Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.
Supplement to: Chan A, Delaloge S, Holmes FA, et al, for the ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2016; published online Feb 10. http://dx.doi.org/10.1016/S1470-2045(15)00551-3.
1
SUPPLEMENTARY APPENDIX
Table of Contents
List of Investigators and Countries ............................................................................................................. ... 2
Academic Steering Committee and Independent Data Monitoring Committee .......................................... ... 4
History of Global Protocol Amendments ................................................................................................... ... 5
Sensitivity Analysis of Early Drop-Outs .................................................................................................... ... 7
Figure S1. Kaplan-Meier Curves Showing Invasive Disease-free Survival in Hormone Receptor–Positive
Patients and in Hormone Receptor–Negative Patients and Disease-free Survival Including Ductal
Carcinoma In Situ in Hormone Receptor–Positive Patients and in Hormone Receptor–Negative Patients
(Intention-to-Treat Population) .................................................................................................................... ... 8
Figure S2. Kaplan-Meier Curves Showing Invasive Disease-free Survival and Disease-free Survival
Including Ductal Carcinoma In Situ (Amended Intention-to-Treat Population) .......................................... ... 9
Figure S3. Kaplan-Meier Curves Showing Invasive Disease-free Survival and Disease-free Survival
Including Ductal Carcinoma In Situ (Centrally-Confirmed HER2-Positive Patients) ................................. . 10
Figure S4. Diarrheal Events by Grade Over Time in Patients Treated with Neratinib ................................ . 11
Figure S5. Mean FACT-B Total Scores and EQ-5D Visual Analog Scale Scores by Treatment Group ..... . 12
Table S1. Efficacy Endpoint Definitions .................................................................................................... . 13
Table S2. Efficacy Endpoint Analyses (Intention-to-Treat Population) ..................................................... . 14
Table S3. Baseline Characteristics of Patients According to Duration of Follow-up (Intention-to-Treat
Population) ................................................................................................................................................. . 15
Table S4. Treatment-Emergent Adverse Events of Grade 3 or Greater in Descending Order of Frequency
(Safety Population) ..................................................................................................................................... . 17
Table S5. Summary of Treatment-Emergent Diarrhea in the ExteNET Study (Safety Population) and Study
5201 ............................................................................................................................................................ . 22
Table S6. Summary of Study Sites, Principle Investigators Responsible for Each Site and the Number of
Patients Enrolled from Each Site ............................................................................................................... . 23
References .................................................................................................................................................. . 34
2
LIST OF INVESTIGATORS AND COUNTRIES
We would like to acknowledge the following investigators who also participated in this trial: Australia: A.
Chan; R. Hui; R. De Boer; T. Healey; P. Mainwaring; D. Kotasek; D. Campbell; W. Patterson; Bahamas: T.
Turnquest; Belgium: G. Jerusalem; J. Mebis; V. Philippe; I. Deleu; M. Borms; J-P. Salmon; A. Bols; R.
D'Hondt; C. Nouwynck; G. Pelgrims; V. Richard; J. Verschuere; K. Geldhof; Brazil: C. Barrios; Bulgaria: P.
Petrov; V. Taskova; C. Timcheva; A. Tomova; T. Koynova; Canada: A. Joy; C. Luk; R. Yasmin; B. Dingle;
S. Sridhar; J. Chang; C. Desbiens; J-P. Ayoub; D. Grenier; P. Dube; S. Chia; B. Lesperance; F. Couture; J.
Wilson; G. Hunt; China: Z-Z. Shen; Q. Sun; X. Wang; Z-S. Tong; J. Yang; B. Xu; Z. Jiang; D-G. Liu; R. Luo;
Colombia: S. Franco; M. E. G. Fernandez; G. Rojas; Croatia: T. Silovski; Z. Vojnovic; D. Gugic; D. Vrbanec;
Czech Republic: K. Petrakova; J. Vanasek; J. Prausova; V. Benesova; P. Garnolova; O. Bednarik; Denmark:
E. H. Jakobsen; S. Cold; A. Luczak; S. Langkjer; P. Sørensen; B. Ejlertsen; E. Harder-Brix; V. Glavicic; L.
Adrian; P. Vestlev; B. Bjerregaard Jensen; V. Haahr; France: S. Delaloge; B. Coudert; C. Levy; D. Khayat; C.
Veyret; J-P. Bergerat; E. Bourbouloux; L-M. Dourthe; P. Bougnoux; V. Dieras; J-P. Jacquin; L. Cany; L.
Vanlemmens; M. Espie; D. Machover; D. Mayeur; N. Trufflandier; V. Delacroix; M. Mousseau; J-M. Nabholtz;
Germany: F. Overkamp; N. Marschner; H. Tesch; H-J. Lück; J. Janssen; I. Schwaner; G. von Minckwitz; J.
Hackmann; T. Neunhoeffer; G. Graffunder; P. Bojko; B. Heinrich; A. von der Assen; J. Schilling; K. Apel; C-
H. Koehne; A. Schneeweiss; S. Fuxius; C. Jackisch; M. Neumann; E-M. Grischke; D. Seeger; V. Moebus; A.
Prechtl; M. Kusche; D. Ossenbühl; D. Fischer; R. Repp; P. Klare; F. Griesinger; L. Hanker; B. Schnappauf; J.
Bischoff; R. Neumeister; M. Schmidt; B. Rack; V. Schulz; R. E. Felberbaum; T. Noesselt; Greece: G.
Fountzilas; S. Kakolyris; H. Kalofonos; I. Varthalitis; V. Georgoulias; D. Pectasidis; C. Papandreou; D.
Pectasidis; Hong Kong: W-H Tsang; T-Y. Ng; L. Chow; T. C. C. Yau; Hungary: I. Láng; Z. Pólya; Z. Nagy;
G. Pajkos; É. Somogyiné; Á. Wéber; B. Pikó; M. Dank; E. Simo; Israel: N. Efrat; B. Kaufman; K. Drumea; D.
Geffen; Italy: P. Tassone; M. Nardi; R. Maisano; G. Tonini; D. Giuffrida; G. Cartenì; F. Nuzzo; C. Falci; S.
Cinieri; F. Roila; S. Barni; P. Bidoli; E. Ruggeri; T. Gamucci; F. Cognetti; G. Gorzegno; C. Gridelli; A. Falcone;
H. J. Soto Parra; M. Di Palma; F. Angelini; Japan: N. Masuda; K. Inoue; Y. Rai; Y. Hozumi; K. Higaki; M.
Takahashi; N. Yamamoto; K. Aogi; S. Shimizu; Y. Ito; M. Tanaka; H. Iwata; S. J. Kim; S. Takao; M. Ishitobi;
Y. Tokuda; N. Sato; R. Nishimura; J. Watanabe; O. Shinji; K. Katsumasa; T. Ueno; M. Hirofumi; Lithuania:
A. Ciceniene; E. Juozaityte; Macedonia: S. Smichkoska; Malaysia: A. Z. Bustam; Malta: S. Brincat; Mexico:
B. Sanchez-Llamas; Netherlands: A. Ten Tije; G.S. Madretsma; C. Van Groeningen; M. Dercksen; F.
Erdkamp; J. Braun; J. Ruit; J.E.A. Portielje; New Zealand: V. Harvey; Peru: V. Bermudez; Poland: K.
Lesniewski-Kmak; E. Chmielowska; T. Sarosiek; W. Rogowski; K. Wozniak; M. Wojtukiewicz; J. Jassem; A.
Piktel; K. Krzemieniecki; R. Banas; Romania: D. Lungulescu; P. Iorga; A. Eniu; Serbia: Z. Neskovic-
Konstantinovic; S. Filipovic; Singapore: Y-S. Yap; Slovakia: S. Spanik; M. Wagnerova; M. Kakalejcik; South
Korea: S-B. Kim; Y-H. Im; K. H. Park; J. S. Ro; S-A. Im; Spain: A. G. Zotano; N. Martinez; A. Murias-
Rosales; S. Morales; M. Ruiz-Borrego; M. Martin Jimenez; A. Arance; J. García-Sáenz; C. Jara Sanchez; M.
Lomas-Garrido; J. R. De La Haba Rodriguez; A. Avella Mestre; S. del Barco Berron; I. Calvo Plaza; A. A.
Torres; E. Martínez de Dueñas; B. Bermejo de las Heras; M. Ramos-Vázquez; S. Gonzalez Santiago; A.
Rodriguez Lescure; R. Cubedo Cervera; J. Valero Alvarez Gallego; A. Arcusa; M. del Pilar Lopez Alvarez; J.
Florian Gerico; C. Saura Manich; A. Sanchez-Muñoz; S. González; J. Cassinello; S. Pernas Simón; M. Margeli
Vila; N. Batista; M. Angel de la Cruz Mora; J. C. Toral-Pena; J. Baena Canadá; P. Martinez del Prado; Sweden:
N. Loman; Switzerland: D. Rauch; R. Popescu; W. Mingrone; C. Clemens; Taiwan: Y-S. Lu; S-C. Chen; M-
F. Hou; Turkey: E. Gokmen; I. Somali; S. Turhal; K. Altundag; P. Saip; A. Sevinc; M. Ozguroglu; N. Alkis;
M. Benekli; T. Evrensel; United Kingdom: A. Armstrong; A. Anand; S. Khan; R. Coleman; M. J. Rolles; J.
Mansi; A. Robinson; W. Ella; H. Algurafi; J. Bishop; T. Perren; I. Boiangiu; J. Stebbing; R. R. Roylance; A.
Harnett; A. D. Chetiyawarda; J. Barret; United States of America: S. Sawhney; M. A. Ghraowi; P. M.
Blanchet; J. J. Choate; M. Venigalla; R. Rao; J. A. Berman; F. Qazi; M. A. Danso; N. Robert; I. Gore; J. Smith;
W. Harker; N. Iannotti; G. Rodriguez; B. Hellerstedt; J. Link; J. Means-Powell; F. Senecal; M. Bhandari; C.
Osborne; V. Hansen; V. Rao; B. Moy; M. Gupta; R. Birhiray; M. Citron; W. Berry; Y. Manalo; J. Smith; I.
Vaziri; S. Papish; R. Somer; P. Flynn; M. Wilkinson; N. Green; A. Sidrys; D. Testori; L. Dickerson; J. Mace;
S. Hallmeyer; R. Rivera; L. Klein; R. Ruxer; S. Wilks; D. Richards; E. Tran-Chiu; C. Henderson; V. Holden;
3
C. Croot; A. Dekker; N. Belman; R. Michaelson; S. Chui; K. Nahum; F. Holmes; J. Nichols; C. Encarnacion;
T. Niederman; R. Gordon; A. Greenspan; M. Ali; J. Wade; J. Chien; Y. Novik; C. Jani; R. L. Rice; R. Bajaj; D.
Brandt; R. Greenberg; A. Eiseman; R. Droder; R. Abbasi; M. Vaysburd; B. Haley; E. L. Robin; R. Inhorn; D.
Hufnagle; E. Spremulli; P. Silverman; S. Jain; M. Keaton; R. Weigand; G. Kimmick; H. Caldera; E. Gartner;
L. Flaherty; E. Ibrahim; P. Hergenroeder; A. Mahmood; E. Kaplan; D. Patel; B. W. Clowney; K. Hoelzer; G.
Schwartz; J. Abraham; R. Mocharnuk; L. Schlabach; S. McCachren; T. Cosgriff; L. P. Dreibach; L. Pawl; J.
Lucas; L. Shinn; D. Lindquist; T. Anderson; S. Witherby; N. Erickson; R. Bose; S. Prakahs; F. Volterra; G.
Capo; S. Baidas; I. Okazaki; B. Nguyen; T. Rakowski; I. Oliff; M. Kubiak; B. Mirtsching; S. Narula; K.
Jabboury; R. McDonough; A. DeMichele; A. Krie; N. Vrindavanam; O. Howard; D. Citrin; I. J. Sanchez-
Rivera; D. Nixon; P. Beatty; K. Edmiston; J. Eneman; C. Lynch; J. Call; A. Conlin; D. Brooks; C. Jones; K.
