N-SAS BC 05 protocol version 1.1

N-SAS BC 05

National Surgical Adjuvant Study of Breast Cancer

Comprehensive Support Project for Oncology Research (CSPOR)
National Surgical Adjuvant Study of Breast Cancer (N-SAS BC)

Randomized Study to Assess the Efficacy of a Further 5 Years of Anastrozole Treatment for Postmenopausal Women
with Breast Cancer After Completing 5 Years of Anastrozole Treatment-Containing Adjuvant Endocrine Therapy

Principal investigator:

Takuji Iwase
Department of Breast Oncology,
The Cancer Institute Hospital of JFCR Ladies Center
3-10-6 Ariake, Koto Ward, Tokyo 135-8550

CSPOR Data Center:

PHONE

03-3520-0111

FAX

03-3570-0343

E-mailtakuji.iwase@jfcr.or.jp

Yasuo Ohashi
Division of Health Sciences and Nursing,
Graduate School of Medicine, The University of Tokyo
5F 1-2-13 Yushima, Bunkyo Ward, Tokyo 113-0034
PHONE

03-3254-8029

FAX

03-5298-8536

E-mailohashi@epistat.m.u-tokyo.ac.jp

Draft created:
Independent Monitoring Committee approval:

March 16, 2007
July 27, 2007

V1.0 created:

August 1, 2007

V1.1 created:

July 1, 2009

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Table of Contents0Overview

3

1

Objectives

7

2

Background8

3

Criteria and definitions used in this study

16

4

Selection and exclusion criteria

195Registration and allocation

22

6

Treatment plan24

7Drug treatment30

8Observation, examination and evaluation

32

9

Data collection

43

10

Reporting of adverse events

45

11

Evaluation of HRQOL and economy of medical care48

12Endpoints

56

13

Statistical matters

59

14

Ethics63

15

Monitoring and auditing

66

16

Announcement of research results

68

17

Conflicts of interest and research funding

68

18

Clinical trial registration

68

19

Accompanying research69

20

Study organization

70

21

Amendment of the study protocol / discontinuation of the study

77

22

List of participating medical facilities

79

23

References80

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0 Overview
0.1

Trial schema
Postmenopausal breast cancer patients receiving ongoing adjuvant
endocrine therapy of anastrozole
Patients who have received adjuvant endocrine therapy of anastrozole for 5 years (At time ofregistration, anastrozole treatment is ongoing and has been received for between a full 4 years 9months and 5 years 2 months)(Patients described below are also admissible) Patients who have received 5 years of adjuvant
endocrine therapy consisting of postoperative tamoxifen treatment, followed by at least a full 2 yearsof anastrozole treatment.(At time of registration, adjuvant endocrine therapy is ongoing and has been
received for between a full 4 years 9 months and 5 years 2 months)

Allocation adjustment factors
Type of adjuvant endocrine therapy
Chemotherapy performed (Yes vs. None)
Axillary lymph node metastasis (Yes vs. None)
Facility

Registration
Randomallocation

STOP GroupCONTINUE GroupEnd anastrozole treatment andobserve untreated for 5 years

Extend anastrozole treatment(1 mg/day) for a further 5 years

Follow-up (up to end of study)
Hospital visit once/year, follow-up of recurrence and survival

Abbreviated Study Title: AERAS (Arimidex Extended adjuvant Randomized Study)
0.2

Study design
This is a multicenter, open label, randomized, parallel-group study.

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0.3

Objectives
1)

To demonstrate the superiority of treatment efficacy in the CONTINUE group against the
STOP group in terms of disease-free survival.
To also evaluate overall survival and distant disease-free survival.

2)

To evaluate the safety of a 5-year extension of anastrozole treatment.

3)

To evaluate health-related quality of life (HRQOL) and cost-effectiveness (utility).

4)

To establish and expand information networks enabled by the participation of generalpractitioners specializing in breast cancer in clinical trials.

