Clinical trial NCT01260701: Akt Inhibitor MK2206 in Treating Patients With Advanced Gastric or Gastroesophageal Junction Cancer
Official title: A Phase II Study of MK-2206 (NSC-749607) as Second Line Therapy for Advanced Gastric and Gastroesophageal Junction Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Adenocarcinoma of the Gastroesophageal Junction
Diffuse Gastric Adenocarcinoma
Gastric Intestinal Type Adenocarcinoma
Gastric Mixed Adenocarcinoma
Recurrent Gastric Carcinoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-12-15
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase II clinical trial studies how well Akt inhibitor MK2206 works in treating patients with advanced gastric or gastroesophageal junction cancer. Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description: PRIMARY OBJECTIVES:

I. To estimate the overall survival (OS) for patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma treated with MK-2206 (Akt inhibitor MK2206).

SECONDARY OBJECTIVES:

I. To estimate the progression free survival (PFS) in this patient population. II. To estimate the response rate (confirmed and unconfirmed complete response \[CR\] and partial response \[PR\] by Response Evaluation Criteria In Solid Tumors \[RECIST\] 1.1) in this patient population.

III. To assess the frequency and severity of toxicity associated with this regimen.

OUTLINE (CLOSED TO ACCRUAL 05/01/13):

Patients receive Akt inhibitor MK2206 orally (PO) every other day on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months for 2 years.

Eligibility criteria: Inclusion Criteria:

* Patients must have histologically or cytologically confirmed adenocarcinoma of the stomach or gastroesophageal (GE) junction that has progressed after first-line treatment, or is recurrent within 6 months after receiving adjuvant therapy; patients must have had exactly one prior systemic treatment regimen; previous adjuvant (chemotherapy \[chemo\]) radiotherapy is permitted; prior chemotherapy given concurrently with radiation for radiosensitization is not considered one prior systemic regimen
* Patients must have measurable disease; computed tomography (CT) scans or magnetic resonance imaging (MRIs) used to assess measurable disease must have been completed within 28 days prior to registration; CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1)
* Patients must not have known brain metastases
* Patients must not have received chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to registration
* Patient must not have received prior treatment with a phosphatidylinositol 3 (PI3), v-akt murine thymoma viral oncogene homolog 1 (AKT) or mechanistic target of rapamycin (Mtor) inhibitor for any reason
* All toxicities from prior therapy must have resolved to =\< grade 1 (Common Terminology Criteria for Adverse Events \[CTCAE\] version 4.0) prior to registration
* Patients must not be receiving or planning to receive any other investigational agents
* Patients must be able to tolerate oral medications and must not have malabsorption or chronic diarrhea (CTCAE version 4.0 grade 2 or higher); administration through a feeding tube is not permitted
* Hemoglobin \>= 9 g/dL
* Absolute neutrophil count (ANC) \>= 1,500/mcL
* Platelets \>= 100,000/mcL
* Total bilirubin =\< institutional upper limit of normal (IULN)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =\< 2.5 x IULN; patients with liver metastases must have AST and ALT =\< 5 x IULN
* Patients must have adequate kidney function as evidenced by at least ONE of the following:

