bradley j. monk, m.d. professor and director division of gynecologic oncology

bradley.monk@chw.edu

Bradley J. Monk, M.D.Professor and Director

Division of Gynecologic OncologyDepartment of Obstetrics and Gynecology

Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center, a Dignity Health Member

University of Arizona Cancer Center-PhoenixArizona USA

Cervical Cancer:Evolutions in the Standard of Care

The Global Burden of Cancer to Women WorldwideNew Cases Annually Deaths Annually

9% of all new cancer cases 8% of total cancer deaths 85% of deaths occur in

developing countries

Jemal A et al CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90.

Age-Standardized Cervical Cancer Rates in 2008

Jemal A et al CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90.

Papillomaviruses in Human Cancer

•1842: Rigoni-Stern – prostitutes higher incidence of cervical cancer than nuns

•1951: George Otto Gey - HeLa (Henrietta Lacks) cells

•1928: Georgious Papanicolaou - “Pap smear”

Harald zur Hausen

•1983: Harald zur Hausen - discovers HPV

•2008: Harald zur Hausen - wins Nobel Prize

Infection With Oncogenic HPV Is Necessary to Cause Cervical Cancer1

1. Walboomers J et al. J Pathol. 1999;189:12-19. 2. Trottier H, Franco E. Vaccine. 2006;24S1:S4-15. 3. Moscicki A et al. Vaccine. 2006;24S3:42-51.4. Einstein M. Cancer Immunol Immunother.2008;57:443-51. 5. Östör A. Int J Gynecol Pathol. 1993;12:186-92.

Precancerous Lesions

Mild Cervical Lesions

Oncogenic InfectionsCommonly caused by HPV types 16 & 18

Persistent Infection

Mild Cervical Lesions/

Genital Warts

Cervical Cancer

Non-oncogenic infections do not lead to precancerous lesions or cervical cancer2

Non-oncogenic Infections

Persistent Infection

Most HPV infections will clear, and most cervical lesions will not progress3-5

bradley.monk@chw.eduPresented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS

HPV E6

HPV E7

p53 degradation TSP-1 VEGF angiogenesis

Displacement ofHDAC1, HDAC4, HDAC7

HIF1α

pRb inactivation p21-RB pathway dysregulation

Tumor Hypoxia and Viral OncogenesDrive Angiogenesis in Cervical Neoplasia

Anti-VEGF therapy

Tewari KS, et al. Gynecol Oncol 2000;77:137-48.Monk BJ, et al. J Clin Oncol. 2009;27(7):1069-74.http://www.microbiologybytes.com/virology/Papillomaviruses.html

Evolution of an HPV infection

HPV Disappearance1-2 y3,4,6

~6–9 mo5,6

CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; HR, high risk.1. Schiffman M, Kjaer SK. J Int Cancer Natl Monogr. 2003;31:14-19; 2. Ostör AG. Int J Gynecol Pathol. 1993;12:186-192;

Colposcopy demonstrates abnormal vasculature and angiogenesis dependent progression

Transient Infection Persistent Infection

Normal Precancerous, potential to regress or persist to severe disease Invasive HPV Infection CIN 1,2 CIN 2,31 Cervical Cancer2

7–10 y1 ≥10 y2

Radical hysterectomy

• Used to treat cervical cancers with invasion > 3mm but confined to the cervix and vagina < 4 cm (Stage IA2 –IB1)

• Removal of parametrium and upper vagina

Wertheim

Wertheim E: Zur frage der radikaloperation beim uteruskebs. Arch Gynecol 61:627, 1900Wertheim E: Discussion on the diagnosis and treatment of carcinoma of the uterus. BMJ 2:689, 1905Wertheim E: The extended abdominal operation for carcinoma uteri. Translated by Grad H Am J Obstet Dis Women Child 66:169, 1912

Acceptable Alternatives to Radical Abdominal Hysterectomy and

Lymphadenectomy forStage IA2 and IB1 Cervical Cancer

• Radical traechelectomy (or cone) and nodes (Fertility sparing)

• Intracavitary brachytherapy and pelvic RT +/- chemo• Laparoscopic radical hysterectomy and nodes• Robotic radical hysterectomy and nodes• Simple hysterectomy and nodes

When is RT or Chemo/RT Indicated After Radical Hysterectomy?

