Cervical Cancer: Disease burden and Screening

Medical Management in Metastatic and Recurrent Cervical Cancer

Dr Alok Gupta

> 500,000diagnosed annually1

> 275,000deaths annually1

CERVICAL CANCER

GLOBAL SCENARIO

>85% of the global burden occurs in

developing countries1

Estimated Cervical Cancer Incidence Worldwide

Estimated Cervical Cancer Mortality Worldwide

> 120,000diagnosed annually1

> 67,000deaths annually1

2nd most

common cancer

in Indian

females1

CERVICAL CANCER

INDIAN SCENARIO

1. Globocan, 2008;

CAUSES?

90%

10%

90%

1% 0.1%

Why Is it feasible to screen for Cancer Cervix?

Method - PAP (Cervical) Smear Test

A cervical smear test is a simple procedure which involves gently scraping some cells from the surface of the cervix and putting them on a slide. The cells are then examined under a microscope in the laboratory to see if they are normal.

Benefit of screening in cervical cancer

70% reduction in cervical cancer deaths.

Now ranks 14th for cancer deaths in developed

world.

5-year survival rate is approximately 92%.

Screening Recommendations

Screening Recommendations

<21 years: No screening

21-30 years: PAP smear every 3 years

30-65 years: PAP smear every 3 years

30-65 years: PAP smear + HPV testing every 5

years

>65 years: No screening

Some practical points about cervical cancer screening

Why to start at 21 years of age?

Why to stop at 65 years of age?

What is the benefit of HPV co-testing?

Can we avoid Pap smear and do only HPV

testing?

Screening in vaccinated individual?

How to act on screening results?

What instructions will you give at the time of

screening?

Some practical points about cervical cancer screening

Why to start at 21 years of age?

Why to stop at 65 years of age?

What is the benefit of HPV co-testing?

Can we avoid Pap smear and do only HPV

testing?

Screening in vaccinated individual?

How to act on screening results?

What instructions will you give at the time of

screening?

Some practical points about cervical cancer screening

Why to start at 21 years of age?

Why to stop at 65 years of age?

What is the benefit of HPV co-testing?

Can we avoid Pap smear and do only HPV testing?

Screening in vaccinated individual?

How to act on screening results?

What instructions will you give at the time of

screening?

Timing of PAP Test

Instructions at the time of PAP Test

ICMR recommendation

Stage II <60%

Stage III <35%

Poorest prognosis

Stage IV and recurrent<15%

Stage I <90%

0

20

40

60

80

100

0 IA IB IIA IIB IIIA IIIB IVA IVB Recurrent or

Persistent

Ob

se

rve

d 5

-ye

ar S

urviv

al

Ra

te

Stage at diagnosis

Recurrent, Persistent or Metastatic Cervical Cancer:High unmet medical need

Very poor prognosis

No longer eligible for surgery or radiation

Receive palliative chemotherapy

5-year survival of women diagnosed with recurrent/persistent or metastatic Cervical Cancer remains a disappointing <5% and 15% respectively

Since the mid 1990s, no single agent or combination of agents have been identified as the standard of care (SOC)

Estimated 5-year survival rate of Cervical Cancer4

Cancer Research UK. Cervical Cancer. Available at: http://www.cancerresearchuk.org/cancer-help/type/cervical-cancer/

Hirte HW, Strychowsky JE, Oliver T, Fung-Kee-Fung M, Elit L, Oza AM. Chemotherapy for recurrent, metastatic, or persistent cervical cancer: a systematic review. Int J Gynecol Cancer 2007; 17: 1194-1204

Colombo N, Carinelli S, Colombo A, Marini C, Rollo D, Sessa C. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 Suppl 7: vii27-vii32.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology - Cervical Cancer Version 2.2015. Available at: http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf.

National Institute of Health and Care Excellence (NICE). High dose rate brachytherapy for carcinoma of the cervix IPG 160. Available at: http://www.nice.org.uk/nicemedia/live/11214/31525/31525.pdf. Last updated March 2006. Accessed 6 January 2014.

Lorusso D, Petrelli F, Coinu A, Raspagliesi F, Barni S. A systematic review comparing cisplatin and carboplatin plus paclitaxel-based chemotherapy for recurrent or metastatic cervical cancer. Gynecol Oncol 2014; 133: 117-123.

