Carboplatin and Paclitaxel With or Without Bevacizumab in Treating Patients With Stage III or Stage IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

NCT00262847CompletedPHASE3INTERVENTIONAL

Summary

This randomized phase III trial studies carboplatin, paclitaxel, and bevacizumab to see how well they work compared to carboplatin, paclitaxel, and placebo in treating patients with stage III or stage IV ovarian epithelial, primary peritoneal, or fallopian tube cancer. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether carboplatin, paclitaxel, and bevacizumab are more effective than carboplatin, paclitaxel, and placebo in treating ovarian epithelial, primary peritoneal, or fallopian tube cancer.

Key Facts

Lead Sponsor

National Cancer Institute (NCI)

Enrollment

1873

Start Date

2005-09-01

Completion Date

2010-11-01

Study Type

INTERVENTIONAL

Official Title

A Phase III Trial of Carboplatin and Paclitaxel Plus Placebo Versus Carboplatin and Paclitaxel Plus Concurrent Bevacizumab (NSC # 704865) Followed by Placebo, Versus Carboplatin and Paclitaxel Plus Concurrent and Extended Bevacizumab, in Women With Newly Diagnosed, Previously Untreated, Stage III or IV Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer

Interventions

BevacizumabCarboplatinLaboratory Biomarker AnalysisPaclitaxelPlaceboQuality-of-Life Assessment

Conditions

Fallopian Tube Clear Cell AdenocarcinomaFallopian Tube Endometrioid AdenocarcinomaFallopian Tube Mucinous AdenocarcinomaFallopian Tube Serous AdenocarcinomaFallopian Tube Transitional Cell CarcinomaMalignant Ovarian Mixed Epithelial TumorOvarian Brenner TumorOvarian Clear Cell AdenocarcinomaOvarian Endometrioid AdenocarcinomaOvarian Mucinous AdenocarcinomaOvarian Serous AdenocarcinomaOvarian Transitional Cell CarcinomaPrimary Peritoneal Serous AdenocarcinomaStage IIIA Fallopian Tube CancerStage IIIA Ovarian CancerStage IIIA Primary Peritoneal CancerStage IIIB Fallopian Tube CancerStage IIIB Ovarian CancerStage IIIB Primary Peritoneal CancerStage IIIC Fallopian Tube CancerStage IIIC Ovarian CancerStage IIIC Primary Peritoneal CancerStage IV Fallopian Tube CancerStage IV Ovarian CancerStage IV Primary Peritoneal CancerUndifferentiated Fallopian Tube CarcinomaUndifferentiated Ovarian Carcinoma

Eligibility

Age Range

18 Years+

Sex

FEMALE

Inclusion Criteria:

* Patients with a histologic diagnosis of epithelial ovarian cancer, peritoneal primary carcinoma or fallopian tube cancer; International Federation of Gynecology and Obstetrics (FIGO) stage III with any gross (macroscopic or palpable) residual disease or FIGO stage IV, defined surgically at the completion of initial abdominal surgery and with appropriate tissue available for histologic evaluation; the minimum surgery required was an abdominal surgery providing tissue for histologic evaluation and establishing and documenting the primary site and stage, as well as a maximal effort at tumor debulking; if additional surgery was performed, it should have been in accordance with appropriate surgery for ovarian or peritoneal carcinoma described in the Gynecologic Oncology Group (GOG) Surgical Procedures Manual; however, the surgeon is not required to have performed all of the items contained in this section of the GOG Surgical Procedures Manual; those patients with stage III cancer in which the largest maximal diameter of any residual tumor implant at the completion of this initial surgery is no greater than 1 cm will be defined as "optimal;" all others will be defined as "suboptimal;" measurable disease on post-operative imaging studies is not required for eligibility
* Patients with the following histologic epithelial cell types are eligible: serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner's Tumor, or adenocarcinoma not otherwise specified (N.O.S.); however, the histologic features of the tumor must be compatible with a primary Müllerian epithelial adenocarcinoma; if doubt exists, it is recommended that the investigator should have the slides reviewed by an independent pathologist or, if necessary, the Pathology Co-Chair, prior to entry; patients may have co-existing fallopian tube carcinoma in-situ so long as the primary origin of invasive tumor is ovarian, peritoneal or fallopian tube
* Absolute neutrophil count (ANC) greater than or equal to 1,500/µl equivalent to Common Toxicity Criteria for Adverse Events version (v)3.0 (CTCAE) grade 1; this ANC cannot have been induced or supported by granulocyte colony stimulating factors
* Platelets greater than or equal to 100,000/µl; (CTCAE grade 0-1)
* Creatinine =\< 1.5 x institutional upper limit normal (ULN), CTCAE grade 1
* Bilirubin less than or equal to 1.5 x ULN (CTCAE grade 1)
* Serum glutamic oxaloacetic transaminase (SGOT) and alkaline phosphatase less than or equal to 2.5 x ULN (CTCAE grade 1)
* Neuropathy (sensory and motor) less than or equal to CTCAE grade 1
* Prothrombin time (PT) such that international normalized ratio (INR) is =\< 1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin for management of venous thrombosis including pulmonary thrombo-embolus) and a partial thromboplastin time (PTT) \< 1.2 times the upper limit of normal
* Patients with a GOG Performance Status of 0, 1, or 2
* Patients must be entered between 1 and 12 weeks after initial surgery performed for the combined purpose of diagnosis, staging and cytoreduction
* Patients with measurable and non-measurable disease are eligible; patients may or may not have cancer-related symptoms
* Patients who have met the pre-entry requirements
* An approved informed consent and authorization permitting release of personal health information must be signed by the patient or guardian
* Patients in this trial may receive ovarian estrogen +/- progestin replacement therapy as indicated at the lowest effective dose(s) for control of menopausal symptoms at any time, but not progestins for management of anorexia while on protocol directed therapy or prior to disease progression

Exclusion Criteria:

