg) IV over two hours days 8, 10, 12, 22, 24, 26 with radiation therapy.
GOG-0219

22. AMENDMENT
A second safety analysis will be performed after treating 30 more patients on the TPZ arm (with the new starting dose). In the event Grade 3 or 4 toxicity continues to be significantly higher among patients on the TPZ arm or duration of radiotherapy is prolonged significantly in any of the arms, the trial committee may recommend further dose modification or study termination.
GOG-0219

23. Korea Cancer Center Hospital
CVM 0801/KGOG 1008
A Randomized Trial of Concurrent Chemoradiation for Postoperative Cervical Cancer with Intermediate Risk Factors
Sang Young Ryu, M.D.
Korea Cancer Center Hospital

24. CVM 0801/KGOG 1008 Adjuvant CCRT- High Risk Factor
SWOG Peters 2000: Stage <IIB, LN, RM, PM:
FP CCRT(x2) + 2 FP vs RT
RR 0.50; PFS 80 vs 63%, OSR 81 vs 71%,
Local rec 20 vs 7, Distant rec 13 vs 9
No brachytherapy
Toxicity; 21 vs 4 Gr IV toxicity
Aedno, adenosquamous CCRT; good but no statistic signif.
GOG 109; FP vs RT only; FP arm is superior to RT alone arm
high hematologic toxicity
Standard treatment

25. CVM 0801/KGOG 1008 Adjuvant CCRT-intermediate risk factors
No Clinical Trials
GOG 92 Sedlis 1999; IB intermediate, adjuvant RT vs no RT;
2 of >1/3 stromal invasion, LVSI, tumor size
Rec Rate; 28 vs 15%
2YDFS; 88 vs79%, RR 0.53

26. KCCH Retrospective Results
RH with BPLND
FIGO stage IB – IIA cervical cancer patients
735 cases
172 cases
Any of intermediate risk factor
34 cases
49 cases
89 cases
No further treatment
RT only
CCRT
Fig. 1. Patients enrolled in this study

27. CVM 0801/KGOG 1008

28. CVM 0801/KGOG 1008 Cervical cancer Control Arm; Radiation therapy
Randomization
Cervical cancer
Stage IB-IIA
Radical hysterectomy+BPLND
>2 of intermediate risk factors
CRT Arm; Weekly CDDP 40mg/m2 concurrent to radiation

29. CVM 0801/KGOG 1008 Primary endpoint; Secondary endpoint; QoL
3 year recurrence free survival
6.3% (87% to 93.3%)
Secondary endpoint;
Recurrence rate
Toxicity
QoL

30. CVM 0801/KGOG 1008

31. CVM 0801/KGOG 1008 Pathology Review pathologic slides H&E only
Tumor cell type
Squamous, adenoca, adenosquamous
Depth of stromal invasion
in thirds of cervical thickness
Tumor diameter; palpation, largest diameter on section, imaging studies
Presence or absence of the LVSI

32. CVM 0801/KGOG 1008 Radiation (GOG 92) Within 4-6 weeks postop ERT
Weekly Hg >11mg/ml, ANC > 1000/ul, Plt >100,000/ul
Tranfusion of P/C or IV iron if necessary
ERT
Four field box technique with megavoltage beam
Dose 46Gy in 23 fraction,or 50.4 Gy in 28 fraction
Treatment break for clinical problems allowed to total no more than 1 week
No brachytherapy

33. CVM 0801/KGOG 1008 Chemotherapy Eligible Schedule (6 cycles)
Total WBC > 2,000/uL, ANC> 1000 /ul, Plt > 100,000/uL
Schedule (6 cycles)
40mg/m2 on days 1, 8, 15, 22, 29, and 36
Dose Reduction
25% DR
grade 3 stomatitis
Nadir Plt < 50,000/ul, WBC <2000/uL->25% DR
50% grade 4 stomatitis
Hold
Caluculated Ccr < 50ml/min
grade III, IV neuropathy

34. CVM 0801/KGOG 1008 Statistics 6.3% increase of RFS Power 80%
Type I error; 0.05
Sample size: 480
Total sample size: 534
Total period: 54month
Expected events: 36 recurrences in control arm