McIntyre; M. Saltzman; M. Castine III; G. Ortega; Y. Choi; C. Reynolds; R. M. Kramer; A. Kohn; J. Micha;
S. Shah; D. Riseberg; M. Morginstin; A. Desai; A. Zahalsky; R. Jaslow; G. Thomas; A. Maini; A. Khojasteh;
M. Gonzalez; L. R. Kong; A. Padmanabha; S. Swain; D. Faig; K. K. Jain; R. Yanagihara; O. Yvonne; E. Tan;
P. Whitworth; A. Bova; I. Anderson; M. Shirinian; C. K. Tin-U; T. O'Rourke; M. S. Roberts; M. Francisco; P.
Byeff; P. Kovach; M. Rarick; W. G. Schmidt; A. Stopeck; M. R. Flores; P. Weinstein; W. Wang; M. Porubcin;
D. Ellison; M. Charif; W. Conkright; E. Rivera; I. Oliff.
4
ACADEMIC STEERING COMMITTEE
Carlos Barrios, MD (Pontifical Catholic University of Rio Grande do Sul School of Medicine, Porto Alegre,
Brazil); Arlene Chan, MD (Breast Cancer Research Centre-WA & Curtin University, Perth, Australia); Stephen
Chia, MD (BC Cancer Agency, Vancouver, BC, Canada); Suzette Delaloge, MD (Institut Gustave Roussy,
Villejuif, France); Bent Ejlertsen, MD (Rigshospitalet, Copenhagen, Denmark); Michael Gnant, MD
(Department of Surgery and Comprehensive Cancer Centre, Medical University of Vienna, Vienna, Austria);
Frankie Ann Holmes, MD (Texas Oncology, P.A., Houston, TX, USA); James Ingle*; Hiroji Iwata, MD (Aichi
Cancer Center, Chikusa-ku, Nagoya, Japan); Janine Mansi, MD (Guy's Hospital, London, BRC, King's College,
London, United Kingdom); Miguel Martin, MD (Instituto de Investigación Sanitaria Gregorio Marañón,
Universidad Complutense de Madrid, Madrid, Spain); Beverly Moy, MD (Massachusetts General Hospital
Cancer Center, Boston, MA, USA); Gunter von Minckwitz, MD (Luisenkrankenhaus, German Breast Group
Forschungs GmbH, Düsseldorf, Neu-lsenburg, Germany); Marc Buyse, ScD (International Drug Development
Institute (IDDI), Louvain-la-Neuve, Belgium).
*Original ASC only.
INDEPENDENT DATA MONITORING COMMITTEE
Joanne Mortimer, MD (City of Hope, CA, USA); Mohammad Jahanzeb, MD (University of Miami, FL, USA);
Jack di Palma, MD (USA Gastroenterology, Mobile, AL, USA); Kendra Schmid, PhD (University of Nebraska
Medical Center, NE, USA).
5
HISTORY OF GLOBAL PROTOCOL AMENDMENTS
There were a total of six global protocol amendments over the course of the study under the supervision of three
sponsors. Three of the global protocol amendments, described below, affected the original study design.
Original Protocol (29-Apr-2009, Wyeth)
The primary objective of the study was to compare invasive disease free survival (iDFS) of women with early-
stage HER2 overexpressed/amplified breast cancer following trastuzumab in the extended adjuvant setting,
receiving neratinib versus that of women receiving placebo. Secondary objectives were to compare the
following additional endpoints for subjects receiving neratinib versus those subjects receiving placebo: disease
free survival including ductal carcinoma in situ (DFS-DCIS), time to distant recurrence (TTDR), distant
disease-free survival (DDFS), incidence of central nervous system (CNS) recurrence, overall survival (OS) and
the short- and long-term safety (including incidence of grade 3 or higher diarrhea). Additional exploratory
objectives encompassed health outcomes and biomarker assessments.
The primary endpoint iDFS, was planned to be analyzed using a 1-sided log-rank test to compare the two
treatment groups. Statistical significance of the log-rank test was used to determine the stopping boundaries for
the 2 planned interim analyses at approximately 135 and 236 iDFS events, respectively, while the final analysis
was planned at approximately 337 iDFS events. The study was designed to provide approximately 90% power
to detect a difference in iDFS between the 2 treatment arms assuming a hazard ratio (HR) of 0·70 based upon
a 1-sided log-rank test controlling the type I error at 0·025.
The required study sample size of 3850 subjects was established by assuming a placebo arm hazard rate of
0·056 events per year per subject, assuming a peak accrual rate of 240 subjects per month and 1 year time for
accrual ramp-up, and assuming a 15% dropout rate in the first year and a 5% annual dropout rate thereafter.
Accrual was projected to last for approximately 2 years and the study was projected to reach the planned number
of iDFS events in 3·6 years from randomization of the first subject.
Global Protocol Amendment 3 (25-Feb-2010, Pfizer)
After study commencement, long-term follow-up data were presented for two adjuvant trastuzumab trials,
NCCTG N98311 and BCIRG 006.2 In both trials, the 5-year DFS rate was reported as approximately 84% for
the subjects treated with the most common concurrent trastuzumab regimen (adjuvant chemotherapy, followed
by a taxane plus trastuzumab, AC-TH), confirming there remained a substantial risk of tumor recurrence for
subjects who have completed adjuvant trastuzumab therapy. However, the 5-year DFS rate for node-negative
subjects treated with AC-TH was reported from the BCIRG 006 study as 93%, indicating the risk of tumor
recurrence was lower than expected when this study was originally designed. Additional efficacy data from
more mature pivotal adjuvant trastuzumab trials suggested that subjects were at higher risk of recurrence closer
to completion of adjuvant trastuzumab, and the risk of recurrence may decrease over time. As a result of the
aforementioned reported data, the study eligibility criteria were updated. Global Amendment 3 only included
subjects with a higher risk of recurrence and to comply with scientific advice provided by the Committee for
Medicinal Products for Human Use (CHMP), and subjects were to be randomized within one year of completion
of trastuzumab therapy.
Approximately 3300 subjects with a higher risk of recurrence were expected to be enrolled under Amendment
3 or if enrolled prior to this amendment satisfy 2 key eligibility criteria: node-positive disease and randomization
within one year from completion of prior trastuzumab therapy. The study was expected to have 90% power to
detect a difference in iDFS if the hazard ratio of the neratinib arm vs the placebo arm was 0·713, based on a 1-
sided log-rank test controlling the type 1 error at 0·025.
The primary efficacy analysis population was changed from the ITT to the amended ITT (aITT). The aITT
population consisted of subjects deemed to be at higher risk of disease recurrence (viz. node positive, had
residual invasive disease following neoadjuvant chemotherapy and had completed adjuvant trastuzumab up to
12 months earlier).
6
Global Protocol Amendment 9 (14-Oct-2011, Pfizer)
Pfizer chose to stop enrollment of new subjects immediately with Global Amendment 9. Furthermore, the
follow-up period was limited to 2 years after randomization and data for the exploratory objectives were no
longer collected, ie, tumor samples for pharmacogenetics and patient-reported health outcomes assessment data
ceased to be collected upon implementation of this amendment. The consequences of this amendment impacted
the original study objectives of evaluating the long-term efficacy of neratinib in the extended adjuvant setting.
The expected sample size for the study was approximately 1700 subjects for the aITT population. For each
subject, the follow-up from randomization was approximately 2 years. There was no pre-specified total number
of iDFS events. Assuming a hazard ratio of 0·667, the study was expected to have 83% power to detect a
difference in iDFS between the 2 treatment arms based on a 1-sided log-rank test controlling the Type 1 error
at 0·05.
Global Protocol Amendment 13 (Oct-2013, Puma Biotechnology)
The rationale for Global Amendment 13 was made following results from the I-SPY2 study, which
demonstrated that the pathological complete response rate for the combination of paclitaxel plus neratinib was
higher than the pathological complete response rate for the combination of paclitaxel plus trastuzumab in a
randomized study. Amendment 13 restored the study to its primary intention, ie, obtain iDFS and OS data for
all randomized subjects in order to evaluate the long-term efficacy of neratinib in the extended adjuvant setting.
The sponsor extended the collection of recurrent disease events and deaths to 5 years post-randomization and
will conduct long-term survival follow-up. Additionally, the primary efficacy analysis population was returned
to ITT, based on a 1-sided log-rank test controlling the Type 1 error at 0·025.
7
SENSITIVITY ANALYSIS OF EARLY DROP-OUTS
One hundred and twenty-seven patients in the neratinib arm dropped out within 3 months of treatment for
reasons other than recurrent disease compared to 44 patients in the placebo arm. The baseline disease
characteristics were balanced between patients who dropped out early and patients who were followed up for
longer in both treatment arms (Table S3).
To assess the potential impact of the early drop-outs (censored <3 months) on the primary analysis, the
following sensitivity analysis was performed. Patients who dropped out early in the neratinib group were
assumed to have iDFS events following the distribution observed in the placebo group. Specifically, imputation
of iDFS events for the neratinib early drop-out patients was achieved via resampling from the placebo patients
by matching hormone receptor status, nodal status and prior trastuzumab regimen (i.e. concurrent vs
sequential). The resampling was done 10,000 times. On average, 9 additional iDFS events were observed in the
resampled populations, ranging from 0 to 24 events. The average hazard ratio was 0·685 with standard deviation
of 0·021. Among the 10,000 resampled populations, 99·8% of the times the stratified log-rank test yielded
statistically significant result with a P-value less than or equal to 0·05.
8
Figure S1. Kaplan-Meier Curves Showing Invasive Disease-free Survival in Hormone Receptor–Positive
Patients (Panel A) and in Hormone Receptor–Negative Patients (Panel B), and Disease-free Survival
Including Ductal Carcinoma In Situ in Hormone Receptor–Positive Patients (Panel C) and in Hormone
Receptor–Negative Patients (Panel D) (Intention-to-Treat Population).
9
Figure S2. Kaplan-Meier Curves Showing Invasive Disease-free Survival (Panel A) and Disease-free
Survival Including Ductal Carcinoma In Situ (Panel B) (Amended Intention-to-Treat Population).
The amended intent-to-treat population consisted of all subjects with node-positive disease and who were
randomized within 1 year of completion of prior trastuzumab.
10
Figure S3. Kaplan-Meier Curves Showing Invasive Disease-free Survival (Panel A) and Disease-free
Survival Including Ductal Carcinoma In Situ (Panel B) (Centrally-Confirmed HER2-Positive Patients).
11
Figure S4. Diarrheal Events by Grade Over Time in Patients Treated with Neratinib.
12
Figure S5. Mean FACT-B Total Scores (Panel A) and EQ-5D Visual Analog Scale Scores (Panel
B) by Treatment Group.
FACT-B is a 37-item questionnaire with 4 subscales of FACT-G assessing physical, social, emotional, and
functional well-being, with an additional breast cancer-specific subscale (9 items). The FACT-B score range is
from 0 to 144, with a minimally important difference of 7-8 points.3 On EQ-5D, general health is measured via
a vertical visual analog scale (0-100), with a minimally important difference of 7-10 units.4 For both
instruments, a higher score indicates a better quality of life. Numbers shown reflect the actual available data.
Adjusted mean changes from baseline are estimated when both the visit and baseline values are available.
13
Table S1. Efficacy Endpoint Definitions.
Endpoint Definition
Primary
Invasive disease-free survival Time from randomization to the first occurrence of the following disease-
free survival events:
(a) Invasive ipsilateral breast tumor recurrence
(b) Invasive contralateral breast cancer
(c) Local/regional invasive recurrence
(d) Distant recurrence
(e) Death from any cause.
Any patient for whom an event had not been observed by the data cut-off
were censored at the date of their last physical examination.
Secondary
Disease-free survival including ductal carcinoma in situ Time from randomization to the first occurrence of a disease-free survival
event or ductal carcinoma in situ event. Disease-free survival including
ductal carcinoma in situ events include ductal carcinoma in situ and all
disease-free survival events. For subjects who have a ductal carcinoma in
situ diagnosis followed by a disease-free survival event, the date of event
for disease-free survival including ductal carcinoma in situ is the date of
ductal carcinoma in situ. Any patient for whom an event had not been
observed by the data cut-off were censored at the date of their last
physical examination.
Time to distant recurrence Time between randomization and the date of the first distance recurrence
or death from breast cancer. Time to distant recurrence events include
distant recurrence and death from breast cancer. Any patient for whom an
event had not been observed by the cut-off date were censored at the date
of their last physical examination.
Distant disease-free survival Time from randomization to the first occurrence of distant recurrence or
death from any cause. Distant disease-free survival events include distant
recurrence and death from any cause. Any patient for whom an event had
not been observed by the data cut-off were censored at the date of their
last physical examination.
Central nervous system recurrence Cumulative incidence of central nervous system recurrences as first
distant recurrence (either isolated central nervous system metastases, or
diagnosed concurrently with other sites of metastatic disease) defined as
time from randomization to central nervous system recurrence as first
distant recurrence. Any patient who was alive and for whom distant
recurrence had not been observed by the data cut-off as censored at the
date of their last physical examination.