Radiation if two of the following: • deep invasion, large tumor or vascular invasion

– GOG 92 (Sedlis A et. al Gyn Onc 73:177-183, 1999)

Chemo-RT if one of the following:• Positive margin, parametrial extension, positive node

– GOG 109 (Peters WA et. al. J Clinic Oncol 18:1606-1613, 2000)

RT=Radiation therapy

Early Stage Intermediate Risk Cervical Cancer• Large, deeply invasive tumors with vascular invasion

limited to the cervix after radical hysterectomy• GOG 92 established to role of postoperative pelvic

radiation (Sedlis et al Gyn Oncol 73, 177–183 1999)

Stage IA2-IB2: Large, deeply invasive tumors with vascular invasion limited to the cervix after radical hysterectomy

RANDOMIZE

Pelvic Radiation

Pelvic Radiation andWeekly cisplatin (CCRT)

GOG/KGOG 263(GOG 92 Replacement)

PI = SANG YOUNG RYUN = 480Primary Endpoint = RFS

Early Stage High Risk Cervical Cancer• Positive nodes, parametrial extension, positive margins

after radical hysterectomy• GOG 109 established the role of postoperative cisplatin

and pelvic radiation (Peters WA et al J Clin Oncol. 2000 Apr;18(8):1606-13)

Stage IA2-IB2: Positive nodes, parametrial extension, positive margins after radical hysterectomy

RTOG 0724 (GOG 109 Replacement)

RANDOMIZE

Pelvic Radiation andWeekly cisplatin (CCRT)

Pelvic Radiation andWeekly cisplatin (CCRT)followed by carboplatin +Paclitaxel x 4 cycles

PI = Anuja JhingranN = 400Primary Endpoint = DFS

What is the Global Standard Therapy for Stage IB2 - IVA?• External beam pelvic radiation (40 to 60 Gy)• Brachytherapy (8,000 to 8,500 cGy to Point A)• I.V. Cisplatin chemotherapy

– Cisplatin 40mg/m2 (Max dose 70mg) IV q wk during RT (6wks)

• GOG 120 (Rose PG et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. NEJM 340(15):1144, 1999

Monk et al J Clin Oncol 25:2952-2965. 2007

Standard Anterior and Lateral External-beam Irradiation Ports Used to Treat Locally

Advanced Cervical Carcinoma Limited to the Pelvis

Monk et al J Clin Oncol 25:2952-2965. 2007

THE OUTBACK TRIAL/GOG 0274A Phase III trial of adjuvant chemotherapy

following chemoradiation as primary treatment for locally advanced cervical

cancer compared to chemoradiation alone Linda Mileshkin on behalf of ANZGOGKathleen Moore on behalf of the GOG

ClinicalTrials.gov Identifier: NCT01414608

Design Stage IB2-IVaCervical cancer:Stratify for- FIGO stage- Pelvic nodal

involvement- Uterine +ve on

Standard chemoXRT

4 cyclesCarboplatin + Paclitaxel

ClinicalTrials.gov Identifier: NCT01414608

• Early stage cervical cancer usually cured with radical local excision

– Randomized trials have established role of adjuvant CCRT• CCRT used to treat locally advanced disease• Tumor stage, tumor grade, race, age and angiogenesis

independently prognostic• Anti-angiogenic agents rationale and underdevelopment

Summary of Primary Treatment

Chemotherapy for Recurrent Cervical Cancer - Lessons Learned in the 80’s and 90’s

• Platinum-based therapies most effective• Cisplatin more active than carboplatin• Two ways to increase response without prolongation in

