fernando cotait maluf director of medical oncology department são josé hospital são paulo são...

State of the art of the management of advanced

and recurrent ovarian cancer

Fernando Cotait Maluf Director of Medical Oncology Department

São José HospitalSão Paulo São Paulo Brazil

[email protected]

A Transformação..............

Primeiro fase (fase I)

Segunda fase (fase II)

• Advanced stages at diagnosis (~75%)

• Highly chemotherapy-sensitive

• Complete clinical response to platinum-based CT: 70-85%

• Stage III: 20-25% of complete remission at 5y

Introduction

Surgery

• 81 studies

• 6885 patients

• Stage III and IV

• Cytoreductive surgery followed by platinum-based CT

Bristow et al. J Clin Oncol, 2002

• CT platinum-based versus CT NON platinum-based 1,2

• HR death: 0.88 [0.79 – 0.98]

Lessons from Chemotherapy-1990’

Ovarian Cancer Meta-Analysis Project (Gynecol Oncol, 2002) 1

Advanced Ovarian Cancer Trialists Group (2002) 2

Ovarian Cancer Meta-Analysis Project (J Clin Oncol, 1991) 3

• CT anthracyline-based versus CT NON anthracyline-based 3

• Absolute survival benefit: 5% ( p = 0.02)

• Cisplatin versus Carboplatin 1,2

• HR death: 1.02 [0.93 – 1.12]

• Platinum-dose not associated with survival benefit 3

• MONOCT platinum-based versus POLICT platinum-based 1,2

• HR death: 0.91 [0.75 – 1.05]


Ovarian Cancer Meta-Analysis Project (Gynecol Oncol, 2002) 1

Advanced Ovarian Cancer Trialists Group (2002) 2

ICON 3: Carboplatin vs Carboplatin + Paclitaxel


GOG 111 and OV 10(Intergroup)

McGuire et al, N Eng J Med, 1996;n=386, suboptimal cytoreduction III/IV SLP SGPT 18m 38mPC 13m 24m

Piccart et al, J Nat Cancer Inst, 2000;n=668, debulking surgery, II-IV SLP SGPT 17m 35mPC 12m 25m

Evolvement of Traditional Chemotherapy

Dose-dense IV chemotherapy

Advanced Ovarian Cancer

(n = 637)

RANDOMIZATION

Carboplatin AUC 6 + Paclitaxel 180mg/m2

q 21 days x 6 cycles

Katsumata N, Lancet: 374, 2009

Carboplatin AUC 6 + Paclitaxel 80mg/m2

d1,8,15

q 21 days x 6 cycles


Dose-dense IV chemotherapy

Katsumata N, Lancet: 374, 2009

Progression-free Survival Overall Survival


IP administration

Standard arm IV

D1 D2 IV IV

D1 Paclitaxel IV 135mg/m2/24hs

D2 Cisplatin IV 75mg/m2

D1 D2 D8

IV IP IP

Experimental arm IV/IP D1 Paclitaxel EV 135mg/m2/24hsD2 Cisplatin IP 100mg/m2

D8 Paclitaxel IP 60mg/m2

GOG 172

Armostrong e al, NEJM, 2006;N=429, optimal debulking surgery, stage III SLP SGPT IV 19m 50mPT IV/IP 24m 65m

Only 42% of pts completed treat. IV/IP arm


IP administration

GOG randomized studies: IV vs IP

PFS (m)

% Advantage

OS (m)

% Advantage

IV IP IV IP

Alberts -- -- 41 49

Markman 22 28 27 52 63

Armstrong 19 24 20 50 65 25

* Statistically significant : p < 0.05

New targets and new agents

GOG-0218: Scheme

Stratification• PS• Stage/Citoreduction BEV 15 mg/kg

15 months

Paclitaxel (P) 175 mg/m2

Carboplatin (C) AUC 6





Placebo

PlaceboBEV 15 mg/kg

First-line : Epithelial OV, PP or F

• Stage III optimal• Stage III suboptimal• Stage IV

n=1800 (planned)

RANDOMIZ E

I

II

III

Arm

1:1:1


GOG-218: Progression-Free SurvivalArm I

CP (n=625)

Arm IICP + BEV(n=625)

Patients with event, n (%) 423 (67.7)

418 (66.9)

Median PFS, months 10.3 11.2

Stratified analysis HR (95% CI)