* Patients with a current diagnosis of borderline epithelial ovarian tumor (formerly "tumors of low malignant potential") or recurrent invasive epithelial ovarian, primary peritoneal or fallopian tube cancer treated with surgery only (such as patients with stage Ia or Ib low grade epithelial ovarian or fallopian tube cancers) are not eligible; patients with a prior diagnosis of a borderline tumor that was surgically resected and who subsequently develop an unrelated, new invasive epithelial ovarian, peritoneal primary or fallopian tube cancer are eligible, provided that they have not received prior chemotherapy for any ovarian tumor
* Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded; prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease
* Patients who have received prior chemotherapy for any abdominal or pelvic tumor including neo-adjuvant chemotherapy for their ovarian, primary peritoneal or fallopian tube cancer are excluded; patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease
* Patients who have received any targeted therapy (including but not limited to vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management of their epithelial ovarian or peritoneal primary cancer
* Patients with synchronous primary endometrial cancer, or a past history of primary endometrial cancer, are excluded, unless all of the following conditions are met: stage not greater than I-B; no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serous, clear cell or other FIGO grade 3 lesions
* With the exception of non-melanoma skin cancer and other specific malignancies as noted above, patients with other invasive malignancies who had (or have) any evidence of the other cancer present within the last five years or whose previous cancer treatment contraindicates this protocol therapy are excluded
* Patients with acute hepatitis or active infection that requires parenteral antibiotics
* Patients with serious non-healing wound, ulcer, or bone fracture; this includes history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days; patients with granulating incisions healing by secondary intention with no evidence of fascial dehiscence or infection are eligible but require weekly wound examinations
* Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels
* Patients with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of treatment on this study
* Patients with clinically significant cardiovascular disease; this includes:
* Uncontrolled hypertension, defined as systolic \> 150 mm Hg or diastolic \> 90 mm Hg
* Myocardial infarction or unstable angina \< 6 months prior to registration
* New York Heart Association (NYHA) grade II or greater congestive heart failure
* Serious cardiac arrhythmia requiring medication; this does not include asymptomatic, atrial fibrillation with controlled ventricular rate
* CTCAE grade 2 or greater peripheral vascular disease (at least brief (\< 24 hrs) episodes of ischemia managed non-surgically and without permanent deficit)
* History of CVA within six months
* Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies
* Patients with clinically significant proteinuria; urine protein should be screened by urine protein-creatinine ratio (UPCR); the UPCR has been found to correlate directly with the amount of protein excreted in a 24 hour urine collection; specifically, a UPCR of 1.0 is equivalent to 1.0 gram of protein in a 24 hour urine collection; obtain at least 4 ml of a random urine sample in a sterile container (does not have to be a 24 hour urine); send sample to lab with request for urine protein and creatinine levels \[separate requests\]; the lab will measure protein concentration (mg/dL) and creatinine concentration (mg/dL); the UPCR is derived as follows: protein concentration (mg/dL)/creatinine (mg/dL); patients must have a UPCR \< 1.0 to allow participation in the study
* Patients with or with anticipation of invasive procedures as defined below:
* Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to the first date of bevacizumab/placebo therapy (cycle 2)
* Major surgical procedure anticipated during the course of the study; this includes, but is not limited to abdominal surgery (laparotomy or laparoscopy) prior to disease progression, such as colostomy or enterostomy reversal, interval or secondary cytoreductive surgery, or second look surgery; please consult with the study chair prior to patient entry for any questions related to the classification of surgical procedures
* Core biopsy, within 7 days prior to the first date of bevacizumab/placebo therapy (cycle 2)
* Patients with GOG Performance Grade of 3 or 4
* Patients who are pregnant or nursing; bevacizumab should not be administered to nursing women; patients of childbearing potential must agree to use contraceptive measures during study therapy and for at least six months after completion of bevacizumab therapy
* Patients who have received prior therapy with any anti-vascular endothelial growth factor (VEGF) drug, including bevacizumab
* Patients with clinical symptoms or signs of gastrointestinal obstruction and who require parenteral hydration and/or nutrition
* Patients with medical history or conditions not otherwise previously specified which in the opinion of the investigator should exclude participation in this study; the investigator should feel free to consult the study chair or study co-chairs for uncertainty in this regard

Outcome Measures

Primary Outcomes

Progression-free Survival

Median progression-free survival (PFS). Onset of progression could be based on radiographic (RECIST) criteria or rising CA-125 (GCIG criteria).

Time frame: From study entry until first disease progression, death or date of last contact, up to 6 years

Secondary Outcomes

Overall Survival

Median overall survival (OS)

Time frame: From study entry to death or last contact, up to 6 years

Frequency and Severity (Grade 3 or Above) of Adverse Events Assessed by Common Terminology Criteria for Adverse Events Version 3.0

Eligible and Evaluable patients

Time frame: Up to 5 years

Impact on Quality of Life Measured by the Functional Assessment of Cancer Therapy-Ovary Trial Outcome Index (FACT-O TOI)

Estimated least squares means from a mixed module of Quality of Life (QOL) scores at each assessment point, adjusted for baseline score and patient's age. Note: The range of possible scores of the FACT-O TOI is 0 - 104 for all treatment groups and at all visits. A higher score indicates better QOL. Baseline mean scores are raw means.

Time frame: At baseline, 9, 18, 36, 60, and 84 weeks

Locations

Northeast Alabama Regional Medical Center, Anniston, United States

University of Alabama at Birmingham Cancer Center, Birmingham, United States

Clearview Cancer Institute, Huntsville, United States

Mobile Infirmary Medical Center, Mobile, United States

Banner Thunderbird Medical Center, Glendale, United States

Banner Desert Medical Center, Mesa, United States

Banner Baywood Medical Center, Mesa, United States

Banner Good Samaritan Medical Center, Phoenix, United States

Western Regional CCOP, Phoenix, United States

Mayo Clinic in Arizona, Scottsdale, United States

Highlands Oncology Group PA - Fayetteville, Fayetteville, United States

Washington Regional Medical Center - Fayetteville, Fayetteville, United States

Mercy Hospital Fort Smith, Fort Smith, United States

University of Arkansas for Medical Sciences, Little Rock, United States

Providence Saint Joseph Medical Center/Disney Family Cancer Center, Burbank, United States

East Bay Radiation Oncology Center, Castro Valley, United States

Eden Hospital Medical Center, Castro Valley, United States

Valley Medical Oncology Consultants-Castro Valley, Castro Valley, United States

John Muir Medical Center-Concord Campus, Concord, United States

Bay Area Breast Surgeons Inc, Emeryville, United States

Northbay Cancer Center, Fairfield, United States

Kaiser Permanente-Fremont, Fremont, United States

Valley Medical Oncology Consultants-Fremont, Fremont, United States

Cancer Care Associates of Fresno Medical Group Inc, Fresno, United States

Saint Jude Medical Center, Fullerton, United States

Loma Linda University Medical Center, Loma Linda, United States

Long Beach Memorial Medical Center-Todd Cancer Institute, Long Beach, United States

Kaiser Permanente Los Angeles Medical Center, Los Angeles, United States

Cedars-Sinai Medical Center, Los Angeles, United States

UCLA / Jonsson Comprehensive Cancer Center, Los Angeles, United States

Contra Costa Regional Medical Center, Martinez, United States

El Camino Hospital, Mountain View, United States

Highland General Hospital, Oakland, United States

Alta Bates Summit Medical Center - Summit Campus, Oakland, United States

Bay Area Tumor Institute, Oakland, United States

Hematology and Oncology Associates-Oakland, Oakland, United States

Tom K Lee Inc, Oakland, United States

Kaiser Permanente-Oakland, Oakland, United States

UC Irvine Health/Chao Family Comprehensive Cancer Center, Orange, United States

Stanford Cancer Institute, Palo Alto, United States

Valley Care Health System - Pleasanton, Pleasanton, United States

Valley Medical Oncology Consultants, Pleasanton, United States

Kaiser Permanente-Redwood City, Redwood City, United States

Kaiser Permanente-Richmond, Richmond, United States

Kaiser Permanente-Roseville, Roseville, United States

University of California Davis Comprehensive Cancer Center, Sacramento, United States

Kaiser Permanente-South Sacramento, Sacramento, United States

Kaiser Permanente - Sacramento, Sacramento, United States

Kaiser Permanente-San Diego Mission, San Diego, United States

Kaiser Permanente-San Francisco, San Francisco, United States

UCSF Medical Center-Mount Zion, San Francisco, United States

Kaiser Permanente-Santa Teresa-San Jose, San Jose, United States

Kaiser Permanente San Leandro, San Leandro, United States

Doctors Medical Center- JC Robinson Regional Cancer Center, San Pablo, United States

Kaiser Permanente-San Rafael, San Rafael, United States

Cancer Center of Santa Barbara, Santa Barbara, United States

Santa Barbara Hematology Oncology Group Inc-Santa Barbara, Santa Barbara, United States