Primary endpoint:

Disease-free survival (DFS)

Secondary endpoints: Overall survival (OS), distant disease-free survival (DDFS), adverse events,
HRQOL, cost-effectiveness (utility)
Other endpoints:

0.4

Bone density, joint symptoms

Selection criteria
Patients will meet all the criteria below.
1)

Patient has been diagnosed histologically with invasive breast cancer, has undergone
surgery on the primary female breast cancer, and is menopausal at registration.
The requirement for being menopausal is to meet at least one of the criteria below.
a)≥55 years of ageb)≥45 years of age with amenorrhea for 2 years or more, and has not undergone a
hysterectomyc)2)

Has undergone bilateral oophorectomy

The patient has not used LH-RHa and any of the below criteria applies regarding
adjuvant endocrine therapy.
a)Initial therapy of anastrozole treatment for 5 years and ongoing (ANA)(At time of registration, anastrozole treatment that is ongoing and has been
received for between a full 4 years 9 months and 5 years 2 months will be
admissible)b)

Initial therapy of tamoxifen treatment followed by at least a full 2 years ofanastrozole treatment, comprising adjuvant endocrine therapy of a total of 5 years
that is ongoing. (TAM→ANA)(At time of registration, adjuvant endocrine therapy that is ongoing and has been
received for between a full 4 years 9 months and 5 years 2 months will be
admissible)

3)

TNM staging at first examination (before surgery) of T1-3, N0-2, M0 (3.1 Clinical stage
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classification)
4)

Positive for at least one of hormone receptors, estrogen receptor or progesterone
receptor.

5)

PS (ECOG) 0, 1 (3.3 Performance status evaluation)

6)

Aged ≤80 years at time of registration.

7)

Neither recurrence nor contralateral breast cancer found on examination within 6 months
prior to registration.
Only either a bilateral mammogram or breast ultrasound (one-sided in patients withmastectomy) is required for this examination. Examination of areas other than the breasts(chest, abdomen, bones, etc.) will be performed according to the normal examination
policies of each facility.

8)

Patient has adequate organ function.
Meets all the criteria below (according to laboratory test results from within 3 months prior
to registration).

9)
0.5

a)

Leukocyte count:≥3,000/mm3b)Platelet count:≥100,000/mm3c)Hemoglobin:≥9.0 g/dl

d)Total bilirubin:≤1.5 mg/dle)

GOT and GPT≤2.5 times the facility upper limit of normalf)Creatinine:≤1.5 mg/dlg)

No history of myocardial infarction or congestive heart failureh)

No ischemic heart disease or valvular disease that requires treatment

Consent for study participation obtained in document form from the patient herself

Exclusion criteria
Patients meet any of the criteria below.
1)

Patient has a metachronous or synchronous bilateral breast cancer

2)

Patient has invasive cancer of another organ within 5 years after the end of treatment

3)

Medical history of deep vein thrombosis

4)

Medical history of bone fracture attributed to osteoporosis, and has symptoms ofosteoporosis at time of registration

5)

Patient is receiving ongoing treatment in the form of hormone replacement therapy or aselective estrogen receptor modulator (SERM)

6)

Currently participating in another clinical trial with the objective of preventing the
postoperative recurrence of breast cancer

7)

Patient is deemed unsuitable for study participation by an attending physician

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0.6

Treatment
Patients are allocated randomly to either the STOP group or CONTINUE group.
STOP group: Observation untreated for 5 years
CONTINUE group: 5-year extension of anastrozole treatment (once daily, 1 mg/day, oral
administration)

0.7

Scheduled number of patients and study period
Scheduled number of patients: 1250 in each group and 2500 patients in total.
Registration period: 5 years (from registration of first patient)
Study period: 10 years
Scheduled follow-up period: 5 years (maximum of 10 years)

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1 Objectives
This randomized study will be performed in patients who have completed 5 years of adjuvant endocrine
therapy for hormone-responsive breast cancer, which will compare the current standard treatment
period for adjuvant endocrine therapy of 5 years (STOP group) with a 5-year extension of endocrine
therapy in the form of anastrozole treatment (CONTINUE group).
The objectives of this study are as described below.
1)

To demonstrate the superiority of treatment efficacy in the CONTINUE group against the
STOP group in terms of disease-free survival (DFS).
To also evaluate overall survival (OS) and distant disease-free survival (DDFS).

2)

To evaluate the safety of a 5-year extension of anastrozole treatment.

3)

To evaluate health-related quality of life (HRQOL) and cost-effectiveness (utility).

4)

To establish and expand information networks enabled by the participation of generalpractitioners specializing in breast cancer in clinical trials..

1.2

Primary endpoint
Disease-free survival (DFS)

1.3

Secondary endpoints
Overall survival (OS), distant disease-free survival (DDFS), adverse events, HRQOL, cost-effectiveness(utility).

