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Notificaciones al usuario

9 Compatibilidad con dispositivos móviles y AutoFirma

9.4 Notificaciones al usuario

regimens (research question 1)

Adverse events that were reported to be different between treatment arms are included in the Table, adverse events which were not significantly different between treatment arms are not reported here.

Study Intervention Comparator Adverse events

Worse on intervention Worse on comparator

Phase III trials OVAR 5, du Bois

200617 Epirubicin + carboplatin + paclitaxel

Carboplatin +

paclitaxel Granulocytopenia (SS), Anaemia (SS), Neutropenia (SS), Febrile neutropenia (SS), Thrombocytopenia (SS), Infections (SS), Nausea and vomiting (SS), Stomatitis (SS), Days on IV antibiotics (SS), RBC transfusions (SS), G-CSF Pain (other) (SS) OVAR 9, du Bois 201018 Gemcitabine + carboplatin + paclitaxel Carboplatin +

paclitaxel Granulocytopenia (SS), Anaemia (SS), Neutropenia (SS), Febrile Neutropenia (SS), Thrombocytopenia (SS), Fatigue, Days on IV antibiotics (SS), RBC transfusions (SS), G- CSF (SS)

Renal toxicity

GOG 182 / ICON 5,

Bookman 200919 i) Gemcitabine + carboplatin + paclitaxel ii) Doxorubicin + carboplatin + paclitaxel iii) Topotecan + carboplatin → carboplatin + paclitaxel iv) Gemcitabine + Carboplatin +

paclitaxel “There was increased hematologic toxicity in the triplet regimens and increased thrombocytopenia in both arms with gemcitabine. Neuropathy was decreased in the doublet regimens, which included only four cycles of paclitaxel. Transient elevations of transaminases were more commonly observed in arms with gemcitabine, but they were generally without clinical impact. There was no significant increase in pulmonary toxicity

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 67

Study Intervention Comparator Adverse events

Worse on intervention Worse on comparator

carboplatin → carboplatin + paclitaxel

associated with gemcitabine.” Bolis 201020 Topotecan +

carboplatin + paclitaxel

Carboplatin +

paclitaxel Higher percentage experienced ≥1 life threatening adverse event (SNR), Leukopenia (SS), Anaemia (SS), Neutropenia (SS), Fatigue (BS), RBC transfusions (SS), G-CSF (SS) OVAR 7, Pfisterer 200621 Carboplatin + paclitaxel → topotecan Carboplatin +

paclitaxel Leukopenia (SS), Anaemia (SS), Neutropenia (SS), Thrombocytopenia (SS), Allergic reaction (SS), Infections (SS), Arrhythmia (SS), Constipation (SS), Days on IV antibiotics (SS), RBC transfusions (SS), G- CSF (SS) OV 16, Hoskins 200822 (abstract only) Cisplatin + topotecan x 4 cycles → paclitaxel + carboplatin x 4 cycles Carboplatin +

paclitaxel x 8 cycles Febrile neutropenia (SNR), Hospitalisations (SNR) HeCOG,

Aravantinos 200823 Cisplatin + doxorubicin + paclitaxel Carboplatin + paclitaxel Deaths from treatment slightly higher (SNR) Febrile neutropenia (SS) Neutropenia Lhomme 200824 Paclitaxel +

carboplatin + valspodar (PSC 833)

Carboplatin +

paclitaxel Grade 3 or 4 adverse events (SS); serious adverse events (SS), Neurotoxicity (SNR), Grade 4 neutropenia (SS), Febrile

neutropenia (SS), Grade 4 thrombocytopenia (SS),

Hyperbilirubinemia (SNR), Ataxia (SS), Gastrointestinal toxicity

GOCCNE, Nicoletto

2007 25 Cisplatin + cyclophosphamide Adriamycin + cyclophosphamide Toxicity not reported

SGCTG, Reed 200615 Treosulfan Carboplatin Anaemia (SS), Neutropenia

(SS) MITO 2, Pignata

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 68

Study Intervention Comparator Adverse events

Worse on intervention Worse on comparator

Stomatitis (any grade: SS, severe: NS)

RBC transfusions (SS) Alopecia (SS), Diarrhoea (any grade: SS, severe: NS) SCOTROC, Vasey