Kaiser Permanente Medical Center - Santa Clara, Santa Clara, United States

Kaiser Permanente-Santa Rosa, Santa Rosa, United States

Kaiser Permanente-South San Francisco, South San Francisco, United States

Kaiser Permanente-Stockton, Stockton, United States

Kaiser Permanente-Vallejo, Vallejo, United States

Kaiser Permanente-Walnut Creek, Walnut Creek, United States

John Muir Medical Center-Walnut Creek, Walnut Creek, United States

Colorado Gynecologic Oncology Group, Aurora, United States

The Medical Center of Aurora, Aurora, United States

Boulder Community Hospital, Boulder, United States

Penrose-Saint Francis Healthcare, Colorado Springs, United States

Memorial Hospital Colorado Springs, Colorado Springs, United States

Porter Adventist Hospital, Denver, United States

Exempla Saint Joseph Hospital, Denver, United States

Presbyterian - Saint Lukes Medical Center - Health One, Denver, United States

Rose Medical Center, Denver, United States

Colorado Cancer Research Program CCOP, Denver, United States

Rocky Mountain Gynecologic Oncology PC, Englewood, United States

Swedish Medical Center, Englewood, United States

Poudre Valley Hospital, Fort Collins, United States

Front Range Cancer Specialists, Fort Collins, United States

Saint Mary's Hospital and Regional Medical Center, Grand Junction, United States

North Colorado Medical Center, Greeley, United States

Saint Anthony Hospital, Lakewood, United States

Sky Ridge Medical Center, Lone Tree, United States

Longmont United Hospital, Longmont, United States

McKee Medical Center, Loveland, United States

Saint Mary Corwin Medical Center, Pueblo, United States

North Suburban Medical Center, Thornton, United States

Exempla Lutheran Medical Center, Wheat Ridge, United States

Hartford Hospital, Hartford, United States

Saint Francis Hospital and Medical Center, Hartford, United States

Manchester Memorial Hospital, Manchester, United States

The Hospital of Central Connecticut, New Britain, United States

Yale University, New Haven, United States

Norwalk Hospital, Norwalk, United States

Stamford Hospital/Bennett Cancer Center, Stamford, United States

Beebe Medical Center, Lewes, United States

Christiana Gynecologic Oncology LLC, Newark, United States

Christiana Care Health System-Christiana Hospital, Newark, United States

Washington Hospital Center, Washington D.C., United States

Morton Plant Hospital, Clearwater, United States

Holy Cross Hospital, Fort Lauderdale, United States

Lee Memorial Health System, Fort Myers, United States

Florida Gynecologic Oncology, Fort Myers, United States

Saint Vincent's Medical Center, Jacksonville, United States

Mayo Clinic in Florida, Jacksonville, United States

Jupiter Medical Center, Jupiter, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center, Miami, United States

Mount Sinai Medical Center, Miami Beach, United States

Florida Hospital Orlando, Orlando, United States

UF Cancer Center at Orlando Health, Orlando, United States

Sarasota Memorial Hospital, Sarasota, United States

Bayfront Outpatient Health Clinic, St. Petersburg, United States

Florida Cancer Specialists-West Palm Beach, West Palm Beach, United States

Phoebe Putney Memorial Hospital, Albany, United States

Grady Health System, Atlanta, United States

Emory University/Winship Cancer Institute, Atlanta, United States

Georgia Regents University Medical Center, Augusta, United States

Northeast Georgia Medical Center, Gainesville, United States

Central Georgia Gynecologic Oncology, Macon, United States

Memorial University Medical Center, Savannah, United States

Oncare Hawaii Inc-POB II, Honolulu, United States

Queen's Medical Center, Honolulu, United States

Straub Clinic and Hospital, Honolulu, United States

University of Hawaii Cancer Center, Honolulu, United States

Oncare Hawaii Inc-Kuakini, Honolulu, United States

The Cancer Center of Hawaii-Liliha, Honolulu, United States

Kapiolani Medical Center for Women and Children, Honolulu, United States

Tripler Army Medical Center, Honolulu, United States

Maui Memorial Medical Center, Wailuku, United States

Pacific Cancer Institute of Maui, Wailuku, United States

Pali Momi Medical Center, ‘Aiea, United States

Saint Luke's Mountain States Tumor Institute, Boise, United States

Saint Anthony's Health, Alton, United States

Northwest Community Hospital, Arlington Heights, United States

Rush - Copley Medical Center, Aurora, United States

Saint Joseph Medical Center, Bloomington, United States

Graham Hospital Association, Canton, United States

Memorial Hospital, Carthage, United States

Mount Sinai Hospital Medical Center, Chicago, United States

Northwestern University, Chicago, United States

Rush University Medical Center, Chicago, United States

University of Illinois, Chicago, United States

Swedish Covenant Hospital, Chicago, United States

Presence Resurrection Medical Center, Chicago, United States

University of Chicago Comprehensive Cancer Center, Chicago, United States

Weiss Memorial Hospital, Chicago, United States

Decatur Memorial Hospital, Decatur, United States

Elmhurst Memorial Hospital, Elmhurst, United States

Eureka Hospital, Eureka, United States

NorthShore University HealthSystem-Evanston Hospital, Evanston, United States

Saint Francis Hospital, Evanston, United States

Galesburg Cottage Hospital, Galesburg, United States

Illinois CancerCare Galesburg, Galesburg, United States

Ingalls Memorial Hospital, Harvey, United States

Mason District Hospital, Havana, United States

Hopedale Medical Complex - Hospital, Hopedale, United States

Joliet Oncology-Hematology Associates Limited, Joliet, United States

Kewanee Hospital, Kewanee, United States

Mcdonough District Hospital, Macomb, United States

Loyola University Medical Center, Maywood, United States

Garneau, Stewart C MD (UIA Investigator), Moline, United States

Porubcin, Michael MD (UIA Investigator), Moline, United States

Sharis, Christine M MD (UIA Investigator), Moline, United States

Stoffel, Thomas J MD (UIA Investigator), Moline, United States

Good Samaritan Regional Health Center, Mount Vernon, United States

Bromenn Regional Medical Center, Normal, United States

Community Cancer Center Foundation, Normal, United States

Illinois CancerCare-Ottawa Clinic, Ottawa, United States

Ottawa Regional Hospital and Healthcare Center, Ottawa, United States

Chicago Gynecologic Oncology SC, Palatine, United States

Advocate Lutheran General Hospital, Park Ridge, United States

Pekin Cancer Treatment Center, Pekin, United States

Pekin Hospital, Pekin, United States

Methodist Medical Center of Illinois, Peoria, United States

Proctor Hospital, Peoria, United States

Illinois CancerCare-Peoria, Peoria, United States

Illinois Oncology Research Association CCOP, Peoria, United States

OSF Saint Francis Medical Center, Peoria, United States

Illinois Valley Hospital, Peru, United States

Perry Memorial Hospital, Princeton, United States

Saint Anthony Medical Center, Rockford, United States

Saint Margaret's Hospital, Spring Valley, United States

Memorial Medical Center, Springfield, United States

Carle Cancer Center, Urbana, United States

Carle Clinic-Urbana Main, Urbana, United States

Franciscan St. Francis Health-Beech Grove, Beech Grove, United States

Elkhart General Hospital, Elkhart, United States

Fort Wayne Medical Oncology and Hematology Inc-Parkview, Fort Wayne, United States

Indiana University/Melvin and Bren Simon Cancer Center, Indianapolis, United States

