Chemotherapy in Gynecological malignancies

Chemotherapy in Gynaecological Cancers
Dr Chandan K Das MD,DM
Assistant Professor Medical Oncology

OVERVIEW
Ovarian cancer basics
Chemotherapy concept
Prescription for Ca Ovary and GTN

Hanahan and
Weinberg
Hall marks of
cancer

OS & PFS
PFS
OS
Death
Relapse 1
Diagnosis

Female Lifetime Risk of Cancer
 Ovarian Cancer: General population-1.4%/One first-degree relative-4.2%
 Breast Cancer: General population-12.4%/One first-degree relative-24%
 Endometrial Cancer-2.6%

Gynecologic Genetic Cancer Syndromes
Hereditary Breast Ovary Cancer
Syndrome
Lynch Syndrome
Cowden Syndrome
Li-Fraumeni Syndrome
Peutz-Jeghers Syndrome
Gorlin Syndrome
10-
15%

Molecular profiling of Serous Ca Ovary

Hereditary Breast Ovary Cancer Syndrome

BRCA mutation cancer risks
Cancer General
Population
BRCA1 BRCA2
Breast 12% 40-80% 40-70%
Ovarian 1% 24-40% 11-18%
Male Breast 0.1% 1-2% 5-10%
Prostate 15-18% <30% 39%
Pancreatic 0.5% 1-3% 2-7%

Ca Ovary Statistics 2018:New Ca Ovary
HBCR-ICMR-PGIMER 2018

Ovarian Cancer
y
Symptoms
Diagnosis
Chemotherapy
Staging/debulking
Evaluation
Progression
Chemotherapy
Supportive
care
Death
MaintenanceMaintenance

How to decide for Treatment adjuvant
Chemotherapy
 cancer type Serous or clear cell or endometroid
 Stage of cancer
 Operability
 ECOG PS
 Lab Parameters
 BRCA1/2 Mutation status

Advanced Ca Ovary Stage III/IV
 NACT—IDS---ADJUVANT
 SX-ADJUVANT

Paclitaxel-Carboplatin-BEVACIZUMAB- ICON7
XXXXXX 59/F CA OVARY STAGE IV SEROUS POST
TAH+BSO+ICO
WEIGHT: 55Kg HEIGHT: 151 cm, BSA: 1.5M2 ECOG
PS:1
PREMED:
•CAP NETUPITANT
300MG+PALONOSETRON 0. 5 MG
1CAP BEFORE CHEMOTHERAPY D1
ONLY
•INJ DEXAMETHASONE 12 MG/100
ML OF NS OVER 30 MIN D1
•INJ AVIL 1 AMP D1
•INJ RANITIDINE 50 MG IV D1
•INJ PERFALGAN 1000 MG IV D2
•INJ HYDROCORTISONE 100 MG IV
D2
CHEMOTHERAPY
•INJ BEVACIZUMAB XXXX MG / 500
ML OF NS OVER 90 MIN D1(DO NOT
ADMINISTER OR MIX WITH
DEXTROSE SOLUTION)
•INJ. CARBOPLATIN MG IN 500 ML
5% DEXTROSE IV OVER 1 HR ON D1
•INJ PACLITAXEL (@ 175 MG/M2)
MG IN 500 ML OF NS IV OVER 30
MIN D1
POST CHEMOTHERAPY
•TAB PANTOCID DSR 1 TAB OD
BEFORE FOOD 5 DAY
•TAB ULTRACET 1 TAB TDS 5 DAY
•SYP CREMAFFIN/CREMAFFIN
PLUS/DUPHALAC/LACTITOL 20 ML
AT NIGHT FOR 5 DAY
•INJ PEG GCSF 6 MG SC ON D2

MITO:7 Weekly TP
In Practice
Elderly Patients (>age 70)
and/or Those with Comorbidities

Burger RA, et al. Gynecol Oncol. 2013;131:21-6 OV = ovarian; PP = primary peritoneal
AUC: Area Under Curve
GOG: Gynaecologic Oncology Group
Bevacizumab based adjuvant therapy:GOG-0218
In Practice

Phase III ICON7: Carboplatin/Paclitaxel ± Bev in Newly
Diagnosed Ovarian Cancer
Oza AM, et al. Lancet Oncol. 2015;16:928-936.
In
Practice