200427 Docetaxel + carboplatin Carboplatin + paclitaxel Allergic reaction (SS), Neutropenia (SS), Febrile neutropenia (SS), Nausea (SS), Diarrhoea (SS), Stomatitis (SS)

Neurotoxicity (SS),

Alopecia (SS), Myalgia (SS) GOG 158, Ozols

200328 Cisplatin + paclitaxel Carboplatin + paclitaxel Leukopenia (SS), Gastrointestinal, renal and metabolic toxicity Thrombocytopenia (SS) OVAR 3, du Bois

2003, Greimel 200629,30

Cisplatin + paclitaxel Carboplatin +

paclitaxel Neuropathy (SS), Nausea and vomiting (SS) Leukopenia (SS), Neutropenia (SS), Febrile neutropenia (SS),

Thrombocytopenia (SS), Infections (SS), RBC transfusions (SS), G-CSF HeCOG,

Aravantinos 200531 Paclitaxel + carboplatin ↔ cisplatin Carboplatin + paclitaxel Nausea and vomiting (SS) Deaths from treatment slightly higher (SNR) Mouratidou 200732 Cisplatin + paclitaxel Cisplatin +

cyclophosphamide Neurotoxicity (SNR); Neutropenia (SS), Thrombocytopenia (NS), Alopecia (SS), Myalgia (SS),

Nausea and vomiting (NS) OV10, Piccart 2003,

Bezjak 2004, Butler 200433-35

Cisplatin + paclitaxel Cisplatin +

cyclophosphamide Toxicity not reported AOCSG, Dittrich

200336 Cisplatin + carboplatin Cisplatin + cyclophosphamide Granulocytopenia (SS), Anaemia (SS), Thrombocytopenia (SS), Nausea and vomiting (SS), Ototoxicity (SS)

Phase II trials Muthuramalingam

201137 Carboplatin + thalidomide Carboplatin Constipation (SNR), Dizziness (SNR), Fatigue (SNR), Neurotoxicity (SNR) SCOTROC2A, Vasey 200638 Carboplatin → docetaxel + gemcitabine Carboplatin →

docetaxel Anaemia (SS), Thrombocytopenia (SS), Dyspnoea (SS) Neutropenia (SS), Alopecia (SS) SCOTROC2B, Clamp

200639

Carboplatin →

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 69

Study Intervention Comparator Adverse events

Worse on intervention Worse on comparator

neutropenia (SNR) Minagawa 200640 Docetaxel + cisplatin Carboplatin +

docetaxel Grade 4 neutropenia (SS), Diarrhoea (SS), G-CSF (SS)

Mori 200741 Docetaxel +

carboplatin Carboplatin + paclitaxel No significant differences reported JGOG3014,

Takakura 201016 Irinotecan + cisplatin Carboplatin + paclitaxel Gastrointestinal toxicities (NS) Neurotoxicity (SS), Thrombocytopenia (SS) Fruscio 200842 Cisplatin + paclitaxel +

isosfamide Cisplatin + paclitaxel + epirubicin Leukopenia (SS), Anaemia (SS), Grade 3 febrile neutropenia (SS), Fever (SS), Hospitalisations (SS), Transfusions (SS)

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 70

Appendix J Adverse events reported in trials investigating biological therapies

Study Intervention Comparator Adverse events

Worse on intervention Worse on

comparator Phase III trials

OVAR 11 / ICON 7, Perren 201143

Bevacizumab + carboplatin

+ paclitaxel Carboplatin + paclitaxel Overall toxicity higher (SNR), Deaths from treatment slightly higher (SNR), Hypertension higher (SNR) GOG 218,

Burger 201145 i) Bevacizumab + carboplatin + paclitaxel ii) Bevacizumab +

carboplatin + paclitaxel → bevacizumab

Carboplatin +

paclitaxel Hypertension (SS), Deaths from treatment slightly higher, particularly in intervention group (ii) (SNR) “hypertension, proteinuria and pain were more commonly reported in the extended therapy phase among patients in the bevacizumab throughout group (iii).”