0.908(0.759–1.040)

One-sided p-value (log rank) 0.080a

+ BEV (Arm II)CP (Arm I)

+ BEV → BEV maintenance (Arm III)Pro

po

rtio

n s

urv

ivin

g p

rog

ress

ion

fre

e

Months since randomization

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 12 24 36

Arm IIICP + BEV BEV

(n=623)

360 (57.8)

14.1

0.717 (0.625–0.824)

<0.0001a


ICON 7: Scheme

• Open-label study• Endpoints

– primary: PFS– secondary: RR, OS, safety, QoL, cost effectiveness, translational

• Stratification– FIGO stage/surgery; time since surgery; GCIG group

Paclitaxel 175mg/m2 q3w

CarboplatinAUC6* q3w

Bevacizumab 7.5mg/kg q3w

Paclitaxel 175mg/m2 q3w

CarboplatinAUC6* q3w

18 cycles

Stage I or IIa (grade 3 or clear cell) orstage IIb–IV EOC,

PP, FTC(n=1,520)


ICON 7: Progression-Free Survival

Control Experimental

Events, n (%) 130 (17) 111 (15)

Log-rank p=0.098

Hazard ratio (95% CI) 0.81 (0.63–1.04)

Sobrevida 1-ano, % 93 95

1.00

0.75

0.50

0.25

0

Pro

port

ion s

urv

ivin

g

Time (months)

0 3 6 9 12 15 18 21 24 27 30

Management of Recurrent Ovarian Cancer: Importance of Platinum-

intervalPRIMARY TREATMENT

0 3 6 12 18 24

Refractory

Resistent

Sensitive

Highly sensitive

Months

Management of Recurrent Ovarian Cancer: Importance of Platinum-interval

70

60

50

40

30

20

10

0

12

33

59

< 6 months

12-18 months

> 18 months

Overall Response Rate (%)

Interval from prior platinum treatment (months)

Management of Recurrent Disease

Platinum-Sensitive

Platinum-Resistant or Refractory

Platinum-based Therapy

Platinum-sensitive ovarian cancer

ΔT > 6 m

RANDOMIZATION

Carboplatin AUC 5 a 6 EV OR

Cisplatin 75mg/m2 EVq 21 days

Carboplatin AUC 5 EV OR

Cisplatin 50mg/m2 EV +

Paclitaxel 175mg/m2 EVQ 21 days

Parmar MK, Lancet: 361, 2003

ICON-4/AGO-OVAR-2.2 Trial

Recurrent Sensitive Ovarian Cancer:

MonoCT vs PoliCT platinum-based




Progression-free Survival





Overall Survival


End-point HR PoliCT/MonoCT p

RR 1,32 (1,08 - 1,62) 0,05

2-year TTP 0,67 (0,52 - 0,86) 0,02

2-year OS 0,77 (0,64 - 0,91) 0,04

Orlando M, J Clin Oncol 25:18s 2007 (abstr 5524)



Pujades E et al, J Clin Oncol, 2010

Inclusion Criteria:

• Platinum-sensitive (> 6 m)

• 1 or 2 prior platinum-based CT

• Measurable disease (image or CA125)

RANDOMIZATION

Carboplatin AUC 5 EV + Paclitaxel 175 mg/m2 IV 3

q 21 d x 6 cycles

Carboplatin AUC 5 EV + Doxo Lipossomal 30 mg/m2 IV 1 h

q 28 days x 6 cycles*

*or until PD in patients with stable disease or response

CALYPSO: Scheme


Optimal platinum-based combination


Hematologic Toxicity



Doxo Lipossomal + Carboplatin(n = 102)

Paclitaxel + Carboplatin

(n = 98)

Neutropenia, grade 3/4 37% 48%Febrile Neutropenia 3% 2%

Anemia, grade 3/4 9% 5%

Thrombocitopenia, grade 3/4 19% 5%


Neuropathy






CALYPSO: Progression-Free Survival

Recurrent Sensitive Ovarian Cancer: platinum-based combo with optimal

target agents

•Endpoints– primary: PFS– secondary: ORR, OS, response duration, safety– exploratory: IRC, CA125 response, ascites