14
Table S2. Efficacy Endpoint Analyses (Intention-to-Treat Population).
Variable Estimated event-free survival rate at 2 years
(95% CI), %*
Hazard ratio
(95 percent
confidence interval)†
P Value‡
Neratinib
(N = 1420)
Placebo
(N = 1420)
Invasive disease-free survival 93·9 (92·4-95·2) 91·6 (90·0-93·0) 0·67 (0·50, 0·91) 0·0091
Disease-free survival including ductal
carcinoma in situ
93·9 (92·4-95·2) 91·0 (89·3-92·5) 0·63 (0·46, 0·84) 0·0017
Distant disease-free survival 95·1 (93·7-96·2) 93·7 (92·2-94·9) 0·75 (0·53, 1·04) 0·089
Time to distant recurrence 95·4 (94·1-96·5) 93·9 (92·4-95·0) 0·71 (0·50, 1·00) 0·054
CNS recurrence 0·91 (0·49-1·59) 1·25 (0·75-1·99) – 0·44
CI = confidence interval; CNS = central nervous system.
* Event-free rates for all endpoints, except for CNS recurrence for which cumulative incidence is reported.
† Stratified Cox proportional hazards model.
‡ Stratified 2-sided log-rank test for all endpoints, except for CNS recurrence for which Gray’s method was used.
15
Table S3. Baseline Characteristics of Patients According to Duration of Follow-up (Intention-to-Treat
Population).
Variable
Neratinib Placebo
≤3 months
(N = 127)
>3 months
(N = 1291)
≤3 months
(N = 44)
>3 months
(N = 1367)
Region – no. (%)
North America 49 (38·6) 469 (36·3) 16 (36·4) 458 (33·5)
Western Europe, Australia and South Africa 48 (37·8) 438 (33·9) 21 (47·7) 510 (37·3)
Asia Pacific, East Europe and South
America
30 (23·6) 384 (29·7) 7 (15·9) 399 (29·2)
Race – no· (%)
White 104 (81·9) 1059 (82·0) 31 (70·5) 1098 (80·3)
Black 6 (4·7) 21 (1·6) 4 (9·1) 43 (3·1)
Asian 14 (11·0) 174 (13·5) 7 (15·9) 187 (13·7)
Other 3 (2·4) 37 (2·9) 2 (4·5) 39 (2·9)
Age at randomization – no. (%)
<35 yr 2 (1·6) 44 (3·4) 6 (13·6) 49 (3·6)
35–49 yr 46 (36·2) 476 (36·9) 15 (34·1) 495 (36·2)
50–59 yr 40 (31·5) 456 (35·3) 8 (18·2) 479 (35·0)
≥60 yr 39 (30·7) 315 (24·4) 15 (34·1) 344 (25·2)
Age – yr
Median 54·0 52·0 50·5 53·0
Menopausal status at diagnosis – no· (%)
Premenopausal 52 (40·9) 610 (47·3) 20 (45·5) 640 (46·8)
Postmenopausal 75 (59·1) 681 (52·7) 24 (54·5) 727 (53·2)
Nodal status – no. (%)†
Negative 41 (32·3) 294 (22·8) 8 (18·2) 328 (24·0)
1–3 Positive nodes 54 (42·5) 609 (47·2) 22 (50·0) 635 (46·5)
≥4 Positive nodes 32 (25·2) 388 (30·1) 14 (31·8) 404 (29·6)
HR status – no. (%)
Positive (ER and/or PR positive) 78 (61·4) 737 (57·1) 27 (61·4) 784 (57·4)
Negative (ER and/or PR negative) 49 (38·6) 554 (42·9) 17 (38·6) 583 (42·6)
Prior trastuzumab regimen – no. (%)
Concurrent 75 (59·1) 807 (62·5) 21 (47·7) 861 (63·0)
Sequential 52 (40·9) 484 (37·5) 23 (52·3) 506 (37·0)
T-stage – no. (%)
T1 51 (40·2) 389 (30·1) 15 (34·1) 443 (32·4)
T2 49 (38·6) 535 (41·4) 16 (36·4) 534 (39·1)
T3 and above 8 (6·3) 135 (10·5) 4 (9·1) 112 (8·2)
Unknown 19 (15·0) 231 (17·9) 9 (20·5) 277 (20·3)
Missing – 1 (0·1) – 1 (0·1)
Histologic grade of tumor – no. (%)
Undifferentiated 1 (0·8) 6 (0·5) 1 (2·3) 17 (1·2)
Poorly differentiated 62 (48·8) 600 (46·5) 16 (36·4) 660 (48·3)
Moderately differentiated 40 (31·5) 421 (32·6) 16 (36·4) 399 (29·2)
Well differentiated 7 (5·5) 69 (5·3) 4 (9·1) 61 (4·5)
Unknown 17 (13·4) 195 (15·1) 7 (15·9) 230 (16·8)
Prior surgery – no. (%)
Lumpectomy only 49 (38·6) 419 (32·5) 12 (27·3) 498 (36·4)
Mastectomy 78 (61·4) 871 (67·5) 32 (72·7) 868 (63·5)
Missing – 1 (0·1) – 1 (0·1)
Prior radiotherapy – no. (%)
Yes 96 (75·6) 1033 (80·0) 37 (84·1) 1107 (81·0)
No 31 (24·4) 258 (20·0) 7 (15·9) 260 (19·0)
Prior neoadjuvant therapy – no. (%)
No 101 (79·5) 976 (75·6) 32 (72·7) 1003 (73·4)
Yes 26 (20·5) 315 (24·4) 12 (27·3) 364 (26·6)
16
Trastuzumab 16 (12·6) 215 (16·7) 7 (15·9) 250 (18·3)
Anthracycline only 2 (1·6) 38 (2·9) 0 34 (2·5)
Anthracycline plus taxane 13 (10·2) 201 (15·6) 10 (22·7) 246 (18·0)
Taxane only 11 (8·7) 72 (5·6) 2 (4·5) 82 (6·0)
Non-anthracycline or taxane – 4 (0·3) – 2 (0·1)
Prior adjuvant therapy – no. (%)
No 1 (0·8) 4 (0·3) 0 1 (0·1)
Yes 126 (99·2) 1287 (99·7) 44 (100) 1366 (99·9)
Trastuzumab 125 (98·4) 1287 (99·7) 44 (100) 1364 (99·8)
Anthracycline only 18 (14·2) 128 (9·9) 6 (13·6) 140 (10·2)
Anthracycline plus taxane 60 (47·2) 662 (51·3) 21 (47·7) 652 (47·7)
Taxane only 28 (22·0) 253 (19·6) 6 (13·6) 281 (20·6)
Non-anthracycline or taxane 20 (15·7) 244 (18·9) 11 (25·0) 293 (21·4)
Duration of prior adjuvant trastuzumab therapy –
months
n=125 n=1286 n=44 n=1363
Median (IQR) 11·4 (10·9-12·0) 11·5 (10·9-
11·9)
11·5 (11·1-
12·1)
11·4 (10·8-
11·9)
Time since last dose of trastuzumab to randomization –
months
Median (IQR) 6·2 (2·0-11·0) 4·3 (1·6-10·3) 5·9 (1·6-10·7) 4·6 (1·5-10·8)
17
Table S4. Treatment-Emergent Adverse Events of Grade 3 or Greater in Descending Order of Frequency
(Safety Population).
Preferred Term
Neratinib (N =1408) Placebo (N =1408)
Grade 3 Grade 4 Grade 5 Grade 3 Grade 4 Grade 5
Diarrhoea 561 (39·8) 1 (0·1) 0 23 (1·6) 0 0
Vomiting 47 (3·3) 0 0 5 (0·4) 0 0
Nausea 26 (1·8) 0 0 2 (0·1) 0 0
Abdominal pain 24 (1·7) 0 0 3 (0·2) 0 0
Fatigue 23 (1·6) 0 0 6 (0·4) 0 0
Alanine aminotransferase increased 15 (1·1) 3 (0·2) 0 3 (0·2) 0 0
Dehydration 12 (0·9) 1 (0·1) 0 1 (0·1) 0 0
Abdominal pain upper 11 (0·8) 0 0 3 (0·2) 0 0
Syncope 10 (0·7) 0 0 4 (0·3) 0 0
Headache 8 (0·6) 0 0 6 (0·4) 0 0
Aspartate aminotransferase increased 7 (0·5) 3 (0·2) 0 4 (0·3) 0 0
Asthenia 6 (0·4) 0 0 1 (0·1) 0 0
Cellulitis 6 (0·4) 0 0 3 (0·2) 0 0
Dyspepsia 6 (0·4) 0 0 0 0 0
Electrocardiogram QT prolonged 5 (0·4) 0 0 7 (0·5) 0 0
Erysipelas 5 (0·4) 0 0 0 0 0
Hyponatraemia 5 (0·4) 0 0 5 (0·4) 2 (0·1) 0
Rash 5 (0·4) 0 0 0 0 0
Abdominal distension 4 (0·3) 0 0 0 0 0
Ejection fraction decreased 4 (0·3) 0 0 2 (0·1) 0 0
Hypermagnesaemia 4 (0·3) 0 0 0 0 0
Hypokalaemia 4 (0·3) 1 (0·1) 0 5 (0·4) 0 0
Hypophosphataemia 4 (0·3) 0 0 4 (0·3) 0 0
Lymphopenia 4 (0·3) 0 0 3 (0·2) 0 0
Stomatitis 4 (0·3) 0 0 1 (0·1) 0 0
Decreased appetite 3 (0·2) 0 0 0 0 0
Dizziness 3 (0·2) 0 0 3 (0·2) 0 0
Herpes zoster 3 (0·2) 0 0 1 (0·1) 0 0
Malaise 3 (0·2) 0 0 1 (0·1) 0 0
Mucosal inflammation 3 (0·2) 0 0 0 0 0
Paronychia 3 (0·2) 0 0 0 0 0
Renal failure 3 (0·2) 0 0 0 0 0
Renal failure acute 3 (0·2) 0 0 0 0 0
Anaemia 2 (0·1) 1 (0·1) 0 0 1 (0·1) 0
Arthralgia 2 (0·1) 0 0 4 (0·3) 0 0
Bronchitis 2 (0·1) 0 0 1 (0·1) 0 0
Cholelithiasis 2 (0·1) 0 0 0 0 0
Depression 2 (0·1) 0 0 5 (0·4) 1 (0·1) 0
Dermatitis acneiform 2 (0·1) 0 0 0 0 0
Gamma-glutamyltransferase increased 2 (0·1) 0 0 2 (0·1) 0 0
Gastroenteritis 2 (0·1) 0 0 1 (0·1) 0 0
Hyperglycaemia 2 (0·1) 0 0 4 (0·3) 0 0
Hyperkalaemia 2 (0·1) 0 0 1 (0·1) 0 0
Hypertension 2 (0·1) 0 0 6 (0·4) 0 0
Hypotension 2 (0·1) 0 0 0 0 0
Migraine 2 (0·1) 0 0 0 0 0
Non-cardiac chest pain 2 (0·1) 0 0 0 0 0
Pain 2 (0·1) 0 0 0 0 0
Pulmonary embolism 2 (0·1) 1 (0·1) 0 3 (0·2) 0 0
Skin fissures 2 (0·1) 0 0 0 0 0
Vertigo 2 (0·1) 0 0 1 (0·1) 1 (0·1) 0
Abdominal abscess 1 (0·1) 0 0 0 0 0
Abdominal strangulated hernia 1 (0·1) 0 0 0 0 0
18
Preferred Term
Neratinib (N =1408) Placebo (N =1408)
Grade 3 Grade 4 Grade 5 Grade 3 Grade 4 Grade 5
Amylase increased 1 (0·1) 0 0 0 1 (0·1) 0
Angina pectoris 1 (0·1) 0 0 0 0 0
Ankle fracture 1 (0·1) 0 0 1 (0·1) 0 0