Saint Vincent Hospital and Health Services, Indianapolis, United States

Community Howard Regional Health, Kokomo, United States

IU Health La Porte Hospital, La Porte, United States

Franciscan Saint Anthony Health-Michigan City, Michigan City, United States

Saint Joseph Regional Medical Center-Mishawaka, Mishawaka, United States

The Community Hospital, Munster, United States

Reid Hospital and Health Care Services, Richmond, United States

Memorial Hospital of South Bend, South Bend, United States

South Bend Clinic, South Bend, United States

Northern Indiana Cancer Research Consortium CCOP, South Bend, United States

McFarland Clinic PC-William R Bliss Cancer Center, Ames, United States

Constantinou, Costas L MD (UIA Investigator), Bettendorf, United States

Cedar Rapids Oncology Association, Cedar Rapids, United States

Mercy Hospital, Cedar Rapids, United States

Oncology Associates at Mercy Medical Center, Cedar Rapids, United States

Medical Oncology and Hematology Associates-West Des Moines, Clive, United States

Genesis Medical Center - East Campus, Davenport, United States

Genesis Medical Center - West Campus, Davenport, United States

Mercy Capitol, Des Moines, United States

Iowa Methodist Medical Center, Des Moines, United States

Iowa Oncology Research Association CCOP, Des Moines, United States

Medical Oncology and Hematology Associates-Des Moines, Des Moines, United States

Medical Oncology and Hematology Associates-Laurel, Des Moines, United States

Mercy Medical Center - Des Moines, Des Moines, United States

Iowa Lutheran Hospital, Des Moines, United States

University of Iowa/Holden Comprehensive Cancer Center, Iowa City, United States

Siouxland Regional Cancer Center, Sioux City, United States

Siouxland Regional Cancer Center, Sioux City, United States

Mercy Medical Center-Sioux City, Sioux City, United States

Saint Luke's Regional Medical Center, Sioux City, United States

Cedar Valley Medical Specialists, Waterloo, United States

Covenant Medical Center, Waterloo, United States

Cancer Center of Kansas - Chanute, Chanute, United States

Cancer Center of Kansas - Dodge City, Dodge City, United States

Cancer Center of Kansas - El Dorado, El Dorado, United States

Cancer Center of Kansas-Independence, Independence, United States

Providence Medical Center, Kansas City, United States

University of Kansas Cancer Center, Kansas City, United States

Cancer Center of Kansas-Kingman, Kingman, United States

Lawrence Memorial Hospital, Lawrence, United States

Cancer Center of Kansas - Newton, Newton, United States

Menorah Medical Center, Overland Park, United States

Radiation Oncology Practice Corporation Southwest, Overland Park, United States

Cancer Center of Kansas - Parsons, Parsons, United States

Cancer Center of Kansas - Pratt, Pratt, United States

Cancer Center of Kansas - Salina, Salina, United States

Shawnee Mission Medical Center-KCCC, Shawnee Mission, United States

Stormont-Vail Regional Health Center, Topeka, United States

Saint Francis Hospital and Medical Center - Topeka, Topeka, United States

Cancer Center of Kansas - Wellington, Wellington, United States

Associates In Womens Health, Wichita, United States

Cancer Center of Kansas-Wichita Medical Arts Tower, Wichita, United States

Cancer Center of Kansas - Main Office, Wichita, United States

Via Christi Regional Medical Center, Wichita, United States

Wichita CCOP, Wichita, United States

Cancer Center of Kansas - Winfield, Winfield, United States

University of Kentucky/Markey Cancer Center, Lexington, United States

Norton Hospital Pavilion and Medical Campus, Louisville, United States

The James Graham Brown Cancer Center at University of Louisville, Louisville, United States

Tulane University Health Sciences Center, New Orleans, United States

Christus Schumpert Saint Mary's Place, Shreveport, United States

Eastern Maine Medical Center, Bangor, United States

Maine Medical Center-Bramhall Campus, Portland, United States

Greater Baltimore Medical Center, Baltimore, United States

MedStar Franklin Square Medical Center/Weinberg Cancer Institute, Baltimore, United States

Johns Hopkins University/Sidney Kimmel Cancer Center, Baltimore, United States

Memorial Hospital at Easton - Shore Regional Cancer Center, Easton, United States

The Memorial Hospital at Easton, Easton, United States

Union Hospital of Cecil County, Elkton, United States

Associates in Oncology Hematology PC -Kensington, Kensington, United States

Kaiser Permanente - Largo Medical Center, Largo, United States

Kaiser Permanente - Towson Medical Center, Lutherville, United States

Kaiser Permanente - Shady Grove Medical Center, Rockville, United States

Maryland Oncology Hematology PA-Aquilino Cancer Center, Rockville, United States

Holy Cross Hospital, Silver Spring, United States

Berkshire Hematology Oncology PC, Pittsfield, United States

Baystate Medical Center, Springfield, United States

Commonwealth Hematology Oncology PC-Worcester, Worcester, United States

University of Massachusetts Medical School, Worcester, United States

Bixby Medical Center, Adrian, United States

Hickman Cancer Center, Adrian, United States

Saint Joseph Mercy Hospital, Ann Arbor, United States

Michigan Cancer Research Consortium CCOP, Ann Arbor, United States

University of Michigan Comprehensive Cancer Center, Ann Arbor, United States

Bronson Battle Creek, Battle Creek, United States

Spectrum Health Big Rapids Hospital, Big Rapids, United States

Oakwood Hospital and Medical Center, Dearborn, United States

Wayne State University/Karmanos Cancer Institute, Detroit, United States

Saint John Hospital and Medical Center, Detroit, United States

Green Bay Oncology - Escanaba, Escanaba, United States

Hurley Medical Center, Flint, United States

Genesys Regional Medical Center-West Flint Campus, Flint, United States

Grand Rapids Clinical Oncology Program, Grand Rapids, United States

Mercy Health Saint Mary's, Grand Rapids, United States

Spectrum Health at Butterworth Campus, Grand Rapids, United States

Spectrum Health-Blodgett Campus, Grand Rapids, United States

Gynecologic Oncology of West Michigan PLLC, Grand Rapids, United States

Holland Community Hospital, Holland, United States

Green Bay Oncology - Iron Mountain, Iron Mountain, United States

Allegiance Health, Jackson, United States

Borgess Medical Center, Kalamazoo, United States

Bronson Methodist Hospital, Kalamazoo, United States

West Michigan Cancer Center, Kalamazoo, United States

Sparrow Hospital, Lansing, United States

Saint Mary Mercy Hospital, Livonia, United States

Mercy Memorial Hospital, Monroe, United States

Toledo Clinic Cancer Centers-Monroe, Monroe, United States

Mercy Health Partners-Hackley Campus, Muskegon, United States

Mercy Health Mercy Campus, Muskegon, United States

McLaren-Northern Michigan, Petoskey, United States

Saint Joseph Mercy Oakland, Pontiac, United States

Saint Joseph Mercy Port Huron, Port Huron, United States

William Beaumont Hospital-Royal Oak, Royal Oak, United States

Saint Mary's of Michigan, Saginaw, United States

Lakeland Hospital, Saint Joseph, United States

Providence Hospital-Southfield Cancer Center, Southfield, United States

Munson Medical Center, Traverse City, United States

Saint John Macomb-Oakland Hospital, Warren, United States

Metro Health Hospital, Wyoming, United States

Fairview Ridges Hospital, Burnsville, United States

Mercy Hospital, Coon Rapids, United States

Essentia Health Cancer Center, Duluth, United States

Essentia Health Saint Mary's Medical Center, Duluth, United States

Miller-Dwan Hospital, Duluth, United States

Fairview-Southdale Hospital, Edina, United States

Unity Hospital, Fridley, United States

Minnesota Oncology Hematology PA-Maplewood, Maplewood, United States

Abbott-Northwestern Hospital, Minneapolis, United States

University of Minnesota Medical Center-Fairview, Minneapolis, United States

Hubert H Humphrey Cancer Center, Robbinsdale, United States

North Memorial Medical Health Center, Robbinsdale, United States

Mayo Clinic, Rochester, United States

Metro-Minnesota NCI Community Oncology Research Program, Saint Louis Park, United States