35. RTOG/GOG combined study for high-risk early stage Cervical Carcinoma
Anuja Jhingran
RTOG-0724

36. Background 90% early stage cured with surgery or xrt alone
15%-20% of early stage present with positive nodes, parametrium or margins - survival drops to 50-70% with surgery alone
Even with adjuvant xrt - 40% fail - 10% in field and 10% out of field
Recent update of the SWOG trial – 5-yr survival with CT/RT – 2 or more positive nodes – 77%
RTOG-0724

37. Concurrent Chemotherapy and Pelvic Radiation Therapy Compared With Pelvic Radiation Therapy Alone as Adjuvant Therapy After Radical Surgery in High-Risk Early-Stage Cancer of the Cervix GOG 109: Peters et al JCO 2000 37

38. Concurrent Chemotherapy and Pelvic Radiation Therapy Compared With Pelvic Radiation Therapy Alone as Adjuvant Therapy After Radical Surgery in High-Risk Early-Stage Cancer of the Cervix GOG 109: Peters et al JCO 2000 38

39. Rethinking the use of radiation and chemotherapy after radical hysterectomy: a clinical–pathologic analysis of a Gynecologic Oncology Group/Southwest Oncology Group/Radiation Therapy Oncology Group trial Monk et al Gyn Onc 2005 39

40. Proposed Intergroup trial Stage I/IIA Cervical Cancer
Radical Hyst:
+LN’s, - include para-aortic nodes, and parametrium
Randomize
ARM 1
ARM 2
XRT Gy
Cisplatin 40 mg/m2 wkly
XRT Gy
Cisplatin 40 mg/m2 wkly
Carboplatin AUC 5
Paclitaxel 135mg/m2 q3weeks X4
PI’s A. Jhingran RTOG
H. Gray GOG
RTOG-0724
400 pts 40

41. Hypothesis
To determine if adjuvant systemic chemotherapy following chemoradiation therapy will improve disease-free and overall survival compared to chemoradiation therapy alone in patients with high-risk early-stage cervical carcinoma found to have positive nodes and/or positive margins and/or positive parametria after a radical hysterectomy. The expected benefit would be approximately 10%-15% – Acrrual patients.
RTOG-0724 41

42. Endpoints 2.1 Primary objective: 2.2 Secondary objective(s): RTOG-0724
Disease-free survival
2.2 Secondary objective(s):
1) Toxicity
2) Overall survival
3) Quality of life
4) To collect fixed tissue to identify tumor molecular signatures that may be associated with patient outcomes.
5) To collect blood from serum and plasma - looking factors correlated with toxicity and outcome
RTOG-0724 42

43. RTOG 0724
IMRT allowed.
Vaginal Brachytherapy allowed.
RTOG-0724

44. New Concepts in Locally Advanced Cervix Cancer
Nick Reed
Personal thoughts
for debate at GCIG Nov 2008

45. Need for Improvement
Improving outcomes of bulky locally advanced cervix cancer
New Approaches
Induction / neoadjuvant schedules
Maintenance treatments
Targeted agents
Functional Imaging

46. Diagnostic Pathway CCRT Newly diagnosed Stage 1B2 – 4A
Baseline Imaging
NACT Induction
Reassessment
Imaging and CCRT
CCRT

47. So where is my evidence?

48. Newer Approaches - Induction
Meta-analysis from data with Cis +/-
Carboplatin vs Cisplatin
Addition of Paclitaxel - Hoskin & Glynne-Jones
Mexico- Duenas -Gonzalez
UCL – McCormack CX2 study
Still premature but exciting interest

50. The Study Options Maintenance chemotherapy NACT Induction CCRT
Observation

51. Reed’s Observations I am convinced NACT is the way forward
I am convinced dose dense and dose intense schedules are needed
I think a taxane  is essential rather than platinum alone
I think TR and  functional imaging should  be  integral

52. So what would I propose?? Fresh tissue for banking +/- serum
Baseline  scan , preferably PET CT +/- MRI (advice from  radiologists)
Explore new imaging agents (hypoxia markers)
9 weekly doses  of  carbo/paclitaxel  (AUC 2-3 and  pac mg/m2) 
Reassess clinically and  radiologically plus repeat samples for  freezing