Few advances in treating persistent, recurrent cervical cancer

Trial (year)

n Regimen OS, months

PFS, months

RR, %

Remarks

GOG-0169 (2004)1 264

Cisplatin 8.8 2.8 19Improvement in ORR and PFS

No significant OS improvementCisplatin + paclitaxel 9.7 4.8 35

GOG-0179 (2005)2 364

Cisplatin 6.5 2.9 13 Supports cisplatin-topotecan label

Some argue that OS in the cisplatin-control arm was low due to high

radiotherapy-cisplatin useCisplatin + topotecan 9.4 4.6 27

GOG-0204 (2009)3 513

Cisplatin + paclitaxel 12.9 5.8 29

Consolidated cisplatin-paclitaxel as SoC

No other combination was better

Cisplatin + topotecan 10.3 4.6 23

Cisplatin + gemcitabine 10.3 4.7 22

Cisplatin + vinorelbine 10.0 4.0 26

JGOG-0505 (2012)4 253

Cisplatin + paclitaxel 18.3 6.90 n/a No difference between cisplatin- and carboplatin-paclitaxel

However, OS benefits suggests that population is different

Carboplatin + paclitaxel 17.5 6.21 n/a

ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RR, response rate; SoC, standard of care 1. Moore DH et al. J Clin Oncol 2004; 2. Long HJ 3rd et al. J Clin Oncol 2005; 3. Monk BJ et al. J Clin Oncol 2009; 4. Kitagawa R et al. J Clin Oncol 2012

CERVICAL CANCER:EMERGING THERAPIES

Inducing

angiogenesis

Angiogenesis: A hallmark of cancer leading to malignant growth

Cancer

Sustaining proliferative

signaling

Evading growth

suppressors

Activating invasion

and metastasis

Enabling replicative

mortality

Resisting cell

death

Hanahan & Weinberg. Cell 2011

Angiogenesis: Essential for tumour development and progression

1. Jain. Nat Med 2001; 2. Jain. Science 2005; 3. Gerber & Ferrara. Cancer Res 2005 4. Folkman, In: “Cancer: Principles & Practice of Oncology. Vol 2. 7th ed”. 2005

Tumour s >2 mm require an independent blood supply

Angiogenic switchLeads to overexpressionof pro-angiogenic signalsand activation of secondary pathways

Continued VEGF expression4

VEGF VEGF

bFGF

TGFβ-1

VEGF

bFGF

TGFβ-1

PLGF

VEGF

bFGF

TGFβ-1

PLGF

PD-ECGF

VEGF

bFGF

TGFβ-1

PLGF

PD-ECGF

Pleiotrophin

Vascular, large tumour with metastatic potential. Tumour vasculature is abnormal and inherently unfavourable to effective antitumour therapy1–3

Angiogenic switchLeads to overexpression of pro-angiogenic signals and activation of secondary pathways

Activation may occur at various stages of tumour development1–4

Angiogenesis is mediated primarily via the interaction of VEGF-A with VEGFR-21–3

– VEGF binding to capillary endothelial cell receptors generates a downstream signal cascade, promoting angiogenesis

Critical role of VEGF throughout angiogenesis

1. Ferrara. Endocr Rev 2004; 2. Hicklin & Ellis. JCO 2005 3. Ferrara Nat Rev Drug Discov 2004; 4. Bergers & Benjamin. Nat Rev Cancer 2003

VEGF

VEGF

receptor

Angiogenesis correlates with disease progression in many tumours1–4

Increases vessel permeability

Contributes to vascular abnormalities1,2,6,7,9

Facilitates survival of existing endothelial cells

Stimulates new vessel growth

AVASTIN: MECHANISM OF ACTION

Avastin precisely targets VEGF to inhibit angiogenesis, for continuous tumour control1,2

55

Bevacizumab

VEGF receptor

VEGF

1. Avastin Summary of Product Characteristics; 2. Presta, et al. Cancer Res 1997; 3. Avastin prescribing information, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf

• Bevacizumab prevents binding of VEGF to receptors1,2

• Bevacizumab has a long elimination half life (approximately 20 days) which may contribute to continuous tumour control3

Avastin (Bevacizumab) is a recombinant humanised anti-VEGF monoclonal antibody

– 93% human, 7% murine

– Recognizes all major isoforms of human VEGF

Terminal half-life = 17–21 days

Anti VEGF therapy: Avastin (Bevacizumab)

Presta Cancer Res 1997

Mechanism of action of Avastin (Bevacizumab)

1. Yuan Proc Natl Acad Sci U S A 1996; 2. Willett Nat Med 2004; 3. Lee Cancer Res 2000 4. Gerber & Ferrara. Cancer Res 2005; 5. Borgström Cancer Res 1996; 6. Borgström Prostate 1998

7. Jain. Nat Med 2001; 8. Jain. Science 2005; 9. Warren J Clin Invest 1995

Regressionof existing tumour vasculature1–3

Inhibitionof new vessel growth1–3,8

Early and continued effects result in:

Maintenance of more functional, normal vasculature

Potentially improved drug delivery

Inhibition of tumour growth and metastasis1–9

Anti-permeabilityof surviving vasculature11–13

CERVICAL CANCER:AVASTIN IN TREATMENT LANDSCAPE

Improved Survival with Bevacizumab in Advanced Cervical Cancer1

GOG 240 study

1. Tewari KS, et al. N Engl J Med 2014;370:734-43.

GOG, Gynecologic Oncology Group;