Frontline Maintenance Ca Ovary
 Bevacizumab
 Olaparib
 Bevacizumab+Olaparib

Relapsed Ovarian Cancer
CA–125level
1ST LINE 5TH LINE
* Bowel
obstruction
†
2ND LINE 3RD LINE 4TH LINE
18.2 months 10.2 months 6.4 months
Surgery
5.6 months 4.4 months
Symptoms
PFS PFS PFS PFS PFS

Effect of Platinum-Free Interval
on Response Rate
% Response to Second-line
Platinum Therapy
Platinum-Free
Interval (mos)
Markman Gore Blackledge
0-6
17%
10%
7-12 27% 29%
13-18
33% 27%
63%
19-24 94%
>24 59% 57%
Non-Platinum
Therapy
15%
20%
30%
30%
Markman M, et al. J Clin Oncol. 1991;9(3):389-393.
Gore ME, et al. Gynecol Oncol. 1990;36:207-211.
Blackledge G, et al. Br J Cancer. 1989;59:650-653.

Agents Targeting the VEGF Pathway
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial Cell Small-Molecule Inhibitors
Anti-VEGFR
Antibodies
VEGF
Anti-VEGF
Antibodies
(bevacizumab)
Soluble
VEGFRs
(VEGF-TRAP)
Podar K, et al. Blood. 2005;105(4):1383-1395.
VEGF = vascular endothelial growth factor
VEGFR = VEGF receptor

Bevacizumab in Platinum Sensitive Ca Ovary:
OCEANS
In
Practice

Adapted from Iglehart JD, Silver DP. N Engl J Med 2009;361(2):189-91.
PARP Inhibition: Olaparib

Synthetic Lethality by PARP Inhibition
Courtesy of Jenny C Chang, MD
HRR/BRCA

Phase II Study 19 of Olaparib Maintenance in
Platinum-Sensitive Recurrent Ovarian Cancer
 Primary endpoint: PFS (RECIST 1.0)
 Secondary endpoints: OS, safety, tolerability
 Exploratory endpoints: time to first subsequent therapy or death, time to
second subsequent therapy or death
Patients with platinum-sensitive,
recurrent high-grade serous
ovarian cancer; ≥ 2 prior
platinum-based regimens with
CR/PR to most recent platinum-
based therapy; stable CA-125
(N = 265)
Treatment until
disease
progression
Olaparib
400 mg BID PO
(n = 136)
Placebo
BID PO
(n = 129)
Ledermann. NEJM. 2012;366:1382.

Study 19 :PFS
Ledermann. NEJM. 2012;366:1382.
HR: 0.35 (95% CI: 0.25-0.49; P < .001)
Treatment
Number of Patients
With Event (%)
Median PFS,
Mos
Olaparib 60 (44.1) 8.4
Placebo 93(72.1) 4.8
Olaparib
Placebo
Mos
150 3 6 9 12
1.0
0.8
0.6
0.4
0.2
0
ProbabilityofPFS
Patients at Risk, n
Olaparib
Placebo
136
129
104
72
51
23
23
7
6
1
0
0

“
”
SOLO2: Final OS Analysis of
Maintenance Olaparib in Platinum-
Sensitive, Relapsed Ovarian Cancer with
BRCA Mutation

SOLO2: Investigator-Assessed PFS
Pujade-Lauraine. Lancet Oncol. 2017;1274.
100
80
60
40
20
0
PFS(%)
Mos
Olaparib
Placebo
HR: 0.30 (95% CI: 0.22-0.41; P <
.0001)
Patients at Risk, n
Olaparib
Placebo
196
99
182
70
156
37
134
22
118
18
104
17
89
14
82
12
32
7
29
6
3
0
2
0
0
0
360 3 6 9 12 15 18 21 24 27 30 33