53. Diagnostic Pathway CCRT TR Biopsy Imaging TR Biopsy Imaging
Newly diagnosed Stage 1B2 – 4A
Baseline Imaging
NACT Induction
Reassessment
Imaging and CCRT
CCRT
TR Biopsy
Imaging
TR Biopsy
Imaging

54. Chemo-Rads CCRT
Proceed to standard  concomitant chemoradiotherapy (CCRT)
Try for international consensus on EBRT dose and also BT

55. The Other Option - Maintenance
Why?
Tierney IPA suggests benefit
Which maintenance?
How many cycles
Conventional or TAT or both
Candidates

56. The Next Steps
Next phase would  be to consider adding a  biological/TAT, maybe  RCT phase 2
Next phase would  be to look at maintenance or no  maintenance

57. The Study Options Maintenance chemotherapy NACT Induction CCRT
Observation

58. Where next?
Discussion
Manchester SOTS??

59. A pilot study of adjuvant chemotherapy for high-risk cervical cancer
Linda Mileshkin, Danny Rischin, Kailash Narayan
ANZGOG 59

60. Background
Early-stage cervical cancer is highly curable with surgical approaches or chemoXRT
Lower cure rates with more advanced disease seen in those who have not participated in screening
Traditional main prognostic factor is the FIGO staging system - principally based on clinical examination
Uterine and nodal involvement on imaging also prognostic
ANZGOG 60

61. Background
Prospective audit data from 238 pts treated with primary chemoXRT for cervical cancer
170 (71%) had corpus invasion on MRI
41% of these recurred cf. 19% without invasion
FIGO stage and clinical diameter not prognostic in the presence of uterine invasion
108 (45%) had PET +ve nodal disease
51% PET +ve recurred cf. 22% in PET -ve
Majority of recurrences distant
ANZGOG
Narayan K 2006 and 2007 61

62. Background – adjuvant chemo
Chemo concurrent with XRT improves survival and is standard care
Additional chemo after chemoXRT may treat distant mets and ↑ survival in high-risk pts
Few small retrospective studies with older chemo in unselected patients suggest no survival advantage and some toxicity
Carboplatin/paclitaxel active in cervical ca and likely more deliverable after XRT than cisplatin/topotecan
ANZGOG 62

63. Background – adjuvant chemo
GOG 109: post-op chemoXRT for those with +ve nodes/ margins or parametrium involved
:2 extra cycles of cis/5FU given after chemoXRT
: subset analysis suggested improved PFS and OS with more cycles of chemo
ANZGOG 63

64. Research Plan Design: Single-arm phase II study (n=30:pragmatic)
Eligibility: Stage 1b-IVa cervical cancer suitable for primary treatment with chemoradiation with curative intent in addition to one of the high-risk features of:
Pelvic nodal involvement on:
staging PET scan
staging CT if >15mm diameter, or
- frozen section during planned surgery leading to abandonment of planned hysterectomy
b) Uterine involvement on MRI
EBR alone; EBR plus brachytherapy; EBR plus Chemo
ANZGOG

65. Aims and Objectives Aim: To test the feasibility of the regimen
Primary objective: To determine the percentage of patients able to complete all treatment components without significant treatment interruptions or omissions due to grade 3 or 4 toxicity
Secondary objectives: To determine the
Acute and long-term toxicities
Patterns of disease recurrence
Failure-free survival
ANZGOG 65

66. Intervention
Gy of external beam XRT in 25 to 28 fractions plus brachytherapy
Cisplatin 40mg/m2 weekly during XRT
Within 4 weeks of completion of XRT and following recovery from toxicities, 4 cycles of 3 weekly adjuvant chemotherapy using Carboplatin AUC 5 and Paclitaxel 175 mg/m2
ANZGOG 66

67. Future phase III study
Stage Ib-IVa Cervical cancer Node positive and/or Uterine invasion
4 cycles
Carboplatin + Paclitaxel
Standard
chemoXRT
Standard
chemoXRT
ANZGOG 67

68. GCIG Consensus: Cervical Brachytherapy
Produce a document that can be used as a template for upcoming GCIG trials that contains “acceptable” evidence based brachytherapy dosing.
Akila Viswanathan has agreed to head the project.
Plan to work via and possibly conference call(s) with goal of finalizing the manuscript by the cervical SOTS meeting in 2009.