Anorectal cellulitis 1 (0·1) 0 0 0 0 0
Anorectal discomfort 1 (0·1) 0 0 0 0 0
Anosmia 1 (0·1) 0 0 0 0 0
Appendicitis 1 (0·1) 0 0 1 (0·1) 0 0
Appendicitis perforated 1 (0·1) 0 0 0 0 0
Basal cell carcinoma 1 (0·1) 0 0 1 (0·1) 0 0
Benign female reproductive tract
neoplasm 1 (0·1) 0 0 0 0 0
Blood alkaline phosphatase increased 1 (0·1) 0 0 0 0 0
Blood creatine phosphokinase increased 1 (0·1) 0 0 0 0 0
Blood creatinine increased 1 (0·1) 1 (0·1) 0 0 0 0
Blood lactate dehydrogenase increased 1 (0·1) 0 0 1 (0·1) 0 0
Blood urea increased 1 (0·1) 0 0 0 0 0
Breast cellulitis 1 (0·1) 0 0 1 (0·1) 0 0
Cancer pain 1 (0·1) 0 0 0 0 0
Carbohydrate antigen 27·29 increased 1 (0·1) 0 0 0 0 0
Cholecystitis 1 (0·1) 0 0 0 0 0
Dermatitis 1 (0·1) 0 0 0 0 0
Dermatitis contact 1 (0·1) 0 0 0 0 0
Device related infection 1 (0·1) 0 0 3 (0·2) 0 0
Dry mouth 1 (0·1) 0 0 0 0 0
Dysgeusia 1 (0·1) 0 0 0 0 0
Dyspnoea 1 (0·1) 0 0 2 (0·1) 0 0
Dysuria 1 (0·1) 0 0 0 0 0
Enterocele 1 (0·1) 0 0 0 0 0
Escherichia urinary tract infection 1 (0·1) 0 0 0 0 0
Facial neuralgia 1 (0·1) 0 0 0 0 0
Faecal incontinence 1 (0·1) 0 0 0 0 0
Flatulence 1 (0·1) 0 0 1 (0·1) 0 0
Flushing 1 (0·1) 0 0 0 0 0
Food poisoning 1 (0·1) 0 0 0 0 0
Fracture 1 (0·1) 0 0 0 0 0
Fungal infection 1 (0·1) 0 0 0 0 0
Furuncle 1 (0·1) 0 0 0 0 0
Gastric disorder 1 (0·1) 0 0 0 0 0
Gastroenteritis salmonella 1 (0·1) 0 0 0 0 0
Gastrointestinal inflammation 1 (0·1) 0 0 0 0 0
Gastrointestinal pain 1 (0·1) 0 0 0 0 0
Gastrointestinal viral infection 1 (0·1) 0 0 0 0 0
Glioblastoma 1 (0·1) 0 0 0 0 0
Glossodynia 1 (0·1) 0 0 0 0 0
Haemoglobin decreased 1 (0·1) 0 0 0 0 0
Hepatic enzyme increased 1 (0·1) 0 0 0 0 0
Hepatotoxicity 1 (0·1) 0 0 0 0 0
Hot flush 1 (0·1) 0 0 1 (0·1) 0 0
Hypertriglyceridaemia 1 (0·1) 0 0 1 (0·1) 0 0
Hypoglycaemia 1 (0·1) 0 0 1 (0·1) 1 (0·1) 0
Inflammation 1 (0·1) 0 0 0 0 0
Influenza 1 (0·1) 0 0 1 (0·1) 0 0
International normalised ratio increased 1 (0·1) 0 0 0 0 0
Joint effusion 1 (0·1) 0 0 0 0 0
Laryngitis 1 (0·1) 0 0 0 0 0
Left ventricular dysfunction 1 (0·1) 0 0 0 0 0
19
Preferred Term
Neratinib (N =1408) Placebo (N =1408)
Grade 3 Grade 4 Grade 5 Grade 3 Grade 4 Grade 5
Lethargy 1 (0·1) 0 0 0 0 0
Lipase increased 1 (0·1) 0 0 0 0 0
Liver function test abnormal 1 (0·1) 0 0 0 0 0
Malignant pleural effusion 1 (0·1) 0 0 0 0 0
Menstruation irregular 1 (0·1) 0 0 0 0 0
Mental status changes 1 (0·1) 0 0 0 0 0
Mouth ulceration 1 (0·1) 0 0 0 0 0
Muscle spasms 1 (0·1) 0 0 1 (0·1) 0 0
Musculoskeletal pain 1 (0·1) 0 0 3 (0·2) 0 0
Myocardial infarction 1 (0·1) 1 (0·1) 0 0 0 0
Myocardial ischaemia 1 (0·1) 0 0 0 0 0
Nail disorder 1 (0·1) 0 0 0 0 0
Neuropathy peripheral 1 (0·1) 0 0 2 (0·1) 0 0
Oedema peripheral 1 (0·1) 0 0 0 0 0
Ophthalmic herpes zoster 1 (0·1) 0 0 0 0 0
Osteoarthritis 1 (0·1) 0 0 1 (0·1) 0 0
Osteoporosis 1 (0·1) 0 0 0 0 0
Palpitations 1 (0·1) 0 0 0 0 0
Pancreatitis 1 (0·1) 0 0 0 0 0
Panniculitis 1 (0·1) 0 0 0 0 0
Paresis 1 (0·1) 0 0 0 0 0
Periodontal disease 1 (0·1) 0 0 0 0 0
Peripheral ischaemia 1 (0·1) 0 0 0 0 0
Pleural effusion 1 (0·1) 0 0 1 (0·1) 0 0
Pneumothorax 1 (0·1) 0 0 0 0 0
Pollakiuria 1 (0·1) 0 0 0 0 0
Procedural complication 1 (0·1) 0 0 0 0 0
Procedural pain 1 (0·1) 0 0 1 (0·1) 0 0
Pruritus 1 (0·1) 0 0 1 (0·1) 0 0
Rectal abscess 1 (0·1) 0 0 0 0 0
Renal colic 1 (0·1) 0 0 0 0 0
Skin necrosis 1 (0·1) 0 0 1 (0·1) 0 0
Staphylococcal infection 1 (0·1) 0 0 0 0 0
Staphylococcus test positive 1 (0·1) 0 0 0 0 0
Streptococcal sepsis 1 (0·1) 0 0 0 0 0
Tattoo 1 (0·1) 0 0 0 0 0
Thrombocytopenia 1 (0·1) 0 0 0 0 0
Tooth disorder 1 (0·1) 0 0 0 0 0
Urinary tract infection 1 (0·1) 0 0 0 0 0
Urticaria 1 (0·1) 0 0 0 0 0
Viral infection 1 (0·1) 0 0 0 0 0
Weight decreased 1 (0·1) 0 0 0 0 0
Wound dehiscence 1 (0·1) 0 0 1 (0·1) 0 0
Wrist fracture 1 (0·1) 0 0 0 0 0
Abdominal wall abscess 0 0 0 1 (0·1) 0 0
Acute myeloid leukaemia 0 0 1 (0·1) 0 0 0
Amnesia 0 0 0 1 (0·1) 0 0
Anxiety 0 0 0 3 (0·2) 0 0
Atrial fibrillation 0 0 0 1 (0·1) 0 0
Back pain 0 0 0 5 (0·4) 0 0
Benign breast neoplasm 0 0 0 1 (0·1) 0 0
Bladder prolapse 0 0 0 1 (0·1) 0 0
Blood creatine increased 0 1 (0·1) 0 0 0 0
Blood phosphorus decreased 0 0 0 1 (0·1) 0 0
Blood pressure increased 0 0 0 2 (0·1) 0 0
Bradyphrenia 0 0 0 1 (0·1) 0 0
20
Preferred Term
Neratinib (N =1408) Placebo (N =1408)
Grade 3 Grade 4 Grade 5 Grade 3 Grade 4 Grade 5
Brain oedema 0 0 0 0 1 (0·1) 0
Breast abscess 0 0 0 1 (0·1) 0 0
Breast cancer 0 0 0 0 2 (0·1) 0
Breast cancer metastatic 0 0 1 (0·1) 0 0 0
Breast neoplasm 0 0 0 1 (0·1) 0 0
Cardiac function test abnormal 0 0 0 1 (0·1) 0 0
Cardiac tamponade 0 0 0 1 (0·1) 0 0
Cartilage injury 0 0 0 1 (0·1) 0 0
Cerebrovascular accident 0 0 0 0 1 (0·1) 0
Colitis 0 0 0 1 (0·1) 0 0
Colitis ischaemic 0 0 0 1 (0·1) 0 0
Constipation 0 0 0 2 (0·1) 0 0
Cough 0 0 0 2 (0·1) 0 0
Cyst 0 0 0 1 (0·1) 0 0
Cystitis 0 0 0 1 (0·1) 0 0
Deep vein thrombosis 0 0 0 1 (0·1) 0 0
Dental caries 0 0 0 1 (0·1) 0 0
Diabetes mellitus 0 0 0 1 (0·1) 0 0
Disturbance in attention 0 0 0 1 (0·1) 0 0
Diverticulitis 0 0 0 1 (0·1) 0 0
Endometrial hyperplasia 0 0 0 1 (0·1) 0 0
Epistaxis 0 0 0 1 (0·1) 0 0
Erythema multiforme 0 0 0 1 (0·1) 0 0
Fall 0 0 0 1 (0·1) 0 0
Food allergy 0 0 0 0 1 (0·1) 0
Gastric cancer 0 0 0 0 0 1 (0·1)
Glioma 0 1 (0·1) 0 0 0 0
Hepatic function abnormal 0 0 0 0 1 (0·1) 0
Hip fracture 0 0 0 1 (0·1) 0 0
Humerus fracture 0 0 0 1 (0·1) 0 0
Hyperbilirubinaemia 0 0 0 1 (0·1) 0 0
Hyperhidrosis 0 0 0 2 (0·1) 0 0
Hypernatraemia 0 1 (0·1) 0 0 0 0
Hyperuricosuria 0 1 (0·1) 0 0 0 0
Hypomagnesaemia 0 0 0 1 (0·1) 0 0
Hysterosalpingo-oophorectomy 0 0 0 1 (0·1) 0 0
Incision site cellulitis 0 0 0 1 (0·1) 0 0
Insomnia 0 0 0 2 (0·1) 0 0
Iritis 0 0 0 1 (0·1) 0 0
Jaundice cholestatic 0 0 0 0 1 (0·1) 0
Laceration 0 0 0 1 (0·1) 0 0
Lumbar spinal stenosis 0 0 0 1 (0·1) 0 0
Lung adenocarcinoma 0 0 0 1 (0·1) 0 0
Mastitis 0 0 0 1 (0·1) 0 0
Menorrhagia 0 0 0 1 (0·1) 0 0
Metastases to eye 0 0 0 0 1 (0·1) 0
Metastases to meninges 0 0 1 (0·1) 0 0 0
Metrorrhagia 0 0 0 1 (0·1) 0 0
Motor dysfunction 0 0 0 1 (0·1) 0 0
Multiple injuries 0 1 (0·1) 0 0 0 0
Muscular weakness 0 0 0 1 (0·1) 0 0
Myalgia 0 0 0 1 (0·1) 0 0
Neck pain 0 0 0 1 (0·1) 0 0
Neutropenia 0 1 (0·1) 0 2 (0·1) 0 0
Neutrophil count decreased 0 0 0 1 (0·1) 0 0
Pain in extremity 0 0 0 2 (0·1) 0 0
21
Preferred Term
Neratinib (N =1408) Placebo (N =1408)
Grade 3 Grade 4 Grade 5 Grade 3 Grade 4 Grade 5
Patella fracture 0 0 0 1 (0·1) 0 0
Pelvic pain 0 0 0 1 (0·1) 0 0
Peripheral sensory neuropathy 0 0 0 1 (0·1) 0 0
Pneumonia 0 0 0 3 (0·2) 0 0
Postoperative wound complication 0 0 0 1 (0·1) 0 0
Rectal cancer 0 1 (0·1) 0 0 0 0
Sarcoma uterus 0 0 0 0 1 (0·1) 0
Septic shock 0 0 0 0 1 (0·1) 0
Seroma 0 0 0 1 (0·1) 0 0
Tachycardia 0 0 0 1 (0·1) 0 0
Thermal burn 0 0 0 1 (0·1) 0 0
Tibia fracture 0 0 0 1 (0·1) 0 0
Tooth abscess 0 0 0 2 (0·1) 0 0
Tooth infection 0 0 0 1 (0·1) 0 0
Transient ischaemic attack 0 0 0 1 (0·1) 0 0
Tremor 0 0 0 1 (0·1) 0 0
Uterine leiomyoma 0 0 0 1 (0·1) 0 0
Vascular neoplasm 0 0 0 1 (0·1) 0 0
Weight increased 0 0 0 1 (0·1) 0 0
Wound complication 0 0 0 1 (0·1) 0 0
Data are n (%).