1.4

Other endpoints
Bone density, joint symptoms

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2 Background
2.1

Standard adjuvant endocrine therapy for postmenopausal breast cancer patients
An examination of data on postmenopausal breast cancer patients by the Japanese Breast Cancer
Society (JBCS) in 2004 found that postmenopausal breast cancer accounted for approx. 60% of all
female breast cancers in Japan, and that over 70% of all breast cancers were hormone responsive
breast cancers. Consequently, improving the prognosis for postmenopausal, hormone responsive
breast cancers will lead to an overall improvement in breast cancer prognosis.
The use of tamoxifen (TAM) as a adjuvant endocrine therapy has resulted in a marked improvement inprognosis, and 5 years of TAM treatment has been the recommended standard therapy in hormone
responsive patients (St Gallen, 2003[1]). However, TAM use entails problems such as cancer recurrence
and adverse reactions including endometrial cancer and venous thrombosis, and for these reasons has
not been a fully adequate solution (EBCTCG 1998[2]).
Aromatase inhibitors (AIs) have the potential to control breast cancer by lowering the concentration oftumor and systemic female hormones. The mid-1990s saw the appearance of third generation drugs,
anastrozole (ANA) and letrozole, and there was a substantial change from the exclusive use of TAM as
adjuvant endocrine therapy. After reports emerged of results showing the efficacy of these AIs as firstline treatments[3] and even secondary treatments[4] for advanced recurrent breast cancer, a number ofclinical trials were performed with the expectation that these AIs could be applied as postoperative
endocrine therapies, and in turn the results of those clinical trials have been presented. Regarding thequestion as to whether to chose TAM or AIs as the initial treatment for adjuvant endocrine therapy, theATAC trial[5] and BIG1-98 trial[6] were conducted. With regard to the question as to whether AI should
replace TAM for patients receiving TAM currently, the ITA trial and IES trial[7] were conducted. In all
studies, the results from AI treatment surpassed those of TAM treatment.
In 2004 and in light of these trial results, ASCO that was previously extremely wary of changing
treatment away from TAM also decided to recommend AIs as adjuvant endocrine therapy for hormone
responsive postmenopausal breast cancer (ASCO Technology Assessment 2004[8]).

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The usefulness of anastrozole (ANA) as postoperative adjuvant therapy
The usefulness and safety of third generation AIs (anastrozole, exemestane and letrozole) has been
demonstrated against TAM treatment in randomized studies. Below are the results of major clinicalstudies that examined ANA use and distinguished between “Initial Therapy” which uses AI as an initial
therapy after surgery and “Switching Therapy” which uses TAM for 2-3 years then switching to an AI.
(1) Clinical study of AI as initial therapy after surgery (Initial Therapy)
Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial[9]9366 postoperative patients with postmenopausal, invasive cancer were allocated randomly to one ofthree groups, an (1) ANA + placebo group, (2) TAM + placebo group, and (3) ANA + TAM group. The
groups were compared for recurrence-free survival and adverse events. By December 2001, at a
median duration of observation of 33 months, an academic report described the usefulness of treatmentin the ANA group already having been demonstrated in hormone responsive patients. A debate ensued
concerning how to manage the rest of the study. At the same time, results in the concomitant treatmentgroup were not superior to those in the TAM group, and so treatment of concomitant treatment group
was discontinued. By a median observation period of 68 months, the Disease-Free Survival (DFS) was
significantly higher in the ANA group than in the TAM group with the hazard ratio (HR) of 0.83 (P=0.005)
for hormone responsive patients. However, there was no significant difference in the Overall Survival(OS) with a HR of 0.97.
Results at this point also showed significantly fewer drug-related adverse events in the ANA group at
4.7%, compared to 9.0% in the TAM group (P<0.0001) demonstrating superior safety in the ANA group.
(2) Clinical study of 2-3 years of TAM treatment followed by ANA (Switching Therapy)
1)

Italian Tamoxifen Anastrozole trial[10]448postmenopausal

patients

(with

lymph

node

metastasis

andhormoneresponsiveness) receiving ongoing TAM treatment were divided into (1) a group that
continued TAM treatment and (2) another that switched to ANA treatment. Both groups
received treatment for 5 years each in total. By a median observation period of 36 months,
in terms of DFS the HR of 0.35 (P=0.001) demonstrated a significantly more favorable
result in the group that switched to ANA treatment.
2)