•Stratification: time to recurrence, cytoreductive surgery

Gemcitabine 1000mg/m2 days 1 and 8 q3w

CarboplatinAUC4 q3w

Gemcitabine 1000mg/m2 days 1 and 8 q3w

CarboplatinAUC4 q3w

Bevacizumab 15mg/kg

Placebo

EOC = epithelial ovarian; PP = primary peritoneal; FTC = fallopian tube carcinoma

PD

PD

Bev. 15mg/kg

Pretreated platinum-sensitive,

EOC, PP or FTC(n=480)

Placebo

OCEANS: Scheme


target agents

OCEANS: Patients Characteristics

CharacteristicCG + PL (n=242)

CG + BV (n=242)

Median age, years (range)

61(28−86)

60(38–87)

Age ≥65 years, % 38 35

Race, % White Other

928

9010

ECOG PS 0, % 76 75Histologic subtype, % Serous Mucinous/clear cell Other

843 14

785

17

Platinum-free interval, % 6–12 months >12 months

4258

4159

Cytoreductive surgery for recurrent disease, % 10 12


target agents

OCEANS: Progression-free SurvivalCG + PL(n=242)

CG + BV(n=242)

Events, n (%) 148 (61) 119 (49)

Median PFS, months (95% CI)

8.6(8.3–10.2)

12.3(10.7–14.6)

Stratified analysis HR (95% CI)Log-rank p-value

0.451(0.351–0.580)

<0.0001

1.0

0.8

0.6

0.4

0.2

0

Pro

port

ion

pro

gre

ssio

n f

ree

0 6 12 18 24 30

242 168 31 8 3 0CG + PL242 195 73 22 7 0CG + BV

MonthsNo. at risk


target agentsOCEANS: Progression-free Survival vs Subgroups

Median PFS (months)

Baseline risk factorNo. of

patientsCG + PL(n=242)

CG + BV (n=242) HR (95% CI)

CG + BV better

CG + PL better

All patients 484 8.4 12.40.49 (0.40–

0.61)Platinum-free interval, months

6–12 202 8.0 11.90.41 (0.29–

0.58)

>12 282 9.7 12.40.55 (0.41–

0.73)Cytoreductive surgery for recurrent disease

Yes 54 7.5 16.70.50 (0.24–

1.01)

No 430 8.4 12.30.49 (0.39–

0.62)Age, years <65 306 8.5 12.5

0.47 (0.36–0.62)

≥65 178 8.4 12.30.50 (0.34–

0.72)Baseline ECOG PS 0 367 8.6 12.5

0.47 (0.36–0.60)

1 116 8.3 10.60.61 (0.39–

0.95) HR0.2 0.5 1 2 5


target agents

OCEANS: Response Rate

Duration of response CG + PL (n=139)

CG + BV (n=190)

Median, months 7.4 10.4

HR (95% CI) 0.534(0.408–0.698)

p<0.0001a

100

80

60

40

20

0

%

78.5

57.4 PR = 61

PR = 48

CR = 17CR = 9

Difference: 21.1% p<0.0001

aCompared for descriptive purposes only

CG + PL (n=242)

CG + BV (n=242)

Median PFS (months)

Baseline risk factorNo. of

patientsCG + PL(n=242)

CG + BV (n=242) HR (95% CI)

CG + BV better

CG + PL better

All patients 484 8.4 12.40.49 (0.40–

0.61)Platinum-free interval, months

6–12 202 8.0 11.90.41 (0.29–

0.58)

>12 282 9.7 12.40.55 (0.41–

0.73)Cytoreductive surgery for recurrent disease

Yes 54 7.5 16.70.50 (0.24–

1.01)

No 430 8.4 12.30.49 (0.39–

0.62)Age, years <65 306 8.5 12.5

0.47 (0.36–0.62)

≥65 178 8.4 12.30.50 (0.34–

0.72)Baseline ECOG PS 0 367 8.6 12.5

0.47 (0.36–0.60)

1 116 8.3 10.60.61 (0.39–

0.95)

OCEANS: PFS subgroup analyses

HR0.2 0.5 1 2 5


target agents

OCEANS: Overview of AEs

Patients, %CG + PL(n=233)

CG + BV(n=247)

Any AE 100 100

Serious AE 25 35

Grade 3–5 AE 82 90

Grade 3–5 AE of special interest 62 74

Grade 5 AE <1a <1b

aAcute myocardial infarction in one patientbIntracranial hemorrhage in one patient


target agents

OCEANS: AEs of special interest

ATE = arterial thromboembolic event; CHF = congestive heart failure; GI = gastrointestinal; RPLS = reversible posterior leukoencephalopathy syndrome; VTE = venous thromboembolic event aTwo GI perforations occurred 69 days after last BV dose