22
Table S5. Summary of Treatment-Emergent Diarrhea in the ExteNET Study (Safety Population) and
Study 5201.*
This table provides details of treatment-emergent diarrhea in the ExteNET study, which occurred without
implementation of an antidiarrheal prophylactic regimen. In ExteNET, no antidiarrheal prophylaxis was
stipulated in the study protocol, but rather treatment for diarrhea was recommended after symptoms had
developed. Since the ExteNET treatment phase was completed, an antidiarrheal prophylactic regimen has been
implemented in all subsequent studies of neratinib using high-dose loperamide given with the first dose of
neratinib and continuing for the entire first cycle of neratinib treatment.† For the purpose of illustrating how
loperamide prophylaxis reduces neratinib-related diarrhea (compared with ExteNET), this table also includes
the safety data from a study of neratinib monotherapy in patients with metastatic cancer (Study 5201) which
included this antidiarrheal prophylactic regimen.
Variable
ExteNET Study 5201†
Neratinib
(N = 1408)
Placebo
(N = 1408)
Neratinib
(N=97)
Patients ever experienced treatment-emergent diarrhea – no. (%) 1343 (95·4) 499 (35·4) 62 (63·9)
Maximum toxicity – no. (%)
Grade 1 323 (22·9) 382 (27·1) 24 (24·7)
Grade 2 458 (32·5) 94 (6·7) 23 (23·7)
Grade 3 561 (39·8) 23 (1·6) 15 (15·5)
Grade 4 1 (0·1) 0 0
Drug-related diarrhea – no. (%) 1330 (94·5) 411 (29·2) 59 (60·8)
Serious events – no. (%) 22 (1·6) 1 (0·1) 7 (7·2)
Actions taken due to diarrhea – no. (%)
Withdrawn from study 23 (1·6) 0 0
Discontinued study drug 237 (16·8) 3 (0·2) 2 (2·1)
Dose reduction 372 (26·4) 8 (0·6) 1 (1·0)
Hospitalized 20 (1·4) 1 (0·1) 0
Dose hold
Once 263 (18·7) 22 (1·6) 8 (8·2)
Twice 97 (6·9) 2 (0·1) 1 (1·0)
Three or more times 117 (8·3) 2 (0·1) 2 (2·1)
Median (IQR) time to onset of diarrhea – days
Any grade 2 (2–4) 18 (4–82) 7 (3-14)
Grade ≥2 5 (2–15) 90 (17–189) 10·5 (6-38)
Grade ≥3 8 (4–33) 124 (21–257) 8 (6-24)
Duration of grade ≥3 diarrhea per patient – days
Median (IQR) 5 (2–9) 2 (1–5) 5 (2-11)
Grade ≥3 events per patient – no.
Mean 2·7 1·3 1·8
Median (IQR) 2 (1–3) 1 (1–1) 1 (1-2)
Median (IQR) duration of diarrhea per event – days
Any grade 2 (1–3) 2 (1–3) 2 (1-3)
Grade ≥2 1 (1–2) 2 (1–2) 2 (1-4)
Grade ≥3 2 (1–3) 2 (1–4) 2 (1-7)
*A treatment-emergent adverse event is any adverse event that occurs or worsens on or after the first dose of investigational product and
up to 28 days after the last dose.
†Included mandatory prophylaxis for diarrhea using the following regimen: loperamide 4 mg with the first dose of neratinib, then 2 mg
every 4 hours for the first 3 days, then 2 mg every 6-8 hours for the remainder of cycle 1.
23
Table S6. Summary of Study Sites, Principle Investigators Responsible for Each Site and the Number
of Patients Enrolled from Each Site
Principle investigator(s) Investigational site Country Patients
randomized, n
Arlene Chan Mount Hospital, Perth Australia 46
Vernon Harvey Auckland Hospital, Auckland New Zealand 31
Tajana Silovski; Robert Separovic;
Rudolf Tomek Klinika Za Tumore, Zagreb Croatia 29
Erhan Gokmen Ege University, Izmir Turkey 29
Nicholas J. Robert Virginia Cancer Specialists, Fairfax USA 29
Ira Gore Jr. Alabama Oncology, Birmingham USA 26
Suzette Delaloge Institut Gustave Roussy, Villejuif France 25
John W. Smith II Northwest Cancer Specialists, PC, Vancouver USA 25
Norikazu Masuda National Hospital Organization Osaka National Hospital, Osaka
Japan 23
S. Di Sean Kendall; William Graydon
Harker Utah Cancer Specialists, Utah USA 23
Katarina Petrakova Masarykuv Onkologicky ustav, Brno Czech Republic 22
Amparo Ruiz Simon; Angel Guerrero Zotano
Instituto Valenciano de Oncologia, Valencia Spain 22
Zorica Tomasevic; Zora Neskovic
Konstantinovic
Institute of Oncology and Radiology of Serbia,
Belgrade Serbia 22
Nicholas O. Iannotti Hematology Oncology Associates of Treasure Coast,
Port Saint Lucie USA 21
Erik Hugger Jakobsen Vejle Sygehus, Velje Denmark 20
Pierfrancesco Tassone Tommaso Campanella Cancer Center, Catanzaro Italy 20
Gladys I. Rodriguez South Texas Oncology and Hematology, San Antonio USA 20
Anil Abrahma Joy Cross Cancer Institute, Edmonton Canada 19
Noelia Martinez; Carmen Crespo Hospital Universitario Ramon y Cajal, Madrid Spain 19
Sung-Bae Kim Asan Medical Center, Seoul Korea 19
Snezana Smickoska University Clinic for Radiotherapy and Oncology,
Skopje Macedonia 19
Isil Somali; Ugur Yilmaz Dokuz Eylul Universitesi Tip Fakultesi, Izmir Turkey 19
Friedrich Overkamp Oncologianova GmbH, Recklinghausen Germany 18
Mirta Garcia Alonso; Adolfo Murias Rosales
Compejo Hospitalario Materno Insular de Las Palmas Spain 18
Audrone Ciceniene Oncology Institute of Vilnius University, Vilnius Lithuania 18
Soeren Cold; Ann Soegaard Knoop Odense University Hospital, Odense Denmark 17
Beth A. Hellerstedt Texas Oncology, PA, Austin USA 17
Serafin Morales Murillo Hospital Universitari Arnau de Vilanova de Lleida, Lleida
Spain 16
John S. Link Breastlink Medical Group Inc, Long Beach USA 16
Ingrid A. Mayer; Julie Ann Means-Powell
Vanderbilt-Ingram Cancer Center, Nashville USA 16
Rina Hui Sydney West Cancer Trials Centre, Westmead Australia 15
Manuel Ruiz Borrego Hospital Universitario Virgen del Rocio, Sevilla Spain 15
Miguel Martin Jimenez Hospital General Universitario Gregorio Maranon,
Madrid Spain 15
Kenichi Inoue Saitama Cancer Center, Saitama Japan 15
Francis M. Senecal Northwest Medical Specialties PLLC, Tacoma USA 15
Richard Hendry De Boer Royal Melbourne Hospital, Melbourne Australia 14
Zhenzhou Shen Fudan University Cancer Hospital, Shanghai China 14
Adam Andrzej Luczak Aalborg Sygehus, Aalborg Denmark 14
Anne Armstrong Christie Hospital, Manchester UK 14
Janice Wing-hang Tsang Queen Mary Hospital, Hong Kong Hong Kong 14
Istvan Lang Orszagos Onkologiai Intezet "B" Belgyogyaszati osztaly, Budapest
Hungary 14
Yoshiaki Rai Hakuaikai Medical Corporation Sagara Hospital,
Kagoshima Japan 14
Yasuo Hozumi Jichi Medical University Hospital, Tochigi Japan 14
Albert J. Ten Tije Amphia Ziekenhuis, Breda Netherlands 14
24
Principle investigator(s) Investigational site Country Patients
randomized, n
Manish Bhandari Christ Hospital of Cincinnati, Cincinnati USA 14
Cynthia R.C. Osborne Texas Oncology, PA, Dallas USA 14
Shoichiro Ohtani; Kenji Higaki Hiroshima City Hospital, Hiroshima Japan 13
Kenichi Watanabe; Kazunori Taguchi;
Masato Takahashi
National Hospital Organization Hokkaido Cancer
Center, Hokkaido Japan 13
Sladjana Filipovic Clinical Centre Nis, Nis Serbia 13
Vincent L. Hansen North Utah Associates, Ogden USA 13
Beverly Moy Dana Farber Cancer Institute, Boston USA 13
Vijayarama Phooshkooru Rao Mid Dakota Clinic PC, Bismarck USA 13
Manish Gupta Texas Oncology, PA, Garland USA 13
Petar Petrov District Dispensary for Oncology Diseases Internal
Unit, Plovdiv Bulgaria 12
Bruno Coudert Centre Georges Francois Leclerc, Dijon France 12
Zeljko Vojnovic General Hospital Varazdin, Varazdin Croatia 12
Zsofia Polya Jósa András Oktatókórház Egészségügyi Szolgáltató,
Nyiregyhaza Hungary 12
Naohito Yamamoto Chiba Cancer Center, Chiba Japan 12
Stephen Brincat Sir Paul Boffa Hospital, Floriana Malta 12
Krzysztof Lesniewski-Kmak Samodzielny Publiczny Zaklad Opieki Zdrowotnej
Szpital Uniwersytecki w Krakowie, Krakow Poland 12
Ewa Chmielowska Centrum Onkologii im. Prof. Franciszka, Bydgoszcz Poland 12
Ruemu E. Birhiray Hematology Oncology of Indiana, Indianapolis USA 12
Marc L. Citron ProHealth Care Associates, Lake Success USA 12
Steven William Papish Hematology and Oncology Associates of Northern New Jersey, Morristown
USA 12
William R. Berry Raleigh Hematology Oncology Associates, PC,
Raleigh USA 12
Sven Tyge Langkjer Aarhus University Hospital, Aarhus Denmark 11
Jose Angel Garcia Saenz Hospital Clinico San Carlos, Madrid Spain 11
Ana Maria Arance Hospital Clinic i Provincial de Barcelona, Barcelona Spain 11
Noa Efrat Kaplan Medical Center, Rehovot Israel 11
Tomasz Sarosiek Centrum Medyczne Ostrobramska Niepubliczny,
Warsaw Poland 11
Yvonne Manalo Coastal Bend Cancer Center, Corpus Christi USA 11
Julie C. Smith Wenatchee Valley Medical Center, Wenatchee USA 11
Irfan Vaziri Great Plains Regional Medical Center, North Platte USA 11
Beverly Moy Massachusetts General Hospital, Boston USA 11
Tabitha Healey North Adelaide Oncology, North Adelaide Australia 10
Yasmin Rahim; Cynthia Luk Southlake Regional Health Centre, Newmarket Canada 10
Brian Dingle London Regional Cancer Program, London Canada 10
Sandra Franco Administradora Country SA, Bogota Colombia 10
Peter Grundtvig Sorensen Herlev Hospital, Herlev Denmark 10
Anjana Anand; Sarah Khan Nottingham City Hospital, Nottingham UK 10
George Fountzilas Papageorgiou General Peripheral Hospital of Thessaloniki, Thessaloniki
Greece 10
Kenjiro Aogi National Hospital Organization Shikoku Cancer
Center, Ehime Japan 10
Satoru Shimizu Kanagawa Cancer Center, Kanagawa Japan 10
Stanislav Spanik Interna onkologicka klinika, Bratislava Slovakia 10
Robert A. Somer Cooper University Hospital, Voorhees USA 10
Patrick J. Flynn Minnesota Oncology Hematology, PA, Minneapolis USA 10
Paul Mainwaring Mater Adult Hospital, South Brisbane Australia 9
Guy Jerusalem Centre Hospitalier Universitaire de Liege, Liege Belgium 9
Bent Ejlertsen Rigshospitalet, Copenhagen Denmark 9
Carine Segura-Djezzar; Christelle Levy;
Thierry Delozier Centre Francois Baclesse, Caen France 9
David Khayat Hopital Pitie-Salpetriere, Paris France 9
Robert E. Coleman Weston Park Hospital, Sheffield UK 9
Martin J. Rolles Singleton Hospital, Swansea UK 9
25
Principle investigator(s) Investigational site Country Patients
randomized, n
Janine Mansi Guy's Hospital, London UK 9
Robert Maisano; Mario Nardi Azienda Opsedaliera Bianchi Melacrino Morelli,
Reggio Calabria Italy 9
Yoshinori Ito Cancer Institute Hospital of Japanese Foundation for
Cancer Research, Tokyo Japan 9
Perran Fulden Yumuk; Gul Basaran; Nazim Serdar Turhal
Marmara University, Istanbul Turkey 9
Mary J. Wilkinson Medical Oncology & Hematology Associates of
Northern Virginia, Fairfax USA 9
Nathan B. Green Southeast Nebraska Hematology & Oncology
Consultants, PC, Lincoln USA 9
Algis P. Sidrys Cookeville Regional Cancer Center, Cookeville USA 9
Sigrun Hallmeyer Oncology Specialists, SC, Park Ridge USA 9
Douglas J. Testori Hanover Medical Specialists, PA, Wilmington USA 9
Srikala Sridhar Princess Margaret Hospital, Toronto Canada 8
Jose Chang Lakeridge Health Oshawa, Oshawa Canada 8
Qiang Sun Peking Union Medical College Hospital, Beijing China 8
Carlos Jara Sanchez; Xabier Rubio Hospital Universitario Fundacion de Alcorcon,
Madrid Spain 8
Maria Lomas Garrido Complejo Hospitalario de Jaen, Jaan Spain 8
Juan Rafael De La Haba Rodriguez Hospital Universitario Reina Sofia, Cordoba Spain 8
Antoni Avelia Mestre; Julio Rifa Ferrer Hospital Universitario Son Espases, Palma de Mallorca
Spain 8
Sonia del Barco Berron ICO de Girona - Hospital Universitario de Girona Dr.