Survival– Increase platinum dose– Add Ifosfomide to cisplatin

• Single agent cisplatin at 50 mg/m2 became standard

GOG 204

Primary Stage IVB or recurrent/persistent carcinoma of the cervix

measurable diseaseGOG performance status 0-1ANC 1500/µlplatelets 100,000/µlserum creatinine 1.5 mg/dlno CNS diseaseno past or concomitant invasive cancer no prior chemotherapy (unless concurrent with radiation)

Regimen 1Paclitaxel 135 mg/m2 over 24 hours and CDDP 50 mg/m2 repeated q 3 wks for 6 cycles

Regimen 2Vinorelbine 30 mg/m2 IV bolus day1 and 8 and CDDP 50 mg/m2 IV day 1 repeated q 3 wks for 6 cycles

ALL REGIMENSQuality of life Assessment:BaselineBefore cycle 2Before cycle 59 mo. after study entry at follow-up visit

Regimen 3Gemcitabine 1000mg/m2 IV day 1 and 8 and CDDP 50 mg/m2 IV day 1 repeated q 3 wks for 6 cycles

Regimen 4Topotecan 0.75 mg/m2 over 30 minutes days 1, 2, & 3 CDDP 50 mg/m2 IV day 1, q 3 wks for 6 cycles

RANDOMIZE

BJ Monk et al J Clin Oncol. 2009 Oct 1;27(28):4649-55.

By Treatment GroupP

0.00.10.20.30.40.50.60.70.80.91.0

Months on Study0 12 24 36

Treatment Alive Dead Total CIS+PAC 29 74 103

Alive Dead Total

CIS+VIN 23 85 108

Alive Dead Total

CIS+GEM 20 92 112

Alive Dead Total

CIS+TOP 22 89 111

GOG 204: Overall Survival

BJ Monk et al J Clin Oncol. 2009 Oct 1;27(28):4649-55.

Trial Design

(www.jcog.jp/en/)

Multicenter (30 Specialized Institutions), Randomized Phase III Trial

Stage IVB, persistent or recurrent cervical cancer; not amenable to curative surgery / radiotherapy

RANDOMIZE*

Standard arm: TPPaclitaxel 135 mg/m2 24h d1Cisplatin 50 mg/m2 2h d2

every 21 days for 6 cycles

Experimental arm: TCPaclitaxel 175 mg/m2 3h d1Carboplatin AUC 5 1h d1

* Balancing factors: • Tumors outside of the prior

irradiation field(yes or no)

• PS 0-1 or 2• SCC or non-SCC• Institution ClinicalTrials.gov Identifier:NCT00295789

JCOG 0505

Kitagawa R, et al. J Clin Oncol. 2012;30(Suppl): Abstract 5006.

Trial Profile

(www.jcog.jp/en/)

25253 patients enrolled and randomly assigned

127 assigned to TP126 assigned to

TC4 ineligible 5 ineligible25Maximum 6 cycles of treatment

until disease progression or unacceptable toxicity

123 efficacy analysis 125 safety analysis

121 efficacy analysis 126 safety analysis

2/21/2006 ～ 11/20/2009

Best Response – RECIST v1.0Women With Target Lesions

(www.jcog.jp/en/)

Best Response TP (n = 102)

TC (n = 99)

P Value**

No. of patients (%)

Complete response (CR) 4 (3.9%) 7 (7.1%)

Partial response (PR) 56 (54.9%) 55 (55.6%)

Stable disease 　　　 (SD) 23 (22.5%) 19 (19.2%)

Progressive disease (PD) 7 (6.9%) 9 (9.1%)

Not evaluable (NE)* 12 (11.8%) 9 (9.1%)

Objective Response 60 (58.8%) 62 (62.6%) .665** Fisher’s exact test * NE due to missing data

Overall Survival (www.jcog.jp/en/)