Patients, %

CG + PL(n=233)

CG + BV(n=247)

ATE, all grades 1 3

VTE, grade ≥3 3 4

CNS bleeding, all grades <1 1

Non-CNS bleeding, grades ≥3 1 6

CHF, grades ≥3 1 1

Neutropenia, grade ≥3 56 58

Febrile neutropenia, grade ≥3 2 2

Hypertension, grade ≥3 <1 17

Fistula/abscess, all grades <1 2

GI perforation, all grades 0 0a

Proteinuria, grade ≥3 1 9

RPLS, all grade 0 1

Wound-healing complication, grades ≥3 0 1


target agents


Platinum-Sensitive


Retrospective analysis: 111 pts

Recurrence < 3m or Ø Response

Median OS 6 months

SV < 4months 32%SV < 12months 73% Markman et al. Gynecol Oncol, 2004


Platinum-Sensitive


Poli-CT vs Mono-CT


MONO-CT POLI-CT

Better toxicity profile

Worse toxicity profile

Higher response rates

Questionable Higher TTP

No improvement

in Overall Survival

Classic Chemotherapy Agents for Recurrent Resistant Ovarian

Cancer

Liposomal Doxorrubicin Gemcitabine Paclitaxel (weekly) Docetaxel Topotecan Etoposide (oral) Vinorelbine Ifosfamide

Doxo Lipossomal vs Gemcitabina (MITO)*

*Multicentre Italian Trials in Ovarian cancer

Recurrent Ovarian Cancer

TTP 12 m

Randomi z ation

Gemcitabine 1000mg/m2 IV

D1,8,15 q4w

Caelyx 40mg/m2 EV cada 28 dias

Doxo Lipossomal 40 mg/m2 IV D1 q4w

Primary end-point: TTP

Secondary end-points: OS, RR, QOL Ferrandina et al. J Clin Oncol, 2008


Ferrandina et al. J Clin Oncol, 2008


Response Rates



Time to Progression



Quality of Life


Doxo Lipossomal vs Gemcitabina

Randomi z at

ion

Gemcitabine 1000mg/m2

EV D1,8 q 3 w

Doxo Lipossomal 50 mg/m2 EV D1 q 4 w

Primary end-point

Secondary end-point: OS, RR, QOL Mutch et al. J Clin Oncol, 2007


TTP 6 m


Progression-free Survival

Mutch et al. J Clin Oncol, 2007


Overall Survival

Mutch et al. J Clin Oncol, 2007

Management of Recurrent Resistant Ovarian Cancer: evolvement of the role of

target agents

AURELIA/MO22224: Scheme

Physician’s choice: Bevacizumab

15mg/kg q3w or SOC

•Endpoints

– primary: PFS

– secondary endpoints: ORR (RECIST and/or CA125), biological progression-free interval, OS, QoL, safety

•FPI: October 2009 (recruitment: 24 months)EOC = epithelial ovarian; PP = primary peritoneal; FTC = fallopian tube carcinoma; PLD = pegylated liposomal doxorubicin;SOC = standard of care

Bevacizumab 10mg/kg q2w or 15mg/kg q3w +

chemotherapy (physician’s choice, as in control arm)

SOC

Progression

Progression

Chemotherapy alone (physician’s choice):

paclitaxel 80mg/m2 qw or topotecan 4mg/m2 days 1, 8 and 15 q4w or 1.25mg/kg days 1–5 q3w or

PLD 40mg/m2 q4w

EOC, PP or FTC that relapsed

within <6 months after platinum-

based chemotherapy

(n=300)

Statistical design

Primary objective: To compare PFS with chemotherapy (CT) alone vs BEV + CT according to RECIST v1.0

Secondary objectives: To compare Objective response rate (ORR) according to RECIST v1.0 and/or

GCIG CA-125 criteria Overall survival Quality of life Safety and tolerability

Statistical assumptions HR of 0.7 (median PFS 4.0 → 5.7 months with BEV) 80% power for 2-sided log-rank test at α=0.05

Primary analysis: PFS events in 301 of 361 patients Data cut-off: November 14, 2011