  * Serum creatinine (mg/dL) =\< IULN obtained within 14 days prior to registration
  * Calculated creatinine clearance \> 50 ml/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to registration
* Patients must have international normalized ratio (INR) =\< 1.2 unless taking therapeutic doses of warfarin; this result must be obtained within 14 days prior to registration
* Patients must have fasting blood sugar =\< 150 mg/dL within 28 days prior to registration
* Patients must have hemoglobin A1C \< 7% within 28 days prior to registration
* Patients must have an electrocardiogram (ECG) within 28 days prior to registration; patients must have corrected QT interval (QTcF) (by Fridericia's calculation) \< 450 msec (male) or \< 470 msec (female)
* Patients must have a Zubrod performance status of 0-1
* Patient must not have any of the following: a history of congenital long QT syndrome; use of concomitant medications that could prolong the QTc interval; New York Heart Association class III or IV heart failure; history of myocardial infarction within 6 months prior to registration; uncontrolled dysrhythmias; poorly controlled angina; resting heart rate =\< 50 bpm (bradycardia)
* Patients must not be receiving concurrent treatment with drugs that are strong inducers or inhibitors of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4); patients must be able to safely discontinue treatment with these agents for \>= 2 weeks prior to beginning protocol therapy
* Patient must not have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
* Patient must not be pregnant or nursing; women/men of reproductive potential must have agreed to use two forms of contraception for the duration of protocol treatment and for one month after discontinuation of MK-2206; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any time a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
* No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years
* All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to 2 years
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Up to 2 years
measure: Response Rate (Complete and Partial, Confirmed and Unconfirmed)
timeFrame: Up to 2 years
measure: Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Providence Hospital
state: Alabama
city: Fairbanks
country: United States
facility: Fairbanks Memorial Hospital
state: Alaska
city: Tucson
country: United States
facility: The University of Arizona Cancer Center-Orange Grove Campus
state: Arizona
city: Tucson
country: United States
facility: The University of Arizona Cancer Center-North Campus
state: Arizona
city: Tucson
country: United States
facility: The University of Arizona Medical Center-University Campus
state: Arizona
city: Jonesboro
country: United States
facility: Fowler Family Center for Cancer Care
state: Arkansas
city: Jonesboro
country: United States
facility: NEA Baptist Memorial Hospital
state: Arkansas
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: Orange
country: United States
facility: UC Irvine Health/Chao Family Comprehensive Cancer Center
state: California
city: Fort Collins
country: United States
facility: Poudre Valley Hospital
state: Colorado
city: Fort Collins
country: United States
facility: Front Range Cancer Specialists
state: Colorado
city: Hartford
country: United States
facility: Saint Francis Hospital and Medical Center
state: Connecticut
city: Orlando
country: United States
facility: UF Cancer Center at Orlando Health
state: Florida
city: Savannah
country: United States
facility: Memorial University Medical Center
state: Georgia
city: Aiea
country: United States
facility: Oncare Hawaii Inc-Pali Momi
state: Hawaii
city: Aiea
country: United States
facility: Pali Momi Medical Center
state: Hawaii
city: Honolulu
country: United States
facility: Oncare Hawaii Inc-POB II
state: Hawaii
city: Honolulu
country: United States
facility: Queen's Medical Center
state: Hawaii
city: Honolulu
country: United States
facility: Straub Clinic and Hospital
state: Hawaii
city: Honolulu
country: United States
facility: University of Hawaii Cancer Center
state: Hawaii
city: Honolulu
country: United States
facility: OnCare Hawaii-Liliha
state: Hawaii
city: Honolulu
country: United States
facility: Kuakini Medical Center
state: Hawaii
city: Honolulu
country: United States
facility: Oncare Hawaii Inc-Kuakini
state: Hawaii
city: Honolulu
country: United States
facility: Kapiolani Medical Center for Women and Children
state: Hawaii
city: Kailua
country: United States
facility: Castle Medical Center
state: Hawaii
city: Lihue
country: United States
facility: Wilcox Memorial Hospital and Kauai Medical Clinic
state: Hawaii
city: Boise
country: United States
facility: Saint Alphonsus Cancer Care Center-Boise
state: Idaho
city: Geneva
country: United States
facility: Cadence Cancer Center at Delnor