Park Nicollet Clinic - Saint Louis Park, Saint Louis Park, United States

United Hospital, Saint Paul, United States

Saint Francis Regional Medical Center, Shakopee, United States

Ridgeview Medical Center, Waconia, United States

Minnesota Oncology and Hematology PA-Woodbury, Woodbury, United States

Saint Dominic-Jackson Memorial Hospital, Jackson, United States

Singing River Hospital, Pascagoula, United States

Southeast Missouri Hospital, Cape Girardeau, United States

Saint Francis Medical Center, Cape Girardeau, United States

University of Missouri - Ellis Fischel, Columbia, United States

Centerpoint Medical Center LLC, Independence, United States

Capital Regional Medical Center, Jefferson City, United States

Truman Medical Center, Kansas City, United States

Saint Luke's Cancer Institute, Kansas City, United States

Saint Luke's Hospital of Kansas City, Kansas City, United States

Radiation Oncology Practice Corporation South, Kansas City, United States

Saint Joseph Health Center, Kansas City, United States

North Kansas City Hospital, Kansas City, United States

Research Medical Center, Kansas City, United States

Radiation Oncology Practice Corporation - North, Kansas City, United States

Liberty Hospital, Liberty, United States

Liberty Radiation Oncology Center, Liberty, United States

Heartland Regional Medical Center, Saint Joseph, United States

Cancer Research for the Ozarks NCORP, Springfield, United States

Mercy Hospital Springfield, Springfield, United States

CoxHealth South Hospital, Springfield, United States

Saint Louis Cancer and Breast Institute-South City, St Louis, United States

Saint Louis University Hospital, St Louis, United States

Washington University School of Medicine, St Louis, United States

Missouri Baptist Medical Center, St Louis, United States

Center for Cancer Care and Research, St Louis, United States

Mercy Hospital Saint Louis, St Louis, United States

Saint Louis-Cape Girardeau CCOP, St Louis, United States

Montana Cancer Consortium CCOP, Billings, United States

Northern Rockies Radiation Oncology Center, Billings, United States

Saint Vincent Healthcare, Billings, United States

Frontier Cancer Center and Blood Institute-Billings, Billings, United States

Billings Clinic Cancer Center, Billings, United States

Deaconess Medical Center, Billings, United States

Bozeman Deaconess Cancer Center, Bozeman, United States

Bozeman Deaconess Hospital, Bozeman, United States

Saint James Community Hospital and Cancer Treatment Center, Butte, United States

Benefis Healthcare- Sletten Cancer Institute, Great Falls, United States

Berdeaux, Donald MD (UIA Investigator), Great Falls, United States

Big Sky Oncology, Great Falls, United States

Great Falls Clinic, Great Falls, United States

Northern Montana Hospital, Havre, United States

Saint Peter's Community Hospital, Helena, United States

Glacier Oncology PLLC, Kalispell, United States

Kalispell Medical Oncology, Kalispell, United States

Kalispell Regional Medical Center, Kalispell, United States

Community Medical Hospital, Missoula, United States

Montana Cancer Specialists, Missoula, United States

Saint Patrick Hospital - Community Hospital, Missoula, United States

Guardian Oncology and Center for Wellness, Missoula, United States

Nebraska Cancer Research Center, Lincoln, United States

Missouri Valley Cancer Consortium, Omaha, United States

Nebraska Methodist Hospital, Omaha, United States

Alegent Health Immanuel Medical Center, Omaha, United States

Alegent Health Bergan Mercy Medical Center, Omaha, United States

Creighton University Medical Center, Omaha, United States

University of Nebraska Medical Center, Omaha, United States

Center of Hope at Renown Medical Center, Reno, United States

Renown Regional Medical Center, Reno, United States

Saint Mary's Regional Medical Center, Reno, United States

Exeter Hospital, Exeter, United States

Cheshire Medical Center-Dartmouth-Hitchcock Keene, Keene, United States

Dartmouth Hitchcock Medical Center, Lebanon, United States

Frisbie Hospital, Rochester, United States

Ocean Medical Center, Brick, United States

Cooper Hospital University Medical Center, Camden, United States

Hackensack University Medical CCOP, Hackensack, United States

Hackensack University Medical Center, Hackensack, United States

Northern New Jersey CCOP, Hackensack, United States

Monmouth Medical Center, Long Branch, United States

Morristown Medical Center, Morristown, United States

Fox Chase Cancer Center at Virtua Memorial Hospital of Burlington County, Mount Holly, United States

Jersey Shore Medical Center, Neptune City, United States

UMDNJ - New Jersey Medical School, Newark, United States

Riverview Medical Center/Booker Cancer Center, Red Bank, United States

Overlook Hospital, Summit, United States

Community Medical Center, Toms River, United States

Virtua West Jersey Hospital Voorhees, Voorhees Township, United States

Southwest Gynecologic Oncology Associates Inc, Albuquerque, United States

University of New Mexico Cancer Center, Albuquerque, United States

Women's Cancer Care Associates LLC, Albany, United States

Island Gynecologic Oncology, Brightwaters, United States

State University of New York Downstate Medical Center, Brooklyn, United States

Roswell Park Cancer Institute, Buffalo, United States

Queens Hospital Center, Jamaica, United States

North Shore University Hospital, Manhasset, United States

Orange Regional Medical Center, Middletown, United States

Long Island Jewish Medical Center, New Hyde Park, United States

North Shore-LIJ Health System/Center for Advanced Medicine, New Hyde Park, United States

Laura and Issac Perlmutter Cancer Center at NYU Langone, New York, United States

Mount Sinai Medical Center, New York, United States

Columbia University Medical Center, New York, United States

Memorial Sloan-Kettering Cancer Center, New York, United States

Stony Brook University Medical Center, Stony Brook, United States

Saint Joseph's Hospital Health Center, Syracuse, United States

State University of New York Upstate Medical University, Syracuse, United States

Good Samaritan Hospital Medical Center, West Islip, United States

Randolph Hospital, Asheboro, United States

Hope Women's Cancer Centers-Asheville, Asheville, United States

Cone Health Cancer Center at Alamance Regional, Burlington, United States

University of North Carolina at Chapel Hill, Chapel Hill, United States

Carolinas Medical Center/Levine Cancer Institute, Charlotte, United States

Novant Health Presbyterian Medical Center, Charlotte, United States

Duke University Medical Center, Durham, United States

Wayne Memorial Hospital, Goldsboro, United States

Wayne Radiation Oncology, Goldsboro, United States

Cone Health Cancer Center, Greensboro, United States

Gynecologic Oncology Network, Greenville, United States

Kinston Medical Specialists PA, Kinston, United States

FirstHealth of the Carolinas-Moore Regional Hosiptal, Pinehurst, United States

Annie Penn Memorial Hospital, Reidsville, United States

Rutherford Hospital, Rutherfordton, United States

New Hanover Regional Medical Center/Zimmer Cancer Center, Wilmington, United States

