Combination Chemotherapy, PEG-Interferon Alfa-2b, and Surgery in Treating Patients With Osteosarcoma

Metastatic Osteosarcoma Clinical Trial

— EURAMOS-1  

Official title:

A Randomized Trial of the European and American Osteosarcoma Study Group to Optimize Treatment Strategies for Resectable Osteosarcoma Based on Histological Response to Pre-operative Chemotherapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00134030
• Other study ID #: AOST0331/ EURAMOS-1
• Secondary ID: NCI-2009-01066IS
• Status: Completed
• Phase: Phase 3
• Start date: November 14, 2005
• Est. completion date: September 30, 2022

Study information

• Verified date: May 2023
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase III trial is studying combination chemotherapy followed by surgery and two different combination chemotherapy regimens with or without PEG-interferon alfa-2b to compare how well they work in treating patients with osteosarcoma. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Biological therapies, such as PEG-interferon alfa-2b, may interfere with the growth of tumor cells. Giving combination chemotherapy before surgery may shrink the tumor so it can be removed. Giving combination chemotherapy together with PEG-interferon alfa-2b after surgery may kill any remaining tumor cells. It is not yet known whether giving combination therapy together with PEG-interferon alfa-2b is more effective than two different combination chemotherapy regimens alone after surgery in treating osteosarcoma.

Description:

PRIMARY OBJECTIVES: I. Compare whether adjuvant maintenance therapy comprising doxorubicin, cisplatin, and high-dose methotrexate (MAP) alone vs MAP combined with ifosfamide and etoposide improves event-free survival of patients with resectable high-grade osteosarcoma who achieve a poor histological response (HR) to neoadjuvant induction therapy comprising MAP. II. Compare whether adjuvant maintenance therapy comprising MAP alone vs MAP and PEG-interferon alfa-2b improves event-free survival of patients with resectable high-grade osteosarcoma who achieve a good HR to neoadjuvant induction therapy comprising MAP. SECONDARY OBJECTIVES: I. Compare overall survival of patients treated with these regimens. II. Compare short- and long-term toxicity of these regimens in these patients. III. Compare quality of life of patients treated with these regimens. IV. Compare event-free survival and overall survival of patients with localized osteosarcoma treated with these regimens. V. Correlate biological or clinical changes with histological response and outcomes in patients treated with these regimens. VI. Determine outcomes of patients treated with these regimens. OUTLINE: This is a randomized, controlled, multicenter study. INDUCTION THERAPY: (MAP; weeks 1-10) Patients receive doxorubicin IV continuously over 48 hours on days 1-2 and cisplatin IV over 4 hours on days 1 and 2 in weeks 1 and 6. Patients also receive high-dose methotrexate (MTX)* IV over 4 hours on day 1 in weeks 4, 5, 9, and 10. Patients then proceed to surgery. NOTE: *Patients must receive >= 2 but =< 6 doses of high-dose MTX. SURGERY: Patients undergo amputation or limb salvage surgery in week 11. Tumor tissue is evaluated for histological response to induction therapy. Patients whose tumor is not amenable to macroscopically complete surgical resection undergo radiotherapy and/or other investigational therapy off study. Patients who undergo macroscopically complete surgical resection of the primary tumor or metastases AND who have no disease progression or unacceptable toxicity proceed to maintenance therapy. MAINTENANCE THERAPY: Patients are assigned to 1 of 2 groups according to histological response (good [< 10% viable tumor] vs poor [≥ 10% viable tumor]). Patients in each group are stratified according to site of primary tumor and presence of metastases. GROUP 1: (good histological response) Patient are randomized to 1 of 2 treatment arms within 35 days after surgery. ARM I: (MAP; weeks 12-29) Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 17, 22, and 26 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 17. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 16, 20, 21, 24, 25, 28, and 29. ARM II: (MAPifn; weeks 12-104) Patients receive doxorubicin, cisplatin, and high-dose MTX as in arm I. Patients than receive PEG-interferon alfa-2b subcutaneously once daily on day 1 in weeks 30-104. GROUP 2: (poor histological response) Patients are randomized to 1 of 2 treatment arms within 35 days after surgery. ARM I: (MAP; weeks 12-29) Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I. ARM II: (MAPIE; weeks 12-40) Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 20, 28, and 36 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 28. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 19, 23, 27, 31, 35, 39, and 40. Patients receive ifosfamide IV over 4 hours on days 1-5 in weeks 16, 24, and 32 and on days 1-3 in weeks 20 and 36 and etoposide IV over 1 hour on days 1-5 in weeks 16, 24, and 32. In both groups, treatment continues in the absence of disease progression or unacceptable toxicity. Quality of life is assessed periodically. After completion of study treatment, patients are followed every 1½-3 months for 2 years, every 2-4 months for 2 years, every 6 months for 6 years, and then every 6-12 months thereafter. Peer Reviewed and Funded or Endorsed by Cancer Research UK