Baseline characteristics

PFI = platinum-free intervalaStratification factor. bFrom last platinum to subsequent PD

CharacteristicCT (n=182)

n (%)BEV + CT (n=179)

n (%)Median age, years 61 62 (range) (25‒84) (25‒80)Origin of cancer: Ovary 157 (86) 167 (93)Serous/adenocarcinoma at diagnosis 152 (84) 156 (87)Histologic grade at diagnosis

1 9 (5) 10 (6) 2/3 153 (84) 147 (82)Prior anti-angiogenic therapya 14 (8) 12 (7)Two prior chemotherapy regimens 78 (43) 72 (40)PFI <3 monthsa,b 46 (25) 50 (28)ECOG PS

0 99 (54) 107 (60)1/2 80 (44) 70 (39)

Measurable disease 144 (79) 143 (80)Ascites 54 (30) 59 (34)

Progression-free survival

Median duration of follow-up: 13.9 months (CT arm) vs 13.0 months (BEV + CT arm)

CT (n=182)

BEV + CT (n=179)

Events, n (%) 166 (91%) 135 (75%)

Median PFS, months (95% CI)

3.4(2.2‒3.7)

6.7(5.7‒7.9)

HR (unadjusted)(95% CI)Log-rank p-value (2-sided, unadjusted)

0.48 (0.38‒0.60)

<0.001

1.0

0.8

0.6

0.4

0.2

0

Est

imat

ed p

roba

bilit

y

0 6 12 18 24 30Time (months)

182 37 8 1 0179 88 18 1 0

CTBEV + CT

No. at risk: 93140

2049

14

01

3.4 6.7

Subgroup analysis of PFS

aUnadjusted. bMissing n=8

SubgroupNo. of

patients

Median PFS, months

HRa

BEV + CT

betterCT

better CT BEV + CT

All patients 361 3.4 6.7 0.48

Age, years <65

≥65

228

133

3.4

3.5

6.0

7.8

0.49

0.47

PFI, monthsb <3

3‒6

96

257

2.1

3.6

5.4

7.8

0.53

0.46

Measurable disease, cm

No (<1)

Yes (1‒<5)

Yes (≥5)

74

126

161

3.7

3.3

3.3

7.5

7.5

6.0

0.46

0.50

0.47

Ascites Yes

No

113

248

2.5

3.5

5.6

7.6

0.40

0.48

Chemotherapy

Paclitaxel

PLD

Topotecan

115

126

120

3.9

3.5

2.1

10.4

5.4

5.8

0.46

0.57

0.320.2 0.3 0.5 1 2 3 4 5

aTwo-sided chi-square test with Schouten correction

Summary of best overall response rates

Responders (RECIST and/or CA-

125) (n=350)

RECIST responders (n=287)

CA-125 responders (n=297)

0

5

10

15

20

25

30

35

40

45

50

12.6 11.8 11.6

30.927.3

31.8

CT BEV + CT

p=0.001ap<0.001a p<0.001a

Pat

ient

s (%

)

RPLS = reversible posterior leukoencephalopathy syndrome; CHF = congestive heart failure

Adverse events of special interest

Grade ≥3 adverse events of special interest, n (%)

CT (n=181)

BEV + CT(n=179)

Hypertension 2 (1.1) 13 (7.3) Grade ≥2 12 (6.6) 36 (20.1)Proteinuria 0 3 (1.7) Grade ≥2 1 (0.6) 19 (10.6)GI perforation 0 3 (1.7) Grade ≥2 0 4 (2.2)Fistula/abscess 0 2 (1.1) Grade ≥2 0 4 (2.2)Bleeding 2 (1.1) 2 (1.1)Thromboembolic event Arterial Venous

8 (4.4)0

8 (4.4)

9 (5.0)4 (2.2)5 (2.8)

Wound-healing complication 0 0RPLS 0 1 (0.6)CHF 1 (0.6) 1 (0.6)Cardiac disorders (excluding CHF) 0 0

HFS = hand-foot syndromeaPreferred terms. bIncludes abdominal pain upper

Additional grade ≥3 adverse eventsa in ≥2% of patients in

either arm

Neutro

penia

Fatig

ue

Leuk

open

ia

Vomiting HFS

Dyspn

ea

Diarrhe

a

Anem

ia

Thro

mbo

cyto

p...