Josep Trueta, Girona Spain 8
Zsuzsanna Nagy Fovarosi Onkormanyzat Szent Imre Korhaz,
Budapest Hungary 8
Maki Tanaka Kurume Daiichi Social Insurance Hospital, Fukuoka Japan 8
Young-Hyuck Im Samsung Medical Center, Seoul Korea 8
Robert R. Carroll; Laura C. Dickerson Florida Cancer Specialists & Research Institute, Gainesville
USA 8
Joseph R. Mace Gulfcoast Oncology Associates, St Petersburg USA 8
Ragene Rivera El Paso Cancer Treatment Center - West, El Paso USA 8
Leonard M. Klein Cancer Care & Hematology Specialists of
Chicagoland, Niles USA 8
Robert Ruxer Texas Oncology PA, Fort Worth USA 8
Sharon T. Wilks Cancer Care Centers of South Texas, San Antonio USA 8
Dusan Kotasek Adelaide Cancer Centre Research, Adelaide Australia 7
Violina Taskova Interdistrict Dispensary for Oncology Diseases,
Varna Bulgaria 7
Constanta Timcheva Specialised Hospital of Active Treatment in Oncology, Sofia
Bulgaria 7
Christine Desbiens Centre Hospitalier Affilie Universitaire de Quebec,
Qubec Canada 7
Jean-Pierre Ayoub CHUM Hôpital Notre-Dame, Montreal Canada 7
Debjani Grenier CancerCare Manitoba, Winnipeg Canada 7
Norbert Marschner Praxis für interdisziplinaere Onkologie &
Haematologie GbR, Freiburg Germany 7
Hans Tesch Onkologische Gemeinschaftspraxis Frankfurt, Frankfurt am Main
Germany 7
Hans-Joachim Lueck Fachpraxis fuer Frauenheilkunde, Hannover Germany 7
Jan Janssen Gemeinschaftspraxis fuer Haematologie und Onkologie, Westerstede
Germany 7
Ingo Schwaner Onkologische Schwerpunktpraxis, Berlin Germany 7
Eva Harder Brix Hillerod Hospital, Hillerod Denmark 7
Susanne Vallentin; Dan Kristensen;
Anna Andreeva; Vesna Glavicic Næstved Sygehus, Onkologisk Afdeling, Næstved Denmark 7
Isabel Calvo Plaza Hospital de Madrid Norte-Sanchinarro, Madrid Spain 7
Antonio Anton Torres Hospital Universitario Miguel Servet, Zaragoza Spain 7
Corinne Veyret Centre Henri Becquerel, Rouen France 7
Jean-Pierre Bergerat Centre Hospitalier Universitaire Strasbourg,
Strasbourg France 7
26
Principle investigator(s) Investigational site Country Patients
randomized, n
Emmanuelle Bourbouloux Centre Rene Gauducheau, Saint-Herblain France 7
Wendy Ann Ella; Hafiz Algurafi; Anne
Robinson Southend University Hospital, Westcliffe-on-Sea UK 7
Hiroji Iwata Aichi Cancer Center, Nagoya Japan 7
Seung Jin Kim; Tetsuya Taguchi Osaka University Hospital, Osaka Japan 7
Elona Juozaityte Kaunas University of Medicine Hospital, Kaunas Lithuania 7
Stanley Madretsma; Sandra Radema Gelre ZH, Apeldoorn Netherlands 7
Wojciech Rogowski Zaklad Opieki Zdrowotnej MSWiA z Warminsko, Olsztyn
Poland 7
Maria Wagnerova Oddelenie radioterapie a onkologie, Kosice Slovakia 7
Donald A. Richards Texas Oncology, PA, Tyler USA 7
Elizabeth Tan-Chiu Florida Cancer Research Institute, Plantation USA 7
Charles Arthur Henderson Peachtree Hematology Oncology Consultants, PC, Atlanta
USA 7
Viran Roger Holden St. John's Medical Research Institute Inc, Springfield USA 7
Xiaojia Wang Zhejiang Cancer Hospital, Hangzhou China 6
Zhongsheng Tong Tianjin Cancer Hospital, Tianjin China 6
Junlan Yang Chinese People's Liberation Army General Hospital,
Beijing China 6
Manuel Enrique Gonzalez Oncomedica SA IMAT, Cordoba Colombia 6
Gunter von Minckwitz Luisenkrankenhaus, Duesseldorf Germany 6
John Hackmann Marienhospital Witten, Witten Germany 6
Eduardo Martinez de Dueñas Consorcio Hospitalario Provincial de Castellon,
Castellon Spain 6
Begoña Bermejo de las Heras Hospital Clinico Universitario de Valencia, Valencia Spain 6
Louis Marie Dourthe Clinique Sainte Anne, Strasbourg France 6
Philippe Bougnoux Centre Hospitalier Universitaire Bretonneau, Tours France 6
Stylianos Kakolyris University Hospital of Alexandroupoli,
Alexandroupoli Greece 6
Haralabos Kalofonos University General Hospital of Patras, Patras Greece 6
Dimitrios Pectasidis University General Hospital "ATTIKON", Athens Greece 6
Ting Ying Ng Tuen Mun Hospital, Hong Kong Hong Kong 6
Gabor Pajkos Bacs-Kiskun Megyei Korhaz, Onkoradiologiai
kozpont, Kecskemet Hungary 6
Eva Ezer Somogyine Kaposi Mor Oktato Korhaz, Kaposvar Hungary 6
Giuseppe Tonini Universita Campus Bio-Medico, Rome Italy 6
Dario Giuffrida Istituto Oncologico del Mediterraneo, Viagrande Italy 6
Shintaro Takao Hyogo Cancer Center, Hyogo Japan 6
Makoto Ishitobi; Hideo Inaji Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka
Japan 6
Yutaka Tokuda Tokai University Hospital, Kanagawa Japan 6
Katarzyna Wozniak Samodzielny Publiczny Zaklad Opieki Zdrowotnej Szpital Wojewodzki Oddzial, Jelenia Gora
Poland 6
Dan Lungulescu SC Oncolab SRL, Dolj Romania 6
Yen-Shen Lu; King-Jen Chang National Taiwan University Hospital, Taipei Taiwan 6
Christopher Charles Croot North Mississippi Hematology and Oncology
Associates, Ltd, Tupelo USA 6
Albert Dekker Facey Medical Foundation, Mission Hills USA 6
Neil D. Belman Oncology-Hematology of Lehigh Valley, PC,
Bethlehem USA 6
Richard A. Michaelson Saint Barnabas Medical Center, Livingston USA 6
Kathleen Kemmer; Stephen Chui;
Shiuh-Wen Luoh
Oregon Health and Science University, Cancer
Institute, Portland USA 6
Kenneth Nahum Jersey Shore University Medical Center, Neptune USA 6
Frankie Ann Holmes Texas Oncology, PA, Houston USA 6
Andrew R. Greenspan Central Indiana Cancer Centers, Indianapolis USA 6
Joni C. Nichols Cancer Care Northwest-North, Spokane USA 6
Carlos A. Encarnacion Texas Oncology, PA, Waco USA 6
Thomas M.J. Niederman University Cancer Institute, LLC USA 6
27
Principle investigator(s) Investigational site Country Patients
randomized, n
Roland Alexander; Robert Gordon PinnacleHealth Hematology Oncology Associates,
Harrisburg USA 6
Antoanet Tomova District Dispensary for Oncology Diseases Internal Unit, Plovdiv
Bulgaria 5
Daniel Rauch Spital STS AG, Thun Switzerland 5
Razvan Andrei Popescu Hirslanden Medical Center, Aarau Switzerland 5
Gustavo Adolfo Rojas Oncologos del Occidente, Pereira Colombia 5
Jaroslav Vanasek Pardubicka Krajska Nemocnice, Pardubice Czech Republic 5
Tanja Neunhoeffer; Jana Barinoff Dr. Horst Schmidt Klinik GmbH, Wiesbaden Germany 5
Gerd Graffunder Frauenarzt-Zentrum-Zehlendorf, Berlin Germany 5
Peter Bojko Fachpraxis fuer Innere Medizin Elisenhof, Muenchen
Germany 5
Bernhard Heinrich Onkologische Praxis, Augsburg Germany 5
Albert von der Assen Niels-Stensen-Kliniken, Georgsmarienhuette Germany 5
Lene Adrian Onkologisk Ambulatorium, Sonerborg Denmark 5
Manuel Ramos Vazquez Centro Oncologico de Galicia, A Coruna Spain 5
Santiago Gonzalez Santiago Hospital San Pedro de Alcantara, Caceres Spain 5
Veronique Dieras Institut Curie, Paris France 5
Jill Mercia Bishop North West Cancer Treatment Centre, Bodelwydan UK 5
Timothy John Perren St James's University Hospital, Leeds UK 5
Ioannis Varthalitis General Hospital of Chania Ag. Georgios, Chania Greece 5
Vassilis Georgoulias University Hospital of Heraklion, Heraklion Greece 5
Louis W. C. Chow UNIMED Medical Institute, Hong Kong Hong Kong 5
Chung Cheung Thomas Yau; Raymond
Hin-Suen Liang Queen Mary Hospital, Hong Kong Hong Kong 5
Bela Piko Bekes Megyei Pandy Kalman Korhaz, Gyula Hungary 5
Agnes Weber Borsod-Abaúj-Zemplén Megyei Kórház és Egyetemi,
Miskolc Hungary 5
Bella Kaufman Sheba Medical Center, Tel Hashomer Israel 5
Karen Drumea Rambam Health Care Campus, Haifa Israel 5
Andrea De Matteis; Francesco Nuzzo Fondazione Giovanni Pascale Istituto Nazionale per lo Studio e la Cura dei Tumori, Napoli
Italy 5
Giacomo Carteni Azienda Ospedaliera Cardarelli, Napoli Italy 5
Shinji Ohno National Hospital Organization Kyushu Cancer Center, Kukouka
Japan 5
Nobuaki Sato Niigata Cancer Center Hospital, Niigata Japan 5
Katsumasa Kuroi Tokyo Metropolitan Cancer & Infectious Disease Center, Tokyo
Japan 5
Reiki Nishimura Kumamoto Municipal Hospital, Kumamoto Japan 5
Junichiro Watanabe Shizuoka Cancer Center, Shizuoka Japan 5
Yoon Ji Choi; Kyong Hwa Park Korea University Medical Center, Seoul Korea 5
Marek Wojtukiewicz Bialostockie Centrum Onkologii im. M. Sklodowskiej-Curie w Bialymstoku, Bialystok
Poland 5
Jacek Jassem Uniwersyteckie Centrum Kliniczne, Gdansk Poland 5
Niklas Loman Skånes Universitetssjukhus Malmö, Lund Sweden 5
Mustafa Kadri Altundag Hacettepe University, Sihhiye/Ankara Turkey 5
Pinar Saip Istanbul University, Instanbul Turkey 5
Muhammad Amjad Ali Quincy Medical Group, Quincy USA 5
James Lloyd Wade III Decatur Memorial Hospital, Decatur USA 5
(Amy) Jo Chien University of California San Francisco, San Francisco USA 5
Debra Brandt Northwestern Connecticut Oncology and Hematology
Associates, Torrington USA 5
Yelena Novik NYU Clinical Cancer Center, New York USA 5
Chirag Jani Phoebe Cancer Center, Albany USA 5
Robert L. Rice; Yousuf A. Gaffar Alliance Hematology Oncology PA, Westminster USA 5
Mark R. Keaton Augusta Oncology Associates PC, Augusta USA 5
Rajesh Bajaj McLeod Oncology and Hematology Associates, Florence
USA 5
Gretchen Kimmick Duke University Medical Center, Durham USA 5
28
Principle investigator(s) Investigational site Country Patients
randomized, n
David Campbell; Richard Hendry De
Boer Western Hospital, Melbourne Australia 4
Theodore Turnquest Affinity Research Limited, Nassau Bahamas 4
Pierre Dube Hopital Maisonneuve – Rosemont, Montreal Canada 4
Stephen Chia British Columbia Cancer Agency, Vancouver Canada 4
Binghe Xu Cancer Hospital, Beijing China 4
Joerg Schilling Onkologische Schwerpunktpraxis, Berlin Germany 4