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1334
• Est. completion date: September 30, 2022
• Est. primary completion date: January 31, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years to 40 Years

Eligibility

Inclusion Criteria:

• Histologically confirmed high-grade osteosarcoma, including second malignancies
• Localized or metastatic disease
• The primary tumor must be located in the limbs or axial skeleton, including any

of the following sites*:

• Long bone of upper limb
• Short bone of upper limb
• Long bone of lower limb
• Short bone of lower limb
• Vertebral column
• Ribs, sternum, clavicle, or scapula
• Pelvic bones, sacrum, or coccyx
• Tumor (primary, metastatic, or both) resectable OR is expected to become resectable after neoadjuvant induction chemotherapy
• Suitable for neoadjuvant chemotherapy
• Performance status - Lansky 50-100% (for patients under 16 years of age)
• Performance status - Karnofsky 50-100%*
• Performance status - WHO or ECOG 0-2*
• Platelet count = 100,000/mm³
• Neutrophil count = 1,500/mm³
• WBC = 3,000/mm³
• Bilirubin = 1.5 times upper limit of normal
• Creatinine clearance = 70 mL/min
• Creatinine based on age as follows:
• No greater than 1.0 mg/dL (for patients 5 to 10 years of age)
• No greater than 1.2 mg/dL (for patients 11 to 15 years of age)
• No greater than 1.5 mg/dL (for patients over 15 years of age)
• Ejection fraction = 50% by radionuclide angiogram
• Shortening fraction = 28% by echocardiogram
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No known HIV positivity
• No prior chemotherapy for any disease
• Prior radiotherapy for another malignancy allowed
• No prior treatment for osteosarcoma
• No patients with any of the following:
• Craniofacial osteosarcoma

Related Conditions & MeSH terms

• Localized Osteosarcoma
• Metastatic Osteosarcoma
• Osteosarcoma

Intervention

Drug:
• Cisplatin
Given IV
• Doxorubicin Hydrochloride
Given IV
• Etoposide
Given IV
• Ifosfamide
Given IV
• Methotrexate
Given IV

Biological:
• Peginterferon Alfa-2b
Given subcutaneously

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Procedure:
• Therapeutic Conventional Surgery
Undergo amputation or limb salvage surgery