PS, performance status

Carcinoma of the cervix• Primary stage IVb• Recurrent/persistent • Measureable disease • GOG PS 0–1• No prior chemotherapy

for recurrence

N=452

1:1:1:1

Arm

Activated: 6 April 2009

Closed to accrual: 3 January 2012

Stratification factors> Stage IVb vs recurrent/persistent disease

> GOG PS

> Prior cisplatin treatment as radiation-sensitiserYes/No (Yes in 75% of patients)

R

Paclitaxel 135 or 175mg/m2 q3w I

II

III

Cisplatin 50mg/m2 q3w

Paclitaxel 135 or 175mg/m2 q3w

Cisplatin 50mg/m2 q3w

Paclitaxel 175mg/m2 q3w

Topotecan 0.75mg/m2 D1–3 q3w

Topotecan 0.75mg/m2 D1–3 q3w

Bevacizumab 15mg/kg q3w

IIII

Bevacizumab 15mg/kg q3w

Paclitaxel 175mg/m2 q3w

Cycles repeated q21 days until disease progression,

unacceptable toxicity, or complete response

Tewari KS, et al. N Engl J Med 2014;370:734-43.

GOG 240: Study Design

Recovered from surgery/radiation

therapy/chemoradiotherapy:

≥ 6 weeks since last chemoradiotherapy

≥ 3 weeks since last radiation therapy alone

≥ 3 weeks since any major surgical procedure

Free of active infection

GOG Performance Status of 0 or 1

Measurable disease

Primary stage IVB, recurrent or

persistent squamous cell carcinoma,

adenosquamous carcinoma, or

adenocarcinoma of the cervix

Adequate haematological, renal

and hepatic functions

Key Inclusion Criteria

GOG Performance Status of 2, 3 or 4

Bilateral hydronephrosis

Prior chemotherapy or anti-VEGF therapy

Cranio-spinal soft tissue metastases

Concomitant/prior invasive malignancy

History or evidence of CNS disease

Non-healing wound, ulcer, or fracture

Active or high risk of bleeding

Major surgery within 28 days/anticipated

Pregnant or nursing

GI obstruction with parenteral nutrition

Peripheral or cardio-vascular disease

Grade ≥2 peripheral neuropathy

Key Exclusion Criteria

Tewari KS, et al. N Engl J Med 2014;370:734-43.

GOG 240: Inclusion/Exclusion Criteria

Pro

po

rtio

n S

urv

ivin

g

Months on Study

Median follow-up 20.8 months

GOG 240.2: Second Interim AnalysisOS for Chemo vs Chemo + Avastin (Bev)

bev, bevacizumab; CI, confidence interval; chemo, chemotherapy; GOG, Gynecologic Oncology Group; HR, hazard ratio; OS, overall survival.

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3612 24

Chemotherapy(n=225)

Events, n (%) 140 (62)

Median OS, months 13.3

Chemotherapy + Avastin (n=227)

131 (58)

17.0

HR=0.71 (97% CI, 0.54–0.94)P=0.0035

Tewari KS, et al. N Engl J Med 2014;370:734-43.

GOG 240.2: Second Interim AnalysisPFS for Chemo vs Chemo + Avastin (Bev)

bev, bevacizumab; CI, confidence interval; chemo, chemotherapy; CR, complete response; GOG, Gynecologic Oncology Group; HR, hazard ratio; PFS, progression-free survival; RR, response rate.

Pro

po

rtio

n P

rogr

essi

on

-Fre

e

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3612 24

Chemotherapy(n=225)

Events, n (%) 184 (82)

Median OS, months 5.9

RR, % 36 (CR, n=14) 48 (CR, n=28)

2-sided P=.00807

Months on Study

Chemotherapy + Avastin (n=227)

183 (81)

8.2

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

Tewari KS, et al. N Engl J Med 2014;370:734-43.

Subgroup No. of Patients Hazard Ratio

Age Age ≤ 40 years 11240 < 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

GOG 240.2: OS and Prognostic Factors

0.0 0.5 1.0 1.5 2.0 2.5

Chemo + Bev Better Chemo alone Better

48 < Age ≤ 56 years

1

Yes

Recurrent/PersistentNo

Not BlackBlack

Squamous

Yes

Tewari KS, et al. N Engl J Med 2014;370:734-43.