Klaus Apel Facharzt fuer Frauenheilkunde und Geburtshilfe, Erfurt
Germany 4
Peter Grundtvig Sorensen; Peter
Michael Vestlev Roskilde Sygehus, Roskilde Denmark 4
Erik Hugger Jakobsen; Brita
Bjerregaard Jensen Sydvestjysk Sygehus Esbjerg, Esbjerg Denmark 4
Vera Haahr Regionshospital Viborg, Viborg Denmark 4
Alvaro Rodriguez Lescure Hospital General Universitario de Elche, Elche Spain 4
Begona Grana Suarez; Cristina Saura
Manich Hospital Universitario Vall d´Hebron, Barcelona Spain 4
Jean-Philippe Jacquin Institut de Cancerologie de la Loire (ICL) France 4
Ion Boiangiu University Hospitals of Leicester, Leicester UK 4
Magdolna Dank Semmelweis Egyetem Radiologiai es Onkoterapias
Klinika, Budapest Hungary 4
Cristina Falci; Antonio Jirillo Universita degli Studi di Padova, Padova Italy 4
Saverio Cinieri Presidio Ospedaliero di Summa Antonio Perrino,
Brindisi Italy 4
Takayuki Ueno; Fumiaki Sato; Hiroyasu Yamashiro; Tomoharu Sugie
Kyoto University Hospital, Kyoto Japan 4
Keun Seok Lee; Jung Sil Ro; In Hae
Park National Cancer Center, Gyeonggi-do Korea 4
Anita Zarina Bustam University Malaya Medical Centre, Kuala Lumpur Malaysia 4
MalgorzataSuszko-Kazarnowicz; Artur Piktel
Olsztynski Osrodek Onkologiczny, Olsztyn Poland 4
Krzysztof Krzemieniecki Samodzielny Publiczny Zaklad Opieki Zdrowotnej
Szpital Uniwersytecki w Krakowie, Krakow Poland 4
Polizenia Georgeta Iorga Spitalul Universitar de Urgenta, Bururesti Romania 4
Yap Yoon Sim National Cancer Centre Singapore, Singapore Singapore 4
Marian Kakalejcik Poliklinika ADUS, Poprad Slovakia 4
Alper Sevinc Gaziantep University, Sehitkamil/Gaziantep Turkey 4
Mustafa Ozguroglu Istanbul University, Cerrahpasa Turkey 4
Shin-Cheh Chen Chang Gung Medical Foundation, Taipei Branch Taiwan 4
Richard H. Greenberg The Center for Cancer and Hematologic Disease,
Cherry Hill USA 4
Allan D. Eisemann Rutland Regional Medical Center, Rutland USA 4
Robert Droder East Texas Medical Center Cancer Institute, Tyler USA 4
M. Rashid Abbasi Oncology and Hematology Specialist, Danville USA 4
Marina Vaysburd Cedar-Sinai Medical Group, Beverly Hills USA 4
Humberto Jose Caldera Hematology Oncology Associates, Loxahatchee USA 4
Barbara Bacsik Haley University of Texas Southwestern Medical Center,
Dallas USA 4
Erwin Robin Munster Community Hospital, Munster USA 4
Roger C. Inhorn Mercy Hospital, Portland USA 4
David Hufnagel; Peter D. Kenyon Samaritan Hematology & Oncology Consultants, Corvallis
USA 4
Ellen Spremulli Anniston Oncology, Anniston USA 4
Paula Silverman University Hospitals Case Medical Center (UHCMC), Cleveland
USA 4
Sharad Jain Texas Oncology, PA, Denton USA 4
Robert Weigand St. Joseph Oncology Inc, St Joseph USA 4
Jeroen Mebis VZW Jesseziekenhuis - campus Virga Jesse, Hasselt Belgium 3
Tatyana Koynova District Dispensary for Oncology Diseases Internal Unit – Sofia EOOD, Sofia
Bulgaria 3
Bernard Lesperance Hopital du Sacre-Coeur de Montreal, Montreal Canada 3
29
Principle investigator(s) Investigational site Country Patients
randomized, n
Jana Prausova Fakultni Nemocnice v Motole, Praha Czech Republic 3
Claus-Henning Kohne Klinikum Oldenburg gGmbH, Oldenburg Germany 3
Andreas Schneeweiss Universitaetsfrauenklinik, Heidelberg Germany 3
Christian Jackisch Klinik für Gynaekologie und Geburtshilfe, Offenbach Germany 3
Stefan Fuxius Onkologische Schwerpunktpraxis, Heidelberg Germany 3
Ricardo Cubedo Cervera Hospital Puerta de Hierro-Majadahonda,
Majadahonda Spain 3
Ander Urruticoechea Ribate; Sonia Pernas Simon
ICO de Barcelona - Hospital Duran i Reynals, Barcelona
Spain 3
Jose Valero Gallego Hospital Provincial de Zamora, Zamora Spain 3
Angels Arcusa Lanza Consorci Sanitari de Terrassa, Terrassa Spain 3
Maria del Pilar Alvarez Hospital Universitario Nuestra Señora de Candelaria,
Santa Cruz de Tenerife Spain 3
Jesus Florian Gerico Hospital de Barbastro, Barbastro Spain 3
Laurent Cany Polyclinique Francheville, Perigueux France 3
Justin Stebbing Charing Cross Hospital, London UK 3
Damir Gugic University Hospital Centre Osijek, Osijek Croatia 3
Damir Vrbanec University Hospital Zagreb, Zagreb Croatia 3
Fausto Roila Azienda Ospedaliera S. Maria, Terni Italy 3
Sandro Barni Ospedali Treviglio Caravaggio, Treviglio Italy 3
Paolo Bidoli Azienda Ospedaliera San Gerardo, Monza Italy 3
Hirofumi Mukai National Cancer Center Hospital East, Chiba Japan 3
Vanessa Bermudez Clínica Vista Alegre / Unidad de Investigacion, Surco Peru 3
Alexandru Eniu Institutul Oncologic "Prof. Dr. Ion Chiricuta", Cluj-
Napoca Romania 3
Barry C. Mirtsching Center for Research and Treatment PA, Dallas USA 3
Emad Ibrahim Beaver Medical Group, LP, Highland USA 3
Joan Trey; Paul Francis Hergenroeder MetroHealth Medical Center, Cleveland USA 3
Aftab Mahmood; Anneliese Gonzalez Cancer Specialists of South Texas PA, Corpus Christi USA 3
Edward H. Kaplan; Stacy Ban North Shore Cancer Research Association, Skokie USA 3
Dhimant Patel Aurora Health Care Medical Center, Green Bay USA 3
Billy Clowney Santee Hematology Oncology, Sumter USA 3
Karen Hoelzer Springfield Clinic LLP, Springfield USA 3
Garry H. Schwartz Carolinas Medical Center NorthEast, Concord USA 3
Jame Abraham West Virginia University - Mary Babb Randolph
Cancer Center, Morgantown USA 3
Sunil Narula Midwest Center for Hematology Oncology, Joliet USA 3
Khaled Jabboury Jabboury Foundation for Cancer Research Inc,
Houston USA 3
Robert Scott Mocharnuk Simmons Cancer Institute at Southern Illinois
University School of Medicine, Springfield USA 3
Richard F. McDonough; David H. Sikes; Ronald H. Kawanchi
Florida Medical Clinic, PA, Zephyrhillis USA 3
Larry Schlabach Erlanger Health System, Chattanooga USA 3
Samuel Spence McCachren, Jr. Thompson Cancer Survival Center, Knoxville USA 3
Thomas M. Cosgriff Hematology Oncology Specialties LLC, New Orleans USA 3
Luke Dreisbach Desert Hematology Oncology Medical Group, Inc, Rancho Mirage
USA 3
Angela DeMichele University of Pennsylvania, Philadelphia USA 3
Lawrence Pawl Medical Specialty Associates, Grand Rapids USA 3
Jennifer Lucas California Cancer Care Inc, Greenbrae USA 3
Lowell C. Shinn; Nabiel Alkhouri; Manish Monga
Wheeling Hospital, Wheeling USA 3
Deborah L. Lindquist Arizona Oncology Associates, Sedona USA 3
Thomas C. Anderson Texas Oncology, PA, Bedford USA 3
Humera Khurshid; Sabrina Witherby Memorial Hospital of Rhode Island, Pawtucket USA 3
Nicholette Erickson; Ann Traynor Central Maine Medical Center, Lewiston USA 3
Ron Bose; Timothy J. Pluard Washington University School of Medicine, St Louis USA 3
Clyde Michael Jones The Jones Clinic, PC, Germantown USA 3
30
Principle investigator(s) Investigational site Country Patients
randomized, n
Sucharu Prakash Texas Oncology, PA, Paris USA 3
Fabio Volterra Eastchester Center for Cancer Care, Bronx USA 3
Gerardo Capo Trinitas Comprehensive Cancer Center, Elizabeth USA 3
Lawrence E. Flaherty; Elaina Gartner Barbara Ann Karmanos Cancer Institute, Detroit USA 3
Said Baidas MD Anderson Cancer Center, Orlando USA 3
Ian Okazaki Straub Clinic and Hospital, Honolulu USA 3
Bichlien Nguyen Long Beach Memorial Medical Center, Long Beach USA 3
Thomas Rakowski The Valley Hospital, Paramus USA 3
Ira Oliff Orchard Healthcare Research Inc, Skokie USA 3
Joseph W. Leach; Kendra Kubiak; Michaela Tsai
Park Nicollet Institute, St Louis Park USA 3
Philippe Vroman OL Vrouw Ziekenhuis, Aalst Belgium 2
Ines Deleu; Willem Lybaert AZ Nikolaas, St Nikolaas Belgium 2
Marleen Borms AZ Groeninge, Kortrijk Belgium 2
Felix Couture Hotel Dieu de Levis Hospital, Quebec Canada 2
Jonathan J. Wilson Humber River Regional Hospital, Weston Canada 2
Gordon Hunt; David R. Holland Jack Ady Cancer Centre, Lethbridge Canada 2
Walter Mingrone Kantonsspital Olten, Olten Switzerland 2
Donggeng Liu Sun Yat-Sen University Cancer Center, Guangzhou China 2
Zefei Jiang The Hospital Affiliated Academy Military Medical Science, Beijing
China 2
Vera Benesova Nemocnice Jihlava, Jihlava Czech Republic 2
Martin Smakal; Petra Garnolova Institut Onkologie a reahabilitace na Plesi, Nova Ves pod Plesi
Czech Republic 2
Monika Neumann; Wolfgang Janni Universitaetsklinikum Duesseldorf, Duesseldorf Germany 2
Dorothea Fischer Universitaetsklinikum Schleswig-Holstein Brustzentrum, Leubeck
Germany 2
Eva-Maria Grischke Universitaetsfrauenklinik Tuebingen, Tuebingen Germany 2
Dietmar Seeger St. Marienhospital Vechta, Vechta Germany 2
Volker Moebus Staedtische Kliniken Frankfurt am Main-Hoechst
Frauenklinik, Frankfurt am Main Germany 2
Anita Prechtl Praxis Gynaekologie Arabella Muenchen, Muenchen Germany 2
Juan Carlos Camara Toral Hospital de Torrevieja, Alicante Spain 2
Alfonso Sanchez Munoz Hospital Clinico Universitario Virgen de la Victoria, Malaga
Spain 2
Sonia Gonzalez Jimenez Hospital Mutua de Terrassa, Terrassa Spain 2
Javier Cassinello Espinosa Hospital Universitario de Guadalajara, Guadalajara Spain 2
Beatriz Cirauqui; Mireia Margeli Vila Hospital Universitari Germans Trias i Pujol,
Barcelona Spain 2
Norberto Batista Lopez Hospital Universitario de Canarias, Tenerife Spain 2
JoseIgnacio Chacon Lopez-Muniz;
Miguel Angel de la Cruz Mora Hospital Virgen de la Salud, Toledo Spain 2
Audrey Mailliez; Laurence Vanlemmens Centre Oscar Lambret, Lille France 2
Damien Pouessel; Marc Espie Hopital Henri Mondor, Paris France 2