0.00.10.20.30.40.50.60.70.80.91.0

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6Years after randomization

Arm N Events Median(m)[95% CI]

1-yrOS

2-yrOS

3-yrOS

TP 123 106 18.3 m[16.1-22.9] 72.4% 38.8% 18.3%

TC 121 98 17.5 m[14.2-20.3] 67.6% 31.5% 21.3%

#stratified Cox regression with “tumors outside prior irradiation field[yes/no]” as strata

HR: 0.994 [90% CI: 0.789-1.253 (<1.29)]noninferiority one-sided P = .032#

Beyond GOG 204

Novel Agents and Non-platinum Doublets

• Failed first-line cytotoxic drug treatment• 125 mg/m(2) IV over 30 minutes on days 1, 8, and 15 of

each 28 day cycle• Median PFS = 5.0 months• Median OS = 9.4 months• 10 (28.6%; CI 14.6%-46.3%) of 35 patients = PR• 15 patients (42.9%) had SD

Alberts DS, et al. Gynecol Oncol. 2012;127(3):451-455.

Agents Targeting the VEGF Pathway

VEGFR-2VEGFR-1PPP

Endothelial cell Small-molecule inhibitors

Anti-VEGFR antibodies

VEGFAnti-VEGF antibodies

(bevacizumab)Soluble VEGFRs

(VEGF-TRAP)

Podar and Anderson. Blood. 2005;105:1383.

• Persistent or recurrent squamous cervical cancer

• 1-2 prior cytotoxic regimens (not including initial chemo-RT)

• Measurable disease• GOG PS ≤ 2

GOG 227-C

Bevacizumab 15 mg/kg IVq 21 days until diseaseprogression orprohibitive toxicity

Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD.J Clin Oncol. 2009 Mar 1;27(7):1069-74.

GOG 227-CBy Treatment Group

Months on Study0 12

PFS of Bev (Blue) versusGOG Historical Database(Failing one or two cytotoxicregimens, not includingchemo-RT)

Bevacizumab

GOG Historical Database(Failing one or two cytotoxicregimens, not includingchemo-RT)

Monk BJ et al J Clin Oncol. 2009 Mar 1;27(7):1069-74.

GOG 240 Primary Stage IVB or recurrent/persistent carcinoma of the cervix

Measurable diseaseGOG performance status 0-1ANC 1500/µLPlatelets 100,000/µLSerum creatinine 1.5 mg/dLNo CNS diseaseNo past or concomitant invasive cancer No prior chemotherapy (unless concurrent with radiation)

Regimen 1**Paclitaxel* + CDDP 50 mg/m2

Regimen 2**Paclitaxel* + CDDP 50 mg/m2 + Bevacizumab 15/mg/kg

Regimen 3**Paclitaxel 175 mg/m2 over 3 hrs on day 1 +Topotecan 0.75 mg/m2 over 30 mins days 1-3

Regimen 4**Paclitaxel 175 mg/m2 over 3 hrs on day 1 +Topotecan 0.75 mg/m2 over 30 mins days 1-3 +Bevacizumab 15/mg/kg

RANDOMIZE

* 135 mg/m2 over 24 or 175 mg/m2 over 3 hours** Cycles repeated q21 days to progression/toxicity

Open to enrollment April 6, 2009Closed to enrollment Jan 3, 2012Sample size = 452OS HR reduction of 30%Study Chair = KS TewariClinicalTrials.gov Identifier: NCT00803062

Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.

GOG 240 – Non-platinum ObjectivePrimary Stage IVB or recurrent/persistent carcinoma of the cervix

RANDOMIZE

GOG 240 – Bevacizumab ObjectivePrimary Stage IVB or recurrent/persistent carcinoma of the cervix

RANDOMIZE

HR 1.20 (98.74% CI 0.82-1.76; 1-sided p=0.880)Median OS: 15 m (CP) and 12.5 m (TP)RR: 38.4% (CP), 28.7% (TP) [2-sided p=0.0364]CR: n=26 (CP), n=16 (TP) p=NS

Cisplatin-Paclitaxel backbone

Topotecan-Paclitaxel backbone

0 12 24

Months on Study

GOG 240 – Non-platinum Objective

Tewari KS et al. Presented at the 2013 SGO Annual Meeting on Women’s Cancer. Abstract #1.