Wilson Medical Center, Wilson, United States

Novant Health Oncology Specialists, Winston-Salem, United States

Southeast Cancer Consortium-Upstate NCORP, Winston-Salem, United States

Wake Forest University Health Sciences, Winston-Salem, United States

Mid Dakota Clinic, Bismarck, United States

Saint Alexius Medical Center, Bismarck, United States

Sanford Bismarck Medical Center, Bismarck, United States

Altru Cancer Center, Grand Forks, United States

Summa Akron City Hospital/Cooper Cancer Center, Akron, United States

Akron General Medical Center, Akron, United States

Toledo Clinic Cancer Centers-Bowling Green, Bowling Green, United States

Aultman Health Foundation, Canton, United States

University of Cincinnati, Cincinnati, United States

Case Western Reserve University, Cleveland, United States

MetroHealth Medical Center, Cleveland, United States

Cleveland Clinic Cancer Center/Fairview Hospital, Cleveland, United States

Cleveland Clinic Foundation, Cleveland, United States

North Coast Cancer Care-Clyde, Clyde, United States

Ohio State University Comprehensive Cancer Center, Columbus, United States

Riverside Methodist Hospital, Columbus, United States

Mount Carmel Health Center West, Columbus, United States

Grandview Hospital, Dayton, United States

Good Samaritan Hospital - Dayton, Dayton, United States

Samaritan North Health Center, Dayton, United States

Dayton CCOP, Dayton, United States

Veteran Affairs Medical Center, Dayton, United States

Hematology Oncology Center Incorporated, Elyria, United States

Blanchard Valley Hospital, Findlay, United States

Atrium Medical Center-Middletown Regional Hospital, Franklin, United States

Fremont Memorial Hospital, Fremont, United States

Wayne Hospital, Greenville, United States

Kettering Medical Center, Kettering, United States

Lima Memorial Hospital, Lima, United States

Saint Luke's Hospital, Maumee, United States

Toledo Clinic Cancer Centers-Maumee, Maumee, United States

Toledo Radiation Oncology at Northwest Ohio Onocolgy Center, Maumee, United States

Hillcrest Hospital Cancer Center, Mayfield Heights, United States

Lake University Ireland Cancer Center, Mentor, United States

Saint Charles Hospital, Oregon, United States

Toledo Clinic Cancer Centers-Oregon, Oregon, United States

Firelands Regional Medical Center, Sandusky, United States

North Coast Cancer Care, Sandusky, United States

Flower Hospital, Sylvania, United States

Mercy Hospital of Tiffin, Tiffin, United States

The Toledo Hospital/Toledo Children's Hospital, Toledo, United States

Saint Vincent Mercy Medical Center, Toledo, United States

University of Toledo, Toledo, United States

Toledo Community Hospital Oncology Program CCOP, Toledo, United States

Mercy Saint Anne Hospital, Toledo, United States

Toledo Clinic Cancer Centers-Toledo, Toledo, United States

Upper Valley Medical Center, Troy, United States

Fulton County Health Center, Wauseon, United States

Clinton Memorial Hospital, Wilmington, United States

Greene Memorial Hospital, Xenia, United States

University of Oklahoma Health Sciences Center, Oklahoma City, United States

Cancer Care Associates-Midtown, Tulsa, United States

Tulsa Cancer Institute, Tulsa, United States

Bay Area Hospital, Coos Bay, United States

Legacy Good Samaritan Hospital and Medical Center, Portland, United States

Compass Oncology Rose Quarter, Portland, United States

Kaiser Permanente, Portland, United States

Oregon Health and Science University, Portland, United States

Abington Memorial Hospital, Abington, United States

Lehigh Valley Hospital-Cedar Crest, Allentown, United States

Bryn Mawr Hospital, Bryn Mawr, United States

Ephrata Cancer Center, Ephrata, United States

Penn State Milton S Hershey Medical Center, Hershey, United States

Lancaster General Hospital, Lancaster, United States

Riddle Memorial Hospital, Media, United States

Paoli Memorial Hospital, Paoli, United States

University of Pennsylvania/Abramson Cancer Center, Philadelphia, United States

Pennsylvania Hospital, Philadelphia, United States

Thomas Jefferson University Hospital, Philadelphia, United States

Fox Chase Cancer Center, Philadelphia, United States

Chestnut Hill Health System, Philadelphia, United States

UPMC-Magee Womens Hospital, Pittsburgh, United States

West Penn Hospital, Pittsburgh, United States

Mercy Hospital, Scranton, United States

Hematology and Oncology Associates of North East Pennsylvania, Scranton, United States