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 71

Appendix K ASCO clinical practice guideline recommendations for chemotherapy dosing

for obese adults with cancer

76

Clinical Question Recommendation

1. Is there evidence that full weight–based dosing increases toxicity in obese patients with cancer?

Recommendation 1.1: The Panel recommends that actual body weight be used when selecting cytotoxic chemotherapy doses regardless of obesity status. There is no evidence that short- or long-term toxicity is increased among obese patients receiving full weight–based chemotherapy doses. Most data indicate that myelosuppression is the same or less pronounced among the obese than the non-obese administered full weight–based doses. Recommendation 1.2: The Panel recommends full weight–based chemotherapy dosing for morbidly obese patients with cancer, subject to appropriate consideration of other comorbid conditions. Data are extremely limited regarding optimal dose selection among the morbidly obese and other special subgroups. More studies are needed to evaluate optimal agents and agent combinations for obese and morbidly obese patients with cancer; however, based on available information, it seems likely that the same principles regarding dose selection for obese patients apply to the morbidly obese. 2. Is there evidence that less than full

weight–based dosing compromises efficacy in obese patients with cancer?

Recommendation 2.1: The Panel recommends that full weight–based chemotherapy doses (IV and oral) be used in the treatment of the obese patient with cancer, particularly when the goal of treatment is cure. Selecting reduced doses in this setting may result in poorer disease-free and overall survival rates. There are compelling data in patients with breast cancer that reduced dose-intensity chemotherapy is associated with increased disease recurrence and mortality. Although data in other malignancies are more limited, based on improved survival observed with chemotherapy compared with controls, a dose-response relationship exists for many responsive malignancies. Therefore, although data are not available to address this question for all cancer types, in the absence of data demonstrating sustained efficacy for reduced dose chemotherapy, the Panel believes that the prudent approach is to provide full weight–based hemotherapy dosing to obese patients with cancer, especially those receiving treatment with curative intent. Most of the data in support of full weight–based dosing come from the treatment of early-stage disease. Data supporting the use of full weight– based doses in the advanced disease setting are limited.

3. If an obese patient experiences highgrade

toxicity, should chemotherapy doses or schedules be modified differently from modifications used for non-obese patients with cancer?

Recommendation 3.1: Clinicians should follow the same guidelines for dose reduction, regardless of obesity status, for all patients, depending on the type and severity of toxicity, any comorbid conditions, and whether the treatment intention is cure or palliation. There is no evidence to support the need for greater dose reductions for obese patients compared with non-obese patients. If a dose reduction is employed in response to toxicity, consideration should be given to the resumption of full weight–based doses for subsequent cycles, especially if a possible cause of toxicity (eg, impaired renal, hepatic function) has been resolved. The Panel recognizes the need for clinicians to exercise judgment when providing care for patients who have experienced grade 3 or 4 chemotherapy toxicity. The presence of obesity alone should not alter such clinical judgment.

4. Is the use of fixed-dose (dose prescribed independently of weight or BSA) cytotoxic chemotherapy ever justified? Are there unique dosing considerations for certain chemotherapeutic agents?

Recommendation 4.1: The Panel recommends consideration of fixed dosing only with select cytotoxic agents (eg, carboplatin and bleomycin). On the basis primarily of neurotoxicity concerns, vincristine is capped at a maximum dose of 2.0 mg when used as part of the CHOP and CVP regimens. Several other cytotoxic chemotherapeutic agents have been used in clinical trials at a fixed dose independent of patient weight or BSA. However, it is not clear that fixed dosing is optimal for any of these other agents.

5. How should BSA be calculated? Specifically, what is the best formula for use with the obese patient with cancer?

Recommendation 5.1: The Panel recommends that BSA be calculated using any of the standard formulae. There is no evidence to support one formula for calculating BSA over another.

6. What is the role of pharmacokinetic and/ or phamacogenetic factors when determining optimal chemotherapy dose and delivery (bolus, infusional, therapeutic drug monitoring) for obese patients with cancer?

Recommendation 6.1: The Panel recommends further research into the role of pharmacokinetic and pharmacogenetic information for guiding the dosing of IV and oral chemotherapeutic agents for adult patients with cancer who are obese. It should be emphasized that there is a paucity of information on the influence of obesity on the pharmacokinetics of most anticancer drugs from properly powered trials. This is the result, inpart, of empiric eligibility restrictions from the outset in clinical trials and a lack of pharmacokinetic analyses performed and published for this subpopulation. Overall, there are insufficient pharmacokinetic data to reject the recommendation to use a full weight–based dosing strategy for chemotherapeutic agents in patients with cancer who are obese, regardless of route of administration and/or infusion time.