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Warrenville
country: United States
facility: Cadence Cancer Center in Warrenville
state: Illinois
city: Beech Grove
country: United States
facility: Franciscan St. Francis Health-Beech Grove
state: Indiana
city: Indianapolis
country: United States
facility: Franciscan Saint Francis Health-Indianapolis
state: Indiana
city: Richmond
country: United States
facility: Reid Hospital and Health Care Services
state: Indiana
city: Chanute
country: United States
facility: Cancer Center of Kansas - Chanute
state: Kansas
city: Dodge City
country: United States
facility: Cancer Center of Kansas - Dodge City
state: Kansas
city: Fort Scott
country: United States
facility: Cancer Center of Kansas - Fort Scott
state: Kansas
city: Great Bend
country: United States
facility: Saint Rose Ambulatory and Surgery Center
state: Kansas
city: Hays
country: United States
facility: Hays Medical Center
state: Kansas
city: Hutchinson
country: United States
facility: Hutchinson Regional Medical Center
state: Kansas
city: Independence
country: United States
facility: Cancer Center of Kansas-Independence
state: Kansas
city: Kansas City
country: United States
facility: The University of Kansas Cancer Center-West
state: Kansas
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Kingman
country: United States
facility: Cancer Center of Kansas-Kingman
state: Kansas
city: Lawrence
country: United States
facility: Lawrence Memorial Hospital
state: Kansas
city: Liberal
country: United States
facility: Cancer Center of Kansas-Liberal
state: Kansas
city: Newton
country: United States
facility: Cancer Center of Kansas - Newton
state: Kansas
city: Overland Park
country: United States
facility: Kansas City Cancer Centers-Southwest
state: Kansas
city: Parsons
country: United States
facility: Cancer Center of Kansas - Parsons
state: Kansas
city: Pittsburg
country: United States
facility: Via Christi Hospital-Pittsburg
state: Kansas
city: Pratt
country: United States
facility: Cancer Center of Kansas - Pratt
state: Kansas
city: Salina
country: United States
facility: Cancer Center of Kansas - Salina
state: Kansas
city: Salina
country: United States
facility: Salina Regional Health Center
state: Kansas
city: Shawnee Mission
country: United States
facility: Kansas City Cancer Center-Shawnee Mission
state: Kansas
city: Topeka
country: United States
facility: Saint Francis Hospital and Medical Center - Topeka
state: Kansas
city: Wellington
country: United States
facility: Cancer Center of Kansas - Wellington
state: Kansas
city: Wichita
country: United States
facility: Associates In Womens Health
state: Kansas
city: Wichita
country: United States
facility: Cancer Center of Kansas-Wichita Medical Arts Tower
state: Kansas
city: Wichita
country: United States
facility: Cancer Center of Kansas - Main Office
state: Kansas
city: Wichita
country: United States
facility: Via Christi Regional Medical Center
state: Kansas
city: Wichita
country: United States
facility: Wichita CCOP
state: Kansas
city: Winfield
country: United States
facility: Cancer Center of Kansas - Winfield
state: Kansas
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Ann Arbor
country: United States
facility: Saint Joseph Mercy Hospital
state: Michigan
city: Ann Arbor
country: United States
facility: Michigan Cancer Research Consortium CCOP
state: Michigan
city: Battle Creek
country: United States
facility: Bronson Battle Creek
state: Michigan
city: Big Rapids
country: United States
facility: Spectrum Health Big Rapids Hospital
state: Michigan
city: Dearborn
country: United States
facility: Oakwood Hospital and Medical Center
state: Michigan
city: Detroit
country: United States
facility: Saint John Hospital and Medical Center
state: Michigan
city: Flint
country: United States
facility: Hurley Medical Center
state: Michigan
city: Flint
country: United States
facility: Genesys Hurley Cancer Institute
state: Michigan
city: Flint
country: United States
facility: Genesys Regional Medical Center-West Flint Campus
state: Michigan
city: Grand Rapids
country: United States
facility: Grand Rapids Clinical Oncology Program
state: Michigan
city: Grand Rapids
country: United States
facility: Mercy Health Saint Mary's
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health at Butterworth Campus
state: Michigan
city: Jackson
country: United States
facility: Allegiance Health
state: Michigan
city: Lansing
country: United States
facility: Sparrow Hospital
state: Michigan
city: Livonia
country: United States
facility: Saint Mary Mercy Hospital
state: Michigan
city: Muskegon
country: United States
facility: Mercy Health Mercy Campus
state: Michigan
city: Pontiac
country: United States
facility: Saint Joseph Mercy Oakland
state: Michigan
city: Port Huron
country: United States
facility: Saint Joseph Mercy Port Huron