0

2

4

6

8

10

12

14

16

18

CT (n=181)

Pat

ient

s (%

)

Periph

eral

sens

ory

neur

opat

hy

Abdom

inal p

ainb

≈≈

≈

≈

1 cycle = 4 weeks except for q3w (day 1–5) topotecan

Higher chemotherapy exposure in the BEV + CT arm than in the CT

arm

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 180

10

20

30

40

50

60

70

80

90

100

CT (CT arm) (n=181)

CT (BEV + CT arm) (n=179)

Pat

ient

s (%

)

Cycle number

1 2 3 4 5 6 70

10

20

30

40

50

60

70

80

90

100

CT BEV + CT

aIncidence is based on the No. at risk receiving PLD in the respective cycleVertical bars represent 95% Pearson‒Clopper confidence intervalsCycles with <10 patients in each arm not shown

Similar time course of cumulative hand-foot syndrome in the two

armsa

Pat

ient

s (%

)

Cycle numberNo. at riskCT 63 59 36 31 23 18 9BEV + CT 62 61 48 41 30 23 10

Grade ≥2 hand-foot syndrome by cycle (PLD cohort)

aIncidence is based on the No. at risk receiving paclitaxel in the respective cycleVertical bars represent 95% Pearson‒Clopper confidence intervalsCycles with <10 patients in each arm not shown

Similar time course of cumulative neuropathy in the two armsa

Pat

ient

s (%

)

Grade ≥2 peripheral sensory neuropathy by cycle(paclitaxel cohort)

Cycle numberNo. at riskCT 55 54 43 35 24 19 8 6 2BEV + CT 60 58 53 47 41 34 20 16 11

1 2 3 4 5 6 7 8 90

10

20

30

40

50

60

70

80

90

100

CT BEV + CT

Summary

The primary objective was met PFS HR 0.48 (p<0.001) in favor of BEV combination therapy

vs single-agent CT Median PFS: 6.7 vs 3.4 months, respectively

Significant improvement in ORR 30.9% vs 12.6%, respectively (p=0.001) by RECIST and/or

CA-125

BEV safety profile consistent with previous experience Patients at high risk of GI perforation were excluded from

the study

Overall survival data expected in 2013

Management of Recurrent Resistant Ovarian Cancer: evolvement of the role of target agents

PARP inhibitors

Randomized Phase II trial: (Ledermann et al, NEJM, 2012)

N = 265

CT Olaparib vs Placebo

PFS: 8.4 vs 4.8 months (p < 0.00001)

Phase II trial: (Penson et al, ASCO , 2011)

N = 41

Carboplatin + Gemcitabine + Iniparib

OR: 70%

Management of Recurrent Resistant Ovarian Cancer: evolvement of the role of target agents

Recurrent Ovarian Cancer:

The role of Salvage Surgery

* F/U after salvage surgery: 19 months

* Time intervalo between two cytorecuctive surgeries: 36 months

Berek et al. Ann Oncol, 1999

50% !



Berek et al. Ann Oncol, 1999



Secondary cytoreduction in recurrent ovarian cancer:

need for a randomized trial

Chemotherapy

Secondary Cytoreduction Chemotherapy

RANDOMIZED

1:1

Patients

• Platinum sensitive ovarian cancer

• First recurrence

Efficacy end points

Primary:

• OS

Secondary:• Progressin-free

survival• Quality of life• Treatment morbidity

Platinum sensitive

Platinum resistant/refracto

ry


Platinum sensitive


ry

Carboplatin-Gemcitabine-BEVor

Carboplatin + Liposomal Doxo


Platinum sensitive


ry



Salvage Surgery


Platinum sensitive


ry



Platinum resistant/refractory

Salvage Surgery


Platinum sensitive


ry



CT + BEV(PLD/paclitaxel/

topotecan)

Salvage Surgery



Platinum sensitive


ry



CT + BEV(PLD/paclitaxel/

topotecan)

Salvage Surgery

GemcitabinePaclitaxel TopotecanEtoposideIfosfamideHormonal therapy



Thank You

[email protected]

fernando cotait maluf director of medical oncology department são josé hospital são paulo são...

Documents

platinumbased ct bristow

ct anthracyline

cyclesplatinunct x

ip iv ipalberts

chemotherapy vergote

cycleskatsumata n

cytoreductive surgery

polict platinum