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 72

Appendix L Ongoing trials

Research question 1 Trial name and location

Study design

Participants Intervention Control Completion

status NCT00838656 UK Phase 2 RCT, open- label

Stage IIIC or stage IV ovarian cancer, fallopian tube cancer, or primary peritoneal cancer n=88

Neoadjuvant Carboplatin  surgery  adjuvant Paclitaxel and Gemcitabine Neoadjuvant Gemcitabine and Carboplatin  surgery  adjuvant Paclitaxel Unknown NCT00929162 Italy and Germany Phase 2 RCT, double- blind

Advanced ovarian cancer n=120

ZD4054, Paclitaxel, Carboplatin Placebo, Paclitaxel, Carboplatin Completed NCT01583322 France Phase 2 RCT, double- blind

Adenocarcinoma of the ovary, the fallopian tube, or serous adenocarcinoma of the peritoneum

n=188

Neo-adjuvant chemotherapy (Carboplatin and Paclitaxel), interval debulking surgery, Vargatef® (Nintedanib) Neo-adjuvant chemotherapy (Carboplatin and Paclitaxel), interval debulking surgery Ongoing

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 73 Trial name and

location

Study design

Participants Intervention Control Completion

status NCT00452985 Bangladesh Phase 2 RCT, open- label Advanced or metastatic ovarian cancer n=30 Docetaxel, Cisplatin, Cyclophosphamide

Docetaxel, Carboplatin Completed

NCT00391118 US, Belgium, Germany Phase 2 RCT, double- blind

Advanced ovarian cancer, fallopian tube neoplasms, peritoneal neoplasm n=149 Carboplatin, Paclitaxel, Enzastaurin 1125 (LY317615) Carboplatin, Paclitaxel, Placebo Ongoing NCT00610714 International Phase 2 RCT, double- blind

Advanced ovarian cancer n=211

Carboplatin, Paclitaxel, AZD0530

Carboplatin, Paclitaxel Completed

NCT01081262 UK Phase 3 RCT, open- label

Stage II, stage III, stage IV, or recurrent stage I epithelial ovarian cancer or fallopian tube cancer

n=332

Oxaliplatin and Capecitabine +/- Bevacizumab Carboplatin and Paclitaxel +/- Bevacizumab Ongoing NCT00003880 USA Phases 2/3 RCT

Stage III ovarian and primary peritoneal cancers

n= 360

Carboplatin, Paclitaxel, SCH 58500

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 74 Trial name and

location

Study design

Participants Intervention Control Completion

status ISRCTN52615671

International

Phase 3 RCT

Clear cell carcinoma of the ovary

n=652

Irinotecan, Cisplatin

Paclitaxel, Carboplatin Completed

EUCTR2008- 006831-10 International Phase 3 RCT, double- blind

Advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer n=1300

Carboplatin, Paclitaxel, BIBF 1120 Carboplatin, Paclitaxel, placebo Ongoing NTR1491 The Netherlands Phase 2 RCT, open- label

Epithelial ovarian, fallopian tube, or primary peritoneal carcinomas

n=200

Docetaxel, Carboplatin, Celecoxib

Docetaxel, Carboplatin Ongoing

NCT00005051 US

Phase 2 RCT

Advanced ovarian epithelial cancer

n=30

Cisplatin, Topotecan, Paclitaxel, Carboplatin

Cisplatin, Topotecan Completed

ISRCTN51315091 Germany Phase 2 RCT, open- label

Extra-ovarian papillary serous tumors

n=100

Paclitaxel, Carboplatin, Lonafarnib

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 75 Trial name and

location

Study design

Participants Intervention Control Completion

status ISRCTN83438782 International Phase 3 RCT, open- label

Mucinous carcinoma of the ovary

n=330

Oxaliplatin and Capecitabine +/- Bevacizumab Carboplatin and Paclitaxel +/- Bevacizumab Ongoing Research question 2 Trial name and location