Locations

Country	Name	City	State
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Royal Children's Hospital-Brisbane	Herston	Queensland
Australia	John Hunter Children's Hospital	Newcastle	New South Wales
Australia	Women's and Children's Hospital-Adelaide	North Adelaide	South Australia
Australia	Royal Children's Hospital	Parkville	Victoria
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Australia	Queensland Children's Hospital	South Brisbane	Queensland
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Australia	Westmead Hospital	Westmead	New South Wales
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	Children's Hospital	London	Ontario
Canada	Victoria Hospital	London	Ontario
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Centre Hospitalier Universitaire de Quebec	Quebec
Canada	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Starship Children's Hospital	Grafton	Auckland
New Zealand	Wellington Children's Hospital	Wellington
Puerto Rico	San Jorge Children's Hospital	San Juan
Switzerland	Swiss Pediatric Oncology Group - Bern	Bern
Switzerland	Swiss Pediatric Oncology Group - Geneva	Geneva
Switzerland	Swiss Pediatric Oncology Group - Lausanne	Lausanne
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Texas Tech University Health Sciences Center-Amarillo	Amarillo	Texas
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Mission Hospital	Asheville	North Carolina
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Augusta University Medical Center	Augusta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Brooklyn Hospital Center	Brooklyn	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont and State Agricultural College	Burlington	Vermont
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	T C Thompson Children's Hospital	Chattanooga	Tennessee
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Prisma Health Richland Hospital	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Medical City Dallas Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Michigan State University Clinical Center	East Lansing	Michigan
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	University of Connecticut	Farmington	Connecticut
United States	Hurley Medical Center	Flint	Michigan
United States	Broward Health Medical Center	Fort Lauderdale	Florida
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Lee Memorial Health System	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	East Carolina University	Greenville	North Carolina
United States	Greenville Cancer Treatment Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Tripler Army Medical Center	Honolulu	Hawaii
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	Cabell-Huntington Hospital	Huntington	West Virginia
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	Kalamazoo Center for Medical Studies	Kalamazoo	Michigan
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada
United States	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Saint Barnabas Medical Center	Livingston	New Jersey
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Mattel Children's Hospital UCLA	Los Angeles	California
United States	UCLA / Jonsson Comprehensive Cancer Center	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Valley Children's Hospital	Madera	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	Miami Cancer Institute	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Morristown Medical Center	Morristown	New Jersey
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Saint Peter's University Hospital	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Mount Sinai Hospital	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois
United States	Children's Hospital and Research Center at Oakland	Oakland	California
United States	Kaiser Permanente-Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	AdventHealth Orlando	Orlando	Florida
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Nemours Children's Clinic - Orlando	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	UF Cancer Center at Orlando Health	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Sacred Heart Hospital	Pensacola	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Legacy Emanuel Hospital and Health Center	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Carilion Children's	Roanoke	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Beaumont Children's Hospital-Royal Oak	Royal Oak	Michigan
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	UCSF Medical Center-Mount Zion	San Francisco	California
United States	UCSF Medical Center-Parnassus	San Francisco	California
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Overlook Hospital	Summit	New Jersey
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Madigan Army Medical Center	Tacoma	Washington
United States	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Scott and White Memorial Hospital	Temple	Texas
United States	Mercy Children's Hospital	Toledo	Ohio
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	University of Toledo	Toledo	Ohio
United States	Harbor-University of California at Los Angeles Medical Center	Torrance	California
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	UMass Memorial Medical Center - University Campus	Worcester	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
Children's Oncology Group	Medical Research Council, National Cancer Institute (NCI), University College, London

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand,  Puerto Rico,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free Survival (EFS)	EFS is defined as time from randomisation to the first of: death, detection of local recurrence or metastasis, progression of metastatic disease, or detection of a secondary malignancy.; EFS will be assessed using the logrank test and expressed using hazard ratios with appropriate confidence intervals. Follow up per participant will be assessed for up to 10 years. The 3 year EFS is provided as a summary.	From date of randomization to date of the event.
Secondary	Percentage of Patients With Overall Survival	Overall survival is time from randomization until death from any cause.; Will be assessed using the logrank test and expressed using hazard ratios with appropriate confidence intervals. Participants will be assessed for up to 10 years. 5 year overall survival is provided as a summary.	From date of randomization to date of death.
Secondary	Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) v3.0	Percentages of patients experiencing grade 3 and 4 adverse events. These will be compared using chi-square tests or Fisher's exact tests where appropriate.	Adverse events are assessed for up to 10 years per participant.