Overall Survival - Prior Platinum Exposure

HR 1.18 (95% CI 0.84-1.65)RR: 34% (CP) vs 24% (TP)

HR 1.35 (95% CI 0.676-2.688)RR: 54% (CP) vs 42% (TP)

Prior Cisplatin No Prior Cisplatin

Cisplatin-Paclitaxel backbone

Topotecan-Paclitaxel backboneTopotecan-Paclitaxel backbone

GOG 240 – Non-platinum Objective

Tewari KS et al. Presented at the 2013 SGO Annual Meeting on Women’s Cancer. Abstract #1.

GOG 240 – Bevacizumab ObjectivePrimary Stage IVB or recurrent/persistent carcinoma of the cervix

RANDOMIZE

Chemotherapy + Bev (n=227)

183 (81)

HR=0.67 (95% CI, 0.54-0.82)2-sided P=0.0002

0 3612 24

Months on Study

Chemotherapy(n=225)

Events, n (%) 184 (82)

Median PFS, mos 5.9

RR, % 36 (CR, n=14) 48 (CR, n=28)2-sided P=0.00807

GOG 240 – Bevacizumab Objective

Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.

Cis + Pac + Bev(n=115)67 (58.3)

HR=0.68 (95% CI, 0.48-0.97)P=0.0348

Cis + Pac(n=114)

Events, n (%) 69 (60.5)

Median OS, mos 14.3 17.5

0 12 3624

Months on Study

RR, % 45 (CR, n=9) 50 (CR, n=17)

2-sided P=0.5090

GOG 240 – Bevacizumab ObjectiveCisplatin + Paclitaxel Cohort N=229

Subgroup No. of Patients Hazard RatioAge Age ≤ 40 years 112

40 < Age ≤ 48 years 11148 < Age ≤ 56 years 10856 years < Age 121

Performance Status 0 2631 189

Prior Platinum RT No 115Yes 337

Disease Status Advanced 76Recurrent/Persistent 376

Topotecan Treatment No 229Yes 223

Race Not Black 392Black 60

Histology Adenocarcinoma 86Adenosquamous 44Other 12Squamous 310

Pelvic Disease No 210Yes 242

Overall 452

0.0 0.5 1.0 1.5 2.0 2.5Experimental Better Control Better

GOG 240: OS and Prognostic Factors

= HR does not cross 1.0

GOG 240: Treatment Exposure andSpecific Adverse Events

Adverse Event, n (%) Chemo Alone (n=219)

Chemo + Bev (n=220)

Treatment cycles, median (range) 6 (0-30) 7 (0-36)

Grade 5 AE(s) 4 (1.8) 4 (1.8)

GI events, non-fistula (grade ≥2) 96 (44) 114 (52)

GI fistula (grade ≥3)* 0 (0) 7 (3)

GI perforation (grade ≥3) 0 (0) 5 (2)

GU fistula (grade ≥3)* 1 (0) 6 (2)

Hypertension (grade ≥2)* 4 (2) 54 (25)

Proteinuria (grade ≥3) 0 (0) 4 (2)

Pain (grade ≥2) 62 (28) 71 (32)

Neutropenia (grade ≥4)* 57 (26) 78 (35)

Febrile neutropenia (grade >3) 12 (5) 12 (5)

Thromboembolism (grade ≥3)* 3 (1) 18 (8)

Bleeding CNS (any grade) 0 (0) 0 (0)

GI (grade ≥3) 1 (0) 4 (1)

GU (grade ≥3) 1 (0) 6 (3)*p<0.05

GOG 240: Health Related Quality of Life• FACT for Cervical Cancer – Trial Outcome Index

• Physical well-being (7 items)• Functional well-being (7 items)• Cervix Cancer subscale (15 items)• Score range: 0-116 points• Clinically meaningful change: 4-5 points

• Compliance with completion of HRQoL questionnaires ranged from 96% pre-cycle 1 to 63% 9 mos post-cycle 1 and was balanced across arms

Yost KJ, Eton DT. Eval Health Prof 2005;28:172-91.