state: Michigan
city: Reed City
country: United States
facility: Spectrum Health Reed City Hospital
state: Michigan
city: Saginaw
country: United States
facility: Saint Mary's of Michigan
state: Michigan
city: Traverse City
country: United States
facility: Munson Medical Center
state: Michigan
city: Warren
country: United States
facility: Saint John Macomb-Oakland Hospital
state: Michigan
city: Wyoming
country: United States
facility: Metro Health Hospital
state: Michigan
city: Kansas City
country: United States
facility: Truman Medical Center
state: Missouri
city: Kansas City
country: United States
facility: Kansas City Cancer Center - South
state: Missouri
city: Kansas City
country: United States
facility: Kansas City Cancer Centers - North
state: Missouri
city: Lee's Summit
country: United States
facility: Kansas City Cancer Center-Lee's Summit
state: Missouri
city: Rolla
country: United States
facility: Saint John's Clinic-Rolla-Cancer and Hematology
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis University Hospital
state: Missouri
city: Springfield
country: United States
facility: Cancer Research for the Ozarks NCORP
state: Missouri
city: Springfield
country: United States
facility: Mercy Hospital Springfield
state: Missouri
city: Springfield
country: United States
facility: CoxHealth South Hospital
state: Missouri
city: Billings
country: United States
facility: Montana Cancer Consortium NCORP
state: Montana
city: Billings
country: United States
facility: Saint Vincent Healthcare
state: Montana
city: Billings
country: United States
facility: Frontier Cancer Center and Blood Institute-Billings
state: Montana
city: Billings
country: United States
facility: Billings Clinic Cancer Center
state: Montana
city: Bozeman
country: United States
facility: Bozeman Deaconess Cancer Center
state: Montana
city: Bozeman
country: United States
facility: Bozeman Deaconess Hospital
state: Montana
city: Butte
country: United States
facility: Saint James Community Hospital and Cancer Treatment Center
state: Montana
city: Great Falls
country: United States
facility: Benefis Healthcare- Sletten Cancer Institute
state: Montana
city: Great Falls
country: United States
facility: Great Falls Clinic
state: Montana
city: Helena
country: United States
facility: Saint Peter's Community Hospital
state: Montana
city: Kalispell
country: United States
facility: Glacier Oncology PLLC
state: Montana
city: Kalispell
country: United States
facility: Kalispell Regional Medical Center
state: Montana
city: Missoula
country: United States
facility: Montana Cancer Specialists
state: Montana
city: Missoula
country: United States
facility: Saint Patrick Hospital - Community Hospital
state: Montana
city: Mineola
country: United States
facility: Winthrop University Hospital
state: New York
city: Rochester
country: United States
facility: Interlakes Foundation Inc-Rochester
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Asheboro
country: United States
facility: Randolph Hospital
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital
state: North Carolina
city: Greensboro
country: United States
facility: Cone Health Cancer Center
state: North Carolina
city: Statesville
country: United States
facility: Iredell Memorial Hospital
state: North Carolina
city: Winston-Salem
country: United States
facility: Southeast Cancer Control Consortium CCOP
state: North Carolina
city: Akron
country: United States
facility: Akron General Medical Center
state: Ohio
city: Bellefontaine
country: United States
facility: Mary Rutan Hospital
state: Ohio
city: Chillicothe
country: United States
facility: Adena Regional Medical Center
state: Ohio
city: Cincinnati
country: United States
facility: Good Samaritan Hospital - Cincinnati
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: Riverside Methodist Hospital
state: Ohio
city: Columbus
country: United States
facility: Columbus CCOP
state: Ohio
city: Columbus
country: United States
facility: Grant Medical Center
state: Ohio
city: Columbus
country: United States
facility: Mount Carmel Health Center West
state: Ohio
city: Columbus
country: United States
facility: Doctors Hospital
state: Ohio
city: Dayton
country: United States
facility: Grandview Hospital
state: Ohio
city: Dayton
country: United States
facility: Good Samaritan Hospital - Dayton
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospital
state: Ohio
city: Dayton
country: United States
facility: Samaritan North Health Center
state: Ohio
city: Dayton
country: United States
facility: Dayton CCOP
state: Ohio
city: Delaware
country: United States
facility: Grady Memorial Hospital
state: Ohio
city: Findlay
country: United States
facility: Blanchard Valley Hospital
state: Ohio
city: Franklin
country: United States
facility: Atrium Medical Center-Middletown Regional Hospital
state: Ohio
city: Greenville