Scranton Hematology Oncology, Scranton, United States

Reading Hospital, West Reading, United States

Lankenau Medical Center, Wynnewood, United States

Mainline Health CCOP, Wynnewood, United States

WellSpan Health-York Cancer Center, York, United States

WellSpan Health-York Hospital, York, United States

Women and Infants Hospital, Providence, United States

AnMed Health Hospital, Anderson, United States

Medical University of South Carolina, Charleston, United States

Greenville Health System Cancer Institute-Eastside, Greenville, United States

Black Hills Obstetrics and Gynecology, Rapid City, United States

Sanford Cancer Center-Oncology Clinic, Sioux Falls, United States

Sanford USD Medical Center - Sioux Falls, Sioux Falls, United States

Chattanooga Gynecological Oncology, Chattanooga, United States

Chattanooga's Program in Women's Oncology, Chattanooga, United States

East Tennessee State University, Johnson City, United States

Knoxville Gynecologic Cancer Specialists PC, Knoxville, United States

University of Tennesee Health Science Center, Memphis, United States

Meharry Medical College, Nashville, United States

Vanderbilt University/Ingram Cancer Center, Nashville, United States

The Don and Sybil Harrington Cancer Center, Amarillo, United States

Brooke Army Medical Center, Fort Sam Houston, United States

University of Texas Medical Branch, Galveston, United States

M D Anderson Cancer Center, Houston, United States

Texas Tech University Health Sciences Center, Lubbock, United States

Scott and White Memorial Hospital, Temple, United States

American Fork Hospital, American Fork, United States

Sandra L Maxwell Cancer Center, Cedar City, United States

Logan Regional Hospital, Logan, United States

Cottonwood Hospital Medical Center, Murray, United States

Intermountain Medical Center, Murray, United States

McKay-Dee Hospital Center, Ogden, United States

Utah Valley Regional Medical Center, Provo, United States

Intermountain Health Care, Salt Lake City, United States

Utah Cancer Specialists-Salt Lake City, Salt Lake City, United States

Huntsman Cancer Institute/University of Utah, Salt Lake City, United States

LDS Hospital, Salt Lake City, United States

Dixie Medical Center Regional Cancer Center, St. George, United States

University of Vermont Medical Center, Burlington, United States

Northern Virginia Pelvic Surgery Associates, Annandale, United States

University of Virginia Cancer Center, Charlottesville, United States

Danville Regional Medical Center, Danville, United States

Kaiser Permanente - Fair Oaks Medical Center, Fairfax, United States

Fredericksburg Oncology Inc, Fredericksburg, United States

Rappahannock General Hospital, Kilmarnock, United States

Bon Secours Mary Immaculate Hospital, Newport News, United States

Virginia Oncology Associates - Lake Wright, Norfolk, United States

Virginia Commonwealth University/Massey Cancer Center, Richmond, United States

Carilion Clinic Gynecological Oncology, Roanoke, United States

MultiCare Auburn Medical Center, Auburn, United States

Providence Regional Cancer System-Centralia, Centralia, United States

Saint Francis Hospital, Federal Way, United States

Saint Clare Hospital, Lakewood, United States

Providence - Saint Peter Hospital, Olympia, United States

Capital Medical Center, Olympia, United States

MultiCare Good Samaritan Hospital, Puyallup, United States

Virginia Mason CCOP, Seattle, United States

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium, Seattle, United States

University of Washington Medical Center, Seattle, United States

MultiCare Allenmore Hospital, Tacoma, United States

MultiCare Tacoma General Hospital, Tacoma, United States

Northwest CCOP, Tacoma, United States

Northwest Medical Specialties PLLC, Tacoma, United States

Saint Joseph Medical Center, Tacoma, United States

Multicare Health System, Tacoma, United States

Madigan Army Medical Center, Tacoma, United States

Marshfield Clinic-Chippewa Center, Chippewa Falls, United States

Marshfield Clinic Cancer Center at Sacred Heart, Eau Claire, United States

Sacred Heart Hospital, Eau Claire, United States

Green Bay Oncology at Saint Vincent Hospital, Green Bay, United States

Saint Vincent Hospital, Green Bay, United States

Green Bay Oncology Limited at Saint Mary's Hospital, Green Bay, United States

Saint Mary's Hospital, Green Bay, United States

Aurora BayCare Medical Center, Green Bay, United States

Dean Hematology and Oncology Clinic, Madison, United States

University of Wisconsin Hospital and Clinics, Madison, United States

Holy Family Memorial Hospital, Manitowoc, United States

Bay Area Medical Center, Marinette, United States

Marshfield Clinic, Marshfield, United States

Saint Joseph's Hospital, Marshfield, United States

Medical Consultants Limited, Milwaukee, United States

Froedtert and the Medical College of Wisconsin, Milwaukee, United States

Marshfield Clinic-Minocqua Center, Minocqua, United States

Oconomowoc Memorial Hospital-ProHealth Care Inc, Oconomowoc, United States

Green Bay Oncology - Oconto Falls, Oconto Falls, United States

Marshfield Clinic at James Beck Cancer Center, Rhinelander, United States

Marshfield Clinic-Rice Lake Center, Rice Lake, United States

Vince Lombardi Cancer Clinic-Sheboygan, Sheboygan, United States

Vince Lombardi Cancer Clinic - Slinger, Slinger, United States

Saint Michael's Hospital, Stevens Point, United States

Green Bay Oncology - Sturgeon Bay, Sturgeon Bay, United States

Waukesha Memorial Hospital, Waukesha, United States

Aurora West Allis Medical Center, West Allis, United States

Marshfield Clinic - Weston Center, Weston, United States

Marshfield Clinic - Wisconsin Rapids Center, Wisconsin Rapids, United States

Welch Cancer Center, Sheridan, United States

Odette Cancer Centre- Sunnybrook Health Sciences Centre, Toronto, Canada

Tohoku University School of Medicine, Sendai, Japan

Kure National Hospital, Kure, Japan

Iwate Medical University School of Medicine, Morioka, Japan

Kagoshima City Hospital, Kagoshima, Japan

Keio University, Shinjuku-ku, Japan

National Hospital Organization-Kobe Medical Center, Kobe, Japan

Shikoku Cancer Center, Matsuyama, Japan

Saitama Medical University International Medical Center, Saitama, Japan

National Cancer Center Hospital, Tokyo, Japan

Tottori University, Tottori, Japan

Samsung Medical Center, Seoul, South Korea

Seoul National University Hospital, Seoul, South Korea

Yongdong Severence Hospital, Seoul, South Korea

Asan Medical Center, Seoul, South Korea

Korea Cancer Center Hospital, Seoul, South Korea

Ajou University Hospital, Suwon, South Korea

Kangnam Sacred Heart Hospital, Youngdungpo-gu, South Korea

Linked Papers

2023-04-18

Angiogenesis inhibitors for the treatment of epithelial ovarian cancer

Many women, and other females, with epithelial ovarian cancer (EOC) develop resistance to conventional chemotherapy drugs. Drugs that inhibit angiogenesis (development of new blood vessels), essential for tumour growth, control cancer growth by denying blood supply to tumour nodules. To compare the effectiveness and toxicities of angiogenesis inhibitors for treatment of epithelial ovarian cancer (EOC). We identified randomised controlled trials (RCTs) by searching CENTRAL, MEDLINE and Embase (from 1990 to 30 September 2022). We searched clinical trials registers and contacted investigators of completed and ongoing trials for further information. RCTs comparing angiogenesis inhibitors with standard chemotherapy, other types of anti-cancer treatment, other angiogenesis inhibitors with or without other treatments, or placebo/no treatment in a maintenance setting, in women with EOC.  DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our outcomes were overall survival (OS), progression-free survival (PFS), quality of life (QoL), adverse events (grade 3 and above) and hypertension (grade 2 and above). We identified 50 studies (14,836 participants) for inclusion (including five studies from the previous version of this review): 13 solely in females with newly-diagnosed EOC and 37 in females with recurrent EOC (nine studies in platinum-sensitive EOC; 19 in platinum-resistant EOC; nine with studies with mixed or unclear platinum sensitivity). The main results are presented below.  Newly-diagnosed EOC Bevacizumab, a monoclonal antibody that binds vascular endothelial growth factor (VEGF), given with chemotherapy and continued as maintenance, likely results in little to no difference in OS compared to chemotherapy alone (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.88 to 1.07; 2 studies, 2776 participants; moderate-certainty evidence). Evidence is very uncertain for PFS (HR 0.82, 95% CI 0.64 to 1.05; 2 studies, 2746 participants; very low-certainty evidence), although the combination results in a slight reduction in global QoL (mean difference (MD) -6.4, 95% CI -8.86 to -3.94; 1 study, 890 participants; high-certainty evidence). The combination likely increases any adverse event (grade ≥ 3) (risk ratio (RR) 1.16, 95% CI 1.07 to 1.26; 1 study, 1485 participants; moderate-certainty evidence) and may result in a large increase in hypertension (grade ≥ 2) (RR 4.27, 95% CI 3.25 to 5.60; 2 studies, 2707 participants; low-certainty evidence). Tyrosine kinase inhibitors (TKIs) to block VEGF receptors (VEGF-R), given with chemotherapy and continued as maintenance, likely result in little to no difference in OS (HR 0.99, 95% CI 0.84 to 1.17; 2 studies, 1451 participants; moderate-certainty evidence) and likely increase PFS slightly (HR 0.88, 95% CI 0.77 to 1.00; 2 studies, 2466 participants; moderate-certainty evidence). The combination likely reduces QoL slightly (MD -1.86, 95% CI -3.46 to -0.26; 1 study, 1340 participants; moderate-certainty evidence), but it increases any adverse event (grade ≥ 3) slightly (RR 1.31, 95% CI 1.11 to 1.55; 1 study, 188 participants; moderate-certainty evidence) and may result in a large increase in hypertension (grade ≥ 3) (RR 6.49, 95% CI 2.02 to 20.87; 1 study, 1352 participants; low-certainty evidence).  Recurrent EOC (platinum-sensitive) Moderate-certainty evidence from three studies (with 1564 participants) indicates that bevacizumab with chemotherapy, and continued as maintenance, likely results in little to no difference in OS (HR 0.90, 95% CI 0.79 to 1.02), but likely improves PFS (HR 0.56, 95% CI 0.50 to 0.63) compared to chemotherapy alone. The combination may result in little to no difference in QoL (MD 0.8, 95% CI -2.11 to 3.71; 1 study, 486 participants; low-certainty evidence), but it increases the rate of any adverse event (grade ≥ 3) slightly (RR 1.11, 1.07 to 1.16; 3 studies, 1538 participants; high-certainty evidence). Hypertension (grade ≥ 3) was more common in arms with bevacizumab (RR 5.82, 95% CI 3.84 to 8.83; 3 studies, 1538 participants).  TKIs with chemotherapy may result in little to no difference in OS (HR 0.86, 95% CI 0.67 to 1.11; 1 study, 282 participants; low-certainty evidence), likely increase PFS (HR 0.56, 95% CI 0.44 to 0.72; 1 study, 282 participants; moderate-certainty evidence), and may have little to no effect on QoL (MD 6.1, 95% CI -0.96 to 13.16; 1 study, 146 participants; low-certainty evidence). Hypertension (grade ≥ 3) was more common with TKIs (RR 3.32, 95% CI 1.21 to 9.10). Recurrent EOC (platinum-resistant) Bevacizumab with chemotherapy and continued as maintenance increases OS (HR 0.73, 95% CI 0.61 to 0.88; 5 studies, 778 participants; high-certainty evidence) and likely results in a large increase in PFS (HR 0.49, 95% CI 0.42 to 0.58; 5 studies, 778 participants; moderate-certainty evidence). The combination may result in a large increase in hypertension (grade ≥ 2) (RR 3.11, 95% CI 1.83 to 5.27; 2 studies, 436 participants; low-certainty evidence). The rate of bowel fistula/perforation (grade ≥ 2) may be slightly higher with bevacizumab (RR 6.89, 95% CI 0.86 to 55.09; 2 studies, 436 participants). Evidence from eight studies suggest TKIs with chemotherapy likely result in little to no difference in OS (HR 0.85, 95% CI 0.68 to 1.08; 940 participants; moderate-certainty evidence), with low-certainty evidence that it may increase PFS (HR 0.70, 95% CI 0.55 to 0.89; 940 participants), and may result in little to no meaningful difference in QoL (MD ranged from -0.19 at 6 weeks to -3.40 at 4 months). The combination increases any adverse event (grade ≥ 3) slightly (RR 1.23, 95% CI 1.02 to 1.49; 3 studies, 402 participants; high-certainty evidence). The effect on bowel fistula/perforation rates is uncertain (RR 2.74, 95% CI 0.77 to 9.75; 5 studies, 557 participants; very low-certainty evidence). Bevacizumab likely improves both OS and PFS in platinum-resistant relapsed EOC. In platinum-sensitive relapsed disease, bevacizumab and TKIs probably improve PFS, but may or may not improve OS. The results for TKIs in platinum-resistant relapsed EOC are similar. The effects on OS or PFS in newly-diagnosed EOC are less certain, with a decrease in QoL and increase in adverse events. Overall adverse events and QoL data were more variably reported than were PFS data. There appears to be a role for anti-angiogenesis treatment, but given the additional treatment burden and economic costs of maintenance treatments, benefits and risks of anti-angiogenesis treatments should be carefully considered.