Marc Espie Hopital Saint-Louis, Paris France 2
Rebecca Roylance St. Bartholomew's Hospital, London UK 2
Adrian Harnett Norfolk & Norwich University Hospitals, Norwich UK 2
David Geffen Soroka University MC, Beer-Sheva Israel 2
Enzo Maria Ruggeri Ospedale Belcolle Viterbo, Viterbo Italy 2
Teresa Gamucci Ospedale SS Trinita, Sora Italy 2
Cees J. Van Groeningen Ziekenhuis Amstelland, Amstelveen Netherlands 2
Renata Banas Szpital Wojewodzki im. Sw. Lukasza Samodzielny,
Tarnow Poland 2
Niklas Loman Skånes Universitetssjukhus, Malmo Sweden 2
Necati Alkis Dr. Abdurrahman Yurtarslan Ankara Oncology
Hospital, Demetevler/Ankara Turkey 2
Ming-Feng Hou Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung
Taiwan 2
Amy K. Krie Avera Cancer Institute, Sioux Falls USA 2
31
Principle investigator(s) Investigational site Country Patients
randomized, n
Nandagopal S. Vrindavanam Signal Point Clinical Research Center, LLC,
Middletown USA 2
Orion M. Howard Southwestern Vermont Health Care, Bennington USA 2
Dennis Citrin Midwestern Regional Medical Center, Zion USA 2
Mark S. Morginstin; Ajit Desai Albert Einstein Cancer Center, Philadelphia USA 2
Ines J. Sanchez Center for Integrative Cancer Medicine, PA, El Paso USA 2
David Allen Nixon, Jr. Northeast Arkansas Clinic, Jonesboro USA 2
Patrick G. Beatty Montana Cancer Specialists, Missoula USA 2
Kathryn Edmiston University of Massachusetts Memorial Medical
Center, Worcester USA 2
Jonathan D. Eneman York Hospital Oncology Treatment Center, York USA 2
Cynthia A. Lynch; Edward O'Brien Guthrie Clinic Ltd, Sayre USA 2
Justin A. Call Northern Michigan Regional Hospital, Petoskey USA 2
Keith S. Lanier; Alison Conlin Providence Cancer Center, Portland USA 2
Donald J. Brooks Arizona Oncology Associates, Tuscon USA 2
Kristi McIntyre Texas Oncology, PA, Dallas USA 2
Marc A. Saltzman Innovative Medical Research of South Florida Inc,
Aventura USA 2
Michael J. Castine III Hematology-Oncology Clinic, Baton Rouge USA 2
Gregory L. Ortega Mid Florida Hematology & Oncology Centers, PA,
Orange City USA 2
Young M. Choi Wheaton Franciscan Cancer Care-All Saints, Racine USA 2
Craig H. Reynolds Ocala Oncology Center, Ocala USA 2
Frank Brescia; Rita Kramer Medical University of South Carolina, Charleston USA 2
Aimee D. Kohn Cascade Cancer Center, Kirkland USA 2
John P. Micha; Jessica M. Rhee Gynecologic Oncology Associates, Newport Beach USA 2
Satish Shah Gettysburg Cancer Center, Gettysburg USA 2
David A. Riseberg Mercy Medical Center, Baltimore USA 2
William Kevin Patterson The Queen Elizabeth Hospital, Adelaide Australia 1
Jean-Paul Salmon; Chantal Andre Centre Hospitalier Regional de la Citadelle, Liege Belgium 1
Alain Bols AZ St Jan Ruddershove, Brugge Belgium 1
Randal D'hondt AZ Damiaan - Site Sint-Jozef, Oostende Belgium 1
Sylvie Luce; Claire Nouwynck Cliniques Universitaires de Bruxelles, Bruxelles Belgium 1
Gino Pelgrims Sint-Elisabeth Ziekenhuis, Turnhout Belgium 1
Vincent Richard Centre Hospitalier Universitaire Ambroise Paré,
Mons Belgium 1
Johan Verschuere AZ Zusters van Barmhartigheid, Ronse Belgium 1
Kurt Geldhof Jan Yperman Ziekenhuis, Leper Belgium 1
Clemens Caspar Kantonsspital Baden, Baden Switzerland 1
Rongcheng Luo Southern Medical University Nanfang Hospital,
Guangzhou China 1
Otakar Bednarik Fakultni Nemocnice Brno, Brno Czech Republic 1
Kathrin Schwedler Frauenklinik der J.W. Goethe-Universitat, Frankfurt
am Main Germany 1
Marcus Schmidt Klinikum der Johannes Gutenberg-Universitaet,
Mainz Germany 1
Joachim Bischoff Universitaetsklinikum Magdeburg, Magdeburg Germany 1
Brigitte Rack Klinikum Innenstadt der Universitaet Muenchen,
Muenchen Germany 1
Roland Repp; Stefan Fries; Ralf Adrion Sozialstiftung Bamberg Klinik fuer Haematologie
und internistische Onkologie, Bamberg Germany 1
Volker Schulz MVZ Abtrs & Partner Kiel, Kiel Germany 1
Peter Klare Praxisklinik Krebsheilkunde fuer
Frauen/Brustzentrum, Berlin Germany 1
Dirk Ossenbuhl; Jakob Manfred Kusche Marienhospital Aachen, Aachen Germany 1
Frank Griesinger Pius-Hospital Oldenburg, Oldenburg Germany 1
Jose Manuel Baena Hospital Universitario Puerta del Mar, Cadiz Spain 1
Purificacion Martinez del Prado Hospital de Basurto, Vizcaya Spain 1
David Machover Hopital Paul Brousse, Villejuif France 1
32
Principle investigator(s) Investigational site Country Patients
randomized, n
Didier Mayeur Hopital de Versailles, Le Chesnay France 1
Nathalie Trufflandier Centre Hospitalier Universitaire De Bordeaux Saint
Andre, Bordeaux France 1
Valerie Delecroix Pôle Hospitalier Mutualiste, Saint-Nazaire France 1
Mireille Mousseau Hopital Albert Michalon, Grenoble France 1
Marie-Ange Mouret-Reynier; Jean-Marc Nabholtz
Centre Jean Perrin, Clermont-Ferran France 1
Anula D. Chetiyawardana Queens Hospital, Burton-on-Trent UK 1
Christos Papandreou University General Hospital of Larissa, Larissa Greece 1
Lajos Hornyak; Zsolt Faluhelyi;
Erzsebet Simo
Veszprem Megyei Csolnoky Ferenc Korhaz,
Veszprem Hungary 1
Mario Di Palma Ospedale San Pietro Fatebenefratelli, Roma Italy 1
Francesco Cognetti Medica Istituti Fisioterapici Ospitalieri - Istituto
Regina Elena, Roma Italy 1
Gabriella Gorzegno; Luigi Dogliotti Azienda Ospedaliera San Luigi Gonzaga, Orbassano Italy 1
Cesare Gridelli Ospedale San Giuseppe Moscati, Avellino Italy 1
Alfredo Falcone Riuniti Azienda Ospedaliero-Universitaria Pisana,
Pisa Italy 1
Hector Soto Parra; Calogero Buscarino AOU Policlinico - Vittorio Emanuele, Catania Italy 1
Seock-Ah Im Seoul National University Hospital, Seoul Korea 1
Benito Sanchez Llamas Nucleo De Especialidades Oncologicas, Guadalajara Mexico 1
Wouter Dercksen Maxima Medisch Centrum, Noord Brabant Netherlands 1
Franciscus Erdkamp Orbis Medisch Centrum, Sittard-Geleen Netherlands 1
J.B. Ruit; Hans Braun Vlietland Ziekenhuis, Schiedam Netherlands 1
Joanneke E.A. Portielje Haga Ziekenhuis, Den Haag Netherlands 1
Suleyman Buyukberber; Mustafa
Benekli Gazi Universitesi Tip Fakultesi, Besevler/Ankara Turkey 1
Andrew J. Zahalsky Andrew J. Zahalsky, MD, PC, Monongahela USA 1
Rebecca Jaslow Thomas Jefferson University, Philadelphia USA 1
Gary W. Thomas South Carolina Cancer Specialists, Hilton Head
Island USA 1
Archana Maini; Israel Wiznitzer Broward General Medical Center, Fort Lauderdale USA 1
Ali Khojasteh Columbia-Capitol Comprehensive Cancer Care
Clinic, Jefferson City USA 1
Manuel Francisco Gonzalez Francisco Gonzalez MD PA, Columbia USA 1
Lynn R. Kong Ventura County Hematology-Oncology Specialists,
Oxnard USA 1
Aruna Padmanabhan Temple University Hospital, Philadelphia USA 1
William A. Conkright Purchase Cancer Group, Paducah USA 1
Sandra M. Swain Washington Hospital Center, Washington USA 1
Douglas E. Faig North Broward Medical Center, Deerfield Beach USA 1
Kirti Jain Ashland-Bellefonte Cancer Center, Ashland USA 1
Ronald H. Yanagihara Ronald H. Yanagihara, Gilroy USA 1
Yvonne Ottaviano Harry and Jeanette Weinberg Cancer Center,
Baltimore USA 1
Beverly Moy Beth Israel Deaconess Medical Center, Boston USA 1
Heather A. Steele; Gordon K. Rainey;
Penelope J. Harris; Jason K. Burris; Erik J. Rupard; Esther Tan
Dwight David Eisenhower Army Medical Center,
Fort Gordon USA 1
Pat W. Whitworth Nashville Breast Cancer, Nashville USA 1
Abby R. Bova Mercy Clinic Oncology and Hematology – McAuley,
Oklahoma City USA 1
Ian C. Anderson Redwood Regional Medical Group, Santa Rosa USA 1
Mihran Shirinian Glendale Adventist Medical Center Cancer Services,
Glendale USA 1
Caesar Tin-u Texas Oncology, PA, Sugar Land USA 1
Timothy J. O'Rourke Cancer & Hematology Centers of Western Michigan,
Grand Rapids USA 1
Michael S. Roberts Arizona Oncology Associates, PC, Phoenix USA 1
Michael Francisco; A. Scott Pierson Portneuf Medical Center, Pocatello USA 1
33
Principle investigator(s) Investigational site Country Patients
randomized, n
Peter D. Byeff Cancer Center of Central Connecticut, Southington USA 1
Peter A. Kovach; John R. Caton, Jr. Willamette Valley Cancer Institute and Research
Center, Springfield USA 1
Mark Urban Rarick Kaiser Permanente Northwest Region Oncology
Hematology, Portland USA 1
William G. Schimidt, Jr. Bend Memorial Clinic, Bend USA 1
Alison T. Stopeck; Rachel Swart Arizona Cancer Center, Tuscon USA 1
Maria Regina Carrillo Flores; Carlos A.
Alemany; Brennely Lozada Cancer Centers of Florida, Orlando USA 1
Paul L. Weinstein Hematology Oncology, PC, Stanford USA 1
Wei Wang San Francisco Oncology Associates, San Francisco USA 1
Michael Porubcin Medical Arts Association, Ltd, Moline USA 1
David M. Ellison; George F. Geils Charleston Hematology Oncology Associates, PA,
Charleston USA 1
Edgardo Rivera The Methodist Hospital, Houston USA 1
Mahmoud Charif University of Cincinnati Cancer Center, Cincinnati USA 1
34
REFERENCES
1. Perez EA, Suman VJ, Davidson NE, et al. Sequential versus concurrent trastuzumab in adjuvant
chemotherapy for breast cancer. J Clin Oncol 2011; 29: 4491-7.
2. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J
Med 2011; 365: 1273-83.
3. Eton DT, Cella D, Yost KJ, et al. A combination of distribution- and anchor-based approaches determined
minimally important differences (MIDs) for four endpoints in a breast cancer scale. J Clin Epidemiol 2004; 57:
898–910.
4. Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ-5D utility and VAS
scores in cancer. Health Qual Life Outcomes 2007; 5: 70.
Top Related