Study design

Participants Intervention Control Completion

status NCT00660842 Italy Phase 3 RCT, open- label Ovarian cancer n=800

Weekly Carboplatin and Paclitaxel Every 3 weekly Carboplatin and Paclitaxel Ongoing NCT01462890 Germany Phase 3 RCT, open- label

Epithelial ovarian, fallopian tube or peritoneal cancer n=800

Bevacizumab continuously for up to 15 months and

Carboplatin and Paclitaxel

Bevacizumab

continuously for up to 30 months and Carboplatin and Paclitaxel Ongoing NCT00239980 Canada Phase 2 RCT, open- label

Epithelial ovarian cancer One of 3 doses of a LMWH Dalteparin (Fragmin: 50, 100, and 150 IU/kg) in conjunction with standard adjuvant taxane- and platinum-based

chemotherapy

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 76 Trial name and

location

Study design

Participants Intervention Control Completion

status NCT00098878

International

Phase 3 RCT

Fallopian tube cancer, ovarian cancer, peritoneal cavity cancer

Intra-patient dose-escalated Carboplatin on day 1

Flat dose of Carboplatin on day 1 Unknown NCT00002717 US Phase 3 RCT

Stage III or stage IV ovarian cancer of primary peritoneal cavity cancer (residual disease after surgery)

n=324

Paclitaxel continuously over 96 hours  Cisplatin over 2 hours

Paclitaxel continuously over 24 hours  Cisplatin over 2 hours Completed EUCTR2010- 022209-16 International Phase 3 RCT, open- label

High risk early stage (FIGO stage IC/IIA, grade 3 or clear cell histology only) or

advanced stage (FIGO stage IIB-IV, all grades and all histological types) epithelial ovarian, fallopian tube, or primary peritoneal carcinoma n=1485 Dose-fractionated Carboplatin- Paclitaxel Standard Carboplatin- Paclitaxel Ongoing

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 77 Research question 3

Trial name and location

Study design

Participants Intervention Control Completion

status NCT00993655 Canada Phases 2/3 RCT, open- label

Stage IIB, stage IIC, stage III, or stage IV ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer

n=830

Intraperitoneal and intravenous chemotherapy Intravenous Carboplatin and Paclitaxel Ongoing NCT01091636 Korea Phases 2/3 RCT, single- blind

Epithelial ovarian cancer n=168 Intraoperative hyperthermic intraperitoneal chemotherapy followed by intravenous chemotherapy Ongoing Research question 4 Trial name and location Study design

Participants Intervention Control Completion

status NCT007152 86 India Phase 3 RCT, open- label

Advanced epithelial ovarian carcinoma

n=180

Neoadjuvant chemotherapy followed by interval debulking surgery

Upfront surgery followed by chemotherapy

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 78 Research questions 1 and 3

Trial name and location

Study design

Participants Intervention Control Completion

status NCT009514 96 US Phase 3 RCT, open- label

Fallopian tube cancer, ovarian cancer, primary peritoneal cavity cancer

n=1500

Bevacizumab and

intraperitoneal chemotherapy

Bevacizumab with intravenous chemotherapy

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 79

Abbreviations

AUC Area Under The Curve

ACN Australian Cancer Network

ASCO American Society Of Clinical Oncology ANZCTR Australian New Zealand Clinical Trials Registry

BMI Body Mass Index

BRCA Breast Cancer

BSA Body Surface Area

CI Confidence Interval

ESGO European Society Of Gynaecological Oncology

FINOVA Finnish Ovarian Cancer Study

GFR Glomerular Filtration Rate

GIN Guidelines International Network

GOG Gynecologic Oncology Group

HeCOG Hellenic Co-Operative Oncology Group

HDCT High-Dose Chemotherapy

HIDOC-EIS High-Dose Ovarian Cancer-European Intergroup Study

HR Hazard Ratio

IGCS International Gynecologic Cancer Society

IP Intraperitoneal

IV Intravenous

NBOCC National Breast And Ovarian Cancer Centre

NBCC National Breast Cancer Centre

NHMRC National Health And Medical Research Council

ORR Overall Response Rate

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 80

PFS Progression-Free Survival

QoL Quality Of Life

QIMR Queensland Institute Of Medical Research

RCT Randomised Controlled Trial

RR Relative Risk

SGCTG Scottish Gynaecological Clinical Trials Group

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 81

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