2022-10-17

Identification of Patients With Ovarian Cancer Experiencing the Highest Benefit From Bevacizumab in the First-Line Setting on the Basis of Their Tumor-Intrinsic Chemosensitivity (KELIM): The GOG-0218 Validation Study

PURPOSE In patients with high-grade ovarian cancer, predictors of bevacizumab efficacy in first-line setting are needed. In the ICON-7 trial, a poor tumor intrinsic chemosensitivity (defined by unfavorable modeled cancer antigen-125 [CA-125] ELIMination rate constant K [KELIM] score) was a predictive biomarker. Only the patients with high-risk disease (suboptimally resected stage III, or stage IV) exhibiting unfavorable KELIM score &lt; 1.0 had overall survival (OS) benefit from bevacizumab (median: 29.7 v 20.6 months; hazard ratio [HR], 0.78). An external validation study in the GOG-0218 trial was performed. METHODS In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel ± concurrent-maintenance bevacizumab/placebo. Patient KELIM values were calculated with CA-125 kinetics during the first 100 chemotherapy days by the Lyon University team. The association between KELIM score (favorable ≥ 1.0, or unfavorable &lt; 1.0) and bevacizumab benefit for progression-free survival (PFS)/OS was independently assessed by NGR-GOG using univariate/multivariate analyses. RESULTS KELIM was assessable in 1,662 patients with ≥ 3 CA-125 available values. An unfavorable KELIM score was associated with bevacizumab benefit compared with placebo (PFS: HR, 0.70; 95% CI, 0.59 to 0.82; OS: HR, 0.87; 95% CI, 0.73 to 1.03), whereas a favorable KELIM was not (PFS: HR, 0.96; 95% CI, 0.79 to 1.17; OS: HR, 1.11; 95% CI, 0.89 to 1.39). The highest benefit was observed in patients with a high-risk disease exhibiting unfavorable KELIM, for PFS (median: 9.1 v 5.6 months; HR, 0.64; 95% CI, 0.53 to 0.78), and for OS (median: 35.1 v 29.1 months; HR, 0.79; 95% CI, 0.65 to 0.97). CONCLUSION This GOG-0218 trial investigation validates ICON-7 findings about the association between poor tumor chemosensitivity and benefit from concurrent-maintenance bevacizumab, suggesting that bevacizumab may mainly be effective in patients with poorly chemosensitive disease. Bevacizumab may be prioritized in patients with a high-risk and poorly chemosensitive disease to improve their PFS/OS (patient KELIM score calculator available on the Biomarker Kinetics website).

2022-02-11

c-MET/VEGFR-2 co-localisation impacts on survival following bevacizumab therapy in epithelial ovarian cancer: an exploratory biomarker study of the phase 3 ICON7 trial

Abstract Introduction Bevacizumab improves survival outcomes in women diagnosed with epithelial ovarian cancer (EOC). Pre-clinical data showed that the c-MET/VEGFR-2 heterocomplex negates VEGF inhibition through activation of c-MET signalling, leading to a more invasive and metastatic phenotype. We evaluated the clinical significance of c-MET and VEGFR-2 co-localisation and its association with VEGF pathway-related single nucleotide polymorphisms (SNPs) in women participating in the phase 3 trial, ICON7 (ClinicalTrials.gov identifier: NCT00262847). Materials and methods Patients had FIGO stage I-IIA grade 3/poorly differentiated or clear cell carcinoma or stage IIB-IV epithelial ovarian, primary peritoneal or fallopian tube cancer. Immunofluorescence staining for co-localised c-MET and VEGFR-2 on tissue microarrays and genotyping of germline DNA from peripheral blood leukocytes for VEGFA and VEGFR-2 SNPs was performed. The significance of these biomarkers was assessed against survival. Results Tissue microarrays from 178 women underwent immunofluorescence staining. Multivariable analysis showed that greater c-MET/VEGFR-2 co-localisation predicted worse OS in patients treated with bevacizumab after adjusting for FIGO stage and debulking surgery outcome (hazard ratio [HR] 1.034, 95% confidence interval [95%CI] 1.010–1.059). Women in the c-MET/VEGFR-2HIGH group treated with bevacizumab demonstrated significantly reduced OS (39.3 versus &gt; 60 months; HR 2.00, 95%CI 1.08–3.72). Germline DNA from 449 women underwent genotyping. In the bevacizumab group, those women with the VEGFR-2 rs2305945 G/G variant had a trend towards shorter PFS compared with G/T or T/T variants (18.3 versus 23.0 months; HR 0.74, 95%CI 0.53–1.03). Conclusions In bevacizumab-treated women diagnosed with EOC, high c-MET/VEGFR-2 co-localisation on tumour tissue and the VEGFR-2 rs2305945 G/G variant, which may be biologically related, were associated with worse survival outcomes.

Linked Investigators

Andrea E. Wahner Hendrickson

Benoit You

Bradley J. Monk

David E. Cohn

David G. Mutch

Gini F. Fleming

Joan L. Walker

Krishnansu S. Tewari

Larry J. Copeland

Leslie Randall

Mahvish Muzaffar

Michael A. Bookman

Robert D Morgan

Robert L. Coleman