GOG-0240 demonstrated that Avastin-related adverse events (AEs) in CC were similar to those of other tumour types

aOccuring within the time of first study treatment date and 30 days after last study treatment dateAE, adverse event; ATE, arterial thromboembolic event; AV, Avastin; CHF, congestive heart failure; CT, chemotherapy; GI,

gastrointestinal; LVSD, left ventricular systolic dysfunction; SAE, serious adverse event; VTE, venous throboembolic event

AE, n (%) CT alone [n=222] AV + CT [n=218]

All AEsa

Any AE (>1 event) 219 (98.6) 216 (99.1)

SAE 81 (36.5) 111 (50.9)

Grade 3/4/5 127 (57.2) 165 (75.7)

Grade 5 (death) 5 (2.3) 9 (4.1)

Discontinued due to AE 40 (18.0) 56 (25.7)

Deaths

All deaths 145 (65.3) 135 (61.9)

Not due to progression 11 (5.0) 10 (4.6)

AE of special interesta

Any AE (>1 event) 37 (16.7) 87 (39.9)

Grade 3/4/5 37 (16.7) 82 (37.6)

SAE 33 (14.9) 63 (28.9)

CHF/LVSD (Grade ≥3) 0 0

ATE 7 (3.2) 5 (2.3)

Febrile neutropenia (Grade ≥3) 13 (5.9) 12 (5.5)

Proteinuria (Grade ≥3) 0 4 (1.8)

Posterior rev encephalopathy syndrome 0 0

GI perforations 1 (0.5) 22 (10.1)

Hypertension (Grade ≥3) 1 (0.5) 25 (11.5)

Fistula/Abscess (non-GI) 5 (2.3) 9 (4.1)

Bleeding (Grade ≥3) 10 (4.5) 15 (6.9)

VTE (Grade ≥3) 7 (3.2) 18 (8.3)

Wound healing complication (Grade ≥3) 0 2 (0.9)

Gastrointestinal-vaginal fistula was a newly identified AE associated with the use of Avastin in patients with CC.1

Several AEs of special interest were observed at a higher incidence in Avastin-treated patients than those treated with chemotherapy alone.2

AE, n (%) Chemotherapy (n=220)Chemotherapy + Avastin

(n=220)Treatment cycles, median (range) 6 (1–50) 7 (1–40)

Grade 5 AE(s) 3 (1.3) 7 (3.2)

GI events,

Non-fistulae (grade ≥2) 97 (44) 115 (53)

GI perforation (grade ≥2) 0 5 (2.3)

GI fistula (grade ≥2) 1 (0.5) 11 (5)

GU fistula (grade ≥2) 1 (0.5) 8 (3.6)

Hypertension (grade ≥2) 4 (1.8) 55 (25)

Proteinuria (grade ≥3) 0 5 (2.3)

Pain (grade ≥2) 63 (29) 72 (33)

Neutropenia (grade ≥4) 58 (26) 80 (36)

Febrile neutropenia (grade ≥3) 12 (5.5) 12 (5.5)

Thromboembolism (grade ≥3) 4 (1.8) 18 (8.2)

Bleeding

CNS (any grade) 0 0

GI (grade ≥3) 1 (0.5) 4 (1.8)

GU (grade ≥3) 1 (0.5) 6 (2.7)

GOG 240: updated GOG safety analysis

Tewari, et al. ESMO 2014AE, adverse event; CNS, central nervous system; GI, gastrointestinal; GU, genito-urinary

Grade ≥2 fistulae occurred in 8.6% of bevacizumab-treated patients (all of whom had received prior radiotherapy); grade ≥2 GI perforation occurred in 2.3% of bevacizumab-treated patients

GI perforations and GI fistulae: incidence in cervical and other cancers

1. Findings based on literature search from 2003–2013 and ASCO abstract review 2008–2013;2. Hwang JH, et al. Arch Gynecol Obstet 2012;

3. Herrera FJ, et al. Int J Radiat Oncol Biol Phys 2007; 4. Zighelboim I, et al. Gyn Oncol 2013; 5. Tewari K, et al. NEJM 2014; 6. Mackay HJ, et al. Gynecol Oncol 2010

GI, gastrointestinal; NR, not reported

Cancer1 GI perforation GI fistulae

Colorectal 0.13% 2.2%

Rectal 5.6% 0.2–13%

Cervical 5.6% 2–26%2–6

Vaginal NR 7.7%

Ovarian 0–10% 1.7–4%

Endometrial 1.5% 2.3%

Cervical cancer has a high background rate of GI fistulae compared with other cancers

Dose of radiation therapy used in cervical cancer higher

in the pelvis and at the rectovaginal septum than

traditionally used for CRC in the pelvic region

7%Phase II study of topotecan / cisplatinplus bevacizumab4

2–10%Two small studies of concurrent radiation and platinum-based chemotherapy2,3

26% Phase II study of sunitinib6

8.3%Phase III study topotecan / paclitaxel OR cisplatin / paclitaxel, plus bevacizumab5

Summary of Approvals/ Recommendations

Priority review by USFDA and approval in August 2014

EMEA Approval (April 2015)

Fast Track Swiss medic Approval (Dec. 14)

NCCN (Category 1 recommendation)

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