country: United States
facility: Wayne Hospital
state: Ohio
city: Kettering
country: United States
facility: Kettering Medical Center
state: Ohio
city: Lancaster
country: United States
facility: Fairfield Medical Center
state: Ohio
city: Marietta
country: United States
facility: Marietta Memorial Hospital
state: Ohio
city: Mount Vernon
country: United States
facility: Knox Community Hospital
state: Ohio
city: Newark
country: United States
facility: Licking Memorial Hospital
state: Ohio
city: Portsmouth
country: United States
facility: Southern Ohio Medical Center
state: Ohio
city: Springfield
country: United States
facility: Springfield Regional Medical Center
state: Ohio
city: Troy
country: United States
facility: Upper Valley Medical Center
state: Ohio
city: Westerville
country: United States
facility: Saint Ann's Hospital
state: Ohio
city: Wilmington
country: United States
facility: Clinton Memorial Hospital
state: Ohio
city: Xenia
country: United States
facility: Greene Memorial Hospital
state: Ohio
city: Zanesville
country: United States
facility: Genesis HealthCare System
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Florence
country: United States
facility: McLeod Regional Medical Center
state: South Carolina
city: Knoxville
country: United States
facility: University of Tennessee - Knoxville
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: Baylor Saint Luke's Medical Center
state: Texas
city: Houston
country: United States
facility: Ben Taub General Hospital
state: Texas
city: Houston
country: United States
facility: Michael E DeBakey VA Medical Center
state: Texas
city: Danville
country: United States
facility: Danville Regional Medical Center
state: Virginia
city: Martinsville
country: United States
facility: Memorial Hospital Of Martinsville
state: Virginia
city: Anacortes
country: United States
facility: Cancer Care Center at Island Hospital
state: Washington
city: Bellingham
country: United States
facility: PeaceHealth Saint Joseph Medical Center
state: Washington
city: Bremerton
country: United States
facility: Harrison HealthPartners Hematology and Oncology-Bremerton
state: Washington
city: Burien
country: United States
facility: Highline Medical Center-Main Campus
state: Washington
city: Issaquah
country: United States
facility: Swedish Cancer Institute-Issaquah
state: Washington
city: Kennewick
country: United States
facility: Kadlec Clinic Hematology and Oncology
state: Washington
city: Kirkland
country: United States
facility: EvergreenHealth Medical Center
state: Washington
city: Kirkland
country: United States
facility: Seattle Cancer Care Alliance at EvergreenHealth
state: Washington
city: Mount Vernon
country: United States
facility: Skagit Valley Hospital
state: Washington
city: Poulsbo
country: United States
facility: Harrison HealthPartners Hematology and Oncology-Poulsbo
state: Washington
city: Seattle
country: United States
facility: Virginia Mason CCOP
state: Washington
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: Minor and James Medical PLLC
state: Washington
city: Seattle
country: United States
facility: Pacific Medical Center-First Hill
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Seattle
country: United States
facility: Group Health Cooperative of Puget Sound Oncology Consortium
state: Washington
city: Seattle
country: United States
facility: Group Health Cooperative-Seattle
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center-First Hill
state: Washington
city: Seattle
country: United States
facility: The Polyclinic
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Sedro-Woolley
country: United States
facility: United General Hospital
state: Washington
city: Spokane
country: United States
facility: Cancer Care Northwest - Spokane South
state: Washington
city: Spokane
country: United States
facility: Evergreen Hematology and Oncology PS
state: Washington
city: Spokane
country: United States
facility: Rockwood Clinic
state: Washington
city: Wenatchee
country: United States
facility: Wenatchee Valley Hospital and Clinics
state: Washington
city: Casper
country: United States
facility: Rocky Mountain Oncology
state: Wyoming
city: Sheridan
country: United States
facility: Welch Cancer Center
state: Wyoming
city: Vancouver
country: Canada
facility: BCCA-Vancouver Cancer Centre
state: British Columbia
Study officials:
affiliation: SWOG Cancer Research Network
name: Ramesh Ramanathan
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ramanathan RK, McDonough SL, Kennecke HF, Iqbal S, Baranda JC, Seery TE, Lim HJ, Hezel AF, Vaccaro GM, Blanke CD. Phase 2 study of MK-2206, an allosteric inhibitor of AKT, as second-line therapy for advanced gastric and gastroesophageal junction cancer: A SWOG cooperative group trial (S1005). Cancer. 2015 Jul 1;121(13):2193-7. doi: 10.1002/cncr.29363. Epub 2015 Mar 30.