FACT-Cx TOI Score Chemo Alone Chemo + Bev Difference 98.75% CIPre-cycle 1 77.9 75.8 -2.17 -6.43–2.09

Pre-cycle 2 77.4 76.9 -0.47 -3.59–2.64

Pre-cycle 5 77.6 74.7 -2.95 -6.81–0.90

6 mos post-cycle 1 74.0 71.2 -2.84 -7.40–1.73

9 mos post-cycle 1 74.5 72.7 -1.80 -7.10–3.50

GOG 240: Mean FACT-Cx TOIPatients receiving bevacizumab reported 1.2 points lower on average (not significant)

Assessment Time

Chem Alone

Chemo + Bev

Pre-cycle 1 Pre-cycle 2 Pre-cycle 5 5 mos post cycle 1

9 mos post cycle 1

98.75% CI -4.1 – 1.7P=0.3

Progress in Survival in Advanced and Recurrent Cervical Cancer

1989 1997 2002 2004 2005 2009 201302468

1012141618

GOG 110 Cisplatin + Ifosfamide

GOG 149 Cisplatin + Ifosfamide + Bleomycin

GOG 169 Cisplatin + Palitaxel

GOG 179 Cisplatin + Topotecn

GOG 64 Cisplatin

GOG 240 Cisplatin + Palcitaxel + Bevacizumab

Adding Bevacizumab to Chemotherapy Improves Survival

Tumor Type Regimen Median Survival (Months)

Hazard Ration

First-line Metastatic Colorectal Cancer

IFL + Placebo(N=411)

15.6 0.66

IFL + Bev(N=402)

Non-Squamous NSCLC PC(N=444)

10.3 0.80

PC + Bev(N=434)

Recurrent or advanced Cervical Cancer

TP or TT(N=225)

13.3 0.71

TP or TT + Bev(N=227)

Bev = bevacizumab; NSCLC = non-small cell lung cancer; IFL = Irinotecan, 5-FU, leucovorin;PC = paclitaxel and carboplatin; TP = paclitaxel and cisplatin; TT = topotecan and paclitaxel

http://www.gene.com/download/pdf/avastin_prescribing.pdf

• Only pelvic exenteration curative for central pelvic recurrences• Cisplatin doublets plus bevacizumab standard in treating

metastatic disease– Will bevacizumab gain regulatory approval?

Summary of Treatment forRecurrent Disease

Thank You

bradley j. monk, m.d. professor and director division of gynecologic oncology

cervical cancers

cervical cancer11

ca cancer j clin

j pathol

oncogenic hpv

j int cancer natl monogr

new cancer cases8

walboomers j

Documents

blue monk - thelonious monk completo

gynecologic malignancy

petct in gynecologic cancer

hysteroscopes and gynecologic laparoscopes

satoru sagae (jgog) bradley monk (gog) - gcig · satoru...

bradley.monk@chw.edu bradley j. monk, m.d. professor and...

gynecologic cancer

imrt in gynecologic malignancies

obstetric and gynecologic emergencies

blue monk ( thelonius monk )

gynecologic cancers

current concepts in gynecologic...

gynecologic oncology reports - vtechworks.lib.vt.edu

updates on gynecologic malignancies

cancer and pregnancy: concerns, care, and caveats bradley j....

2012 algorithm for management of advanced ovarian cancer...

big 4 cancer conference: gynecologic oncology, special...

gynecologic emergencies

gynecologic tumor markers

gynecologic facts & myths