Two large randomised placebo controlled trials have
evaluated olaparib for the maintenance treatment of
PSR OC1-3
Phase III study3
Recurrent BRCAm ovarian cancer after two prior lines of
platinum therapy (n=295)
Maintenance in patients achieving a CR/PR on
platinum therapy
Olaparib tablets PO 300mg BID
Olaparib significantly prolonged PFS compared with placebo
(HR 0.30; 95% CI 0.22 to 0.41; p<0.0001)
Study 19
Phase II study1,2
Recurrent ovarian cancer after two or more prior lines of
platinum therapy (n=265)
Maintenance in patients achieving a CR/PR on
platinum therapy
Olaparib capsules PO 400mg BID
Olaparib significantly prolonged PFS compared with placebo
(HR 0.35; 95% CI 0.25 to 0.49; p<0.00001)
Trend towards benefit for overall survival (HR of 0.73; 95% CI
0.55 to 0.95; nominal p=0.025; statistical significance not reached)
Improvements in PFS and OS were also seen in the non-BRCAm
subgroup (HR 0.54 [95% CI 0.34 to 0.85], p=0·0075; and HR 0.83
[95% CI 0.55 to 1.24], nominal P=0.37; respectively)
BID=twice daily; BRCAm=BRCA1/2 mutation; CI=confidence interval; CR=complete response; HR=hazard ratio; non-BRCAm=no mutations in BRCA1/2; OC=ovarian cancer; OS=overall survival;
PFS=progression-free survival; PO=orally; PR=partial response; PSR=platinum-sensitive relapsed
1. Ledermann J, et al. N Engl J Med. 2012;366(15):1382–1392; 2. Ledermann J, et al. Lancet Oncol. 2016;17(11):1579–1589; 3. Pujade-Lauraine et al. Lancet Oncol. 2017;18(9):1274–1284

Why Multiple Drugs: EMA
 ACTINOMYCIN D ETOPOSIDE
METHOTREXATE

CO
 CYCLOPHOSPHAMIDE VINCRISTIN/ONCOVIN

EMA PROTOCOL HIGH-RISK GTN
TIME 0 6 12 18 24 32 38 42 48
PH
LCV X X X X
TIME 54 60 66 72 76 82 86 92 X
PH X X X X X X X X X
LCV X X X X X X
CHECKLIST
•NEUTROPHILS ≥ 0.75 X109/L OR WBC ≥ 2.0
X109/L
•PLATELETS ≥ 75 X109/L
•BILIRUBIN ≤ 1.25 X ULN
•GFR ≥ 70 ML/MIN/1.73M2
•DRAIN EFFUSION & ASCITES
PREPARATION
•INJ SODIUM BICARBONATE 75 ML IN 420
ML OF 5%DEXTROSE TOTAL 3L/DAY
•FLUID TO CONTINUE TILL DISCHARGE
•MONITOR URINE PH BY PH STRIP AND IF PH
>7 START METHOTREXATE
PREMED:
•INJ PALONOSETRON 0.25 MG IVP D1
•INJ DEXAMETHASONE 12 MG/100 ML OF
NS OVER 30 MIN D1
•INJ DEXAMETHASONE 8 MG /100 M OF NS
IV OVER 10 MIN D2
CHEMOTHERAPY
•INJ ACTINOMYCIN 0.5 MG IVP D1, D2
•INJ ETOPOSIDE 150 MG IN 500 ML OF 5% IV OVER 30 MIN
D1,D2ONLY
•INJ METHOTREXATE 100 mg IN 10 ML OF NS IVP
•INJ METHOTREXATE 300 ML OF NS IV OVER 12 HR D1ONLY
•INJ LEUCOVORIN 15 MG PO/IV EVERY 6 HRLY AFTER 24 HR
OF MTX X 4-8 DOSE D2
POST CHEMOTHERAPY
•INJ PEG GCSF 6 MG D3 SC SC D3 ONLY
•TAB RABEPRAZOLE -D ONCE A DAY BEFORE
FOOD FOR 5 DAY
•SYP LACTULOSE/LACTITOL 20 ML AT NIGHT FOR
3 DAY
•DEXA 2 MG IN 100 ML OF WATER TO GARGLE
TDS(DON’T DRINK)
•IF FEVER >100 FOR 1 HR OR 101 TAKE TAB
AUGMENTIN 625 MG TDS+TAB LEVOFLOXACIN
500 MG OD+TAB CROCIN 500 MG 6 HRLY CON
CONSULT DOCTOR/PGI EMERGENCY

Gyn-Oncology Team
Medical Oncology
Gyn- Radiology
Clinical Genetics
Gyn-Pathology
Radiotherapy
Gyn
Oncology/Surgical
Oncology

When the world says: “Give Up”
Hope whispers...
‘Try it one more time’

Chemotherapy in Gynecological malignancies

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