ABCSG trial and ARNO 95 trial[11]Two clinical trials have been conducted in patients with postmenopausal, hormone
responsive breast cancer who completed two years of TAM treatment. The two trials
were analyzed together and the result was reported. Approx. 1600 patients wereregistered to each group, consisting of a group switched to ANA treatment and a groupthat continued TAM treatment while treatment was unblinded. By a median observation
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period of 28 months, in terms of DFS the HR of 0.60 (P=0.0009) demonstrated asignificantly more favorable result in the treatment-switching group.
The safety of anastrozole as postoperative adjuvant therapy
In the ATAC trial, the frequency of adverse events when using ANA as adjuvant therapy was lower
relative to TAM. In particular, the frequency of events such as gynecological adverse events including
endometrial cancer, thrombosis, and hot flush was significantly lower.
Conversely, the adverse events, bone fracture and arthralgia, were significantly more frequent with ANA
treatment, observed at respective frequencies of 11% and 35%. Based on these results, 5 years of ANA
treatment is safer than TAM and is not problematic in terms of safety. However, incidence of adverse
events is unknown beyond 5 years of use, care must be taken to observe mainly for bone-related
adverse events.
Extension of endocrine therapy
The use of TAM as endocrine therapy has been compared for administration periods of 1, 2, 5 years
and longer. Up to a period of 5 years, the longer treatment is performed the better the effect becomes.
Since the effects of TAM continue for a period of time after stopping treatment, long-term observationis required to determine the relation between the duration of TAM treatment and the efficacy. The resultsof comparative trials of treatment for 5 or more years, such as NSABP B-14[12], show no efficacy inextending the treatment period past 5 years and, consequently, in current clinical practice the standard
period of treatment is 5 years.
An EBCTCG[13] meta-analysis of TAM treatment for 5 years in estrogen receptor positive (and unknown)
breast cancer patients found recurrence and mortality remained significantly reduced in the TAM
treatment group after 15 years of follow-up relative to the group not treated with TAM. This result isevidence of the usefulness of adjuvant endocrine therapy. However, the cumulative rate of breast
cancer recurrence in the TAM group was 15.1% at 5 years, 24.7% at 10 years and 33.2% at 15 years,
showing that recurrence occurs dependent on time after the completion of 5 years of TAM treatment,
and indicating a need to extend the period of endocrine therapy in estrogen receptor positive breast
cancer patients.
Because of the existence of trial results that show for a small sample group the efficacy of extending
TAM treatment past 5 years cannot be ruled out (ECOG trial[14]), and the results to two additional clinical
trials (ATLAS, aTTom) that explored the efficacy of extended treatment with tamoxifen, based on theseresults a new judgment will be reached.
The MA17 trial[15] demonstrates the additional effect of using an AI (letrozole) to extend endocrine
therapy after 5 years of TAM treatment. After completing 5 years of TAM treatment, more than 5000
patients were allocated to receive letrozole or a placebo for a further 5 years. By a median observation
period of 30 months, the prognosis in terms of DFS in the letrozol group had improved significantly
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N-SAS BC 05 protocol version 1.1(HR=0.58, P<0.01). The results showed no difference in overall survival, but when considering only
patients with lymph node metastasis there was a significant reduction in mortality in the letrozole group(HR=0.61, P=0.04). In light of the above results, it may be efficacious to extend endocrine therapy bychanging to an AI after completing 5 years of TAM treatment.
2.2

Study design rationale
Since both the initial therapy and switching therapy regimes, using ANA described above have resulted
in a favorable prognosis relative to 5 years of TAM treatment only, both 5-year treatment methods havebeen chosen as the standard arm of this study. Although the MA17 trial only suggests the usefulnessof extending endocrine therapy using an AI (letrozole) after completing 5 years of TAM treatment, there
is no data on using an AI to extend endocrine therapy past 5 years when using an AI either from thestart of treatment or switching to an AI during the first 5 years of treatment. An NSABP trial that iscurrently ongoing is being performed in patients who are in just this position, and randomly allocatespatients to either 5 years of letrozole treatment or a placebo (NSABP B-42). The present study differsfrom the NSABP trial in being able to collect data on using the endocrine therapy ANA as its third
generation AI, in limiting pre-study AI treatment to ANA and collecting data on more than 5 years ofadditional ANA treatment, and collecting data over an extended period of ANA treatment lasting 10
years. By incorporating at least 5 years and up to 10 years of ANA treatment, this study will not only
demonstrate the effects of extended endocrine therapy, but can also be used to analyze the efficacy
and safety of ANA treatment for a period that exceeds 5 years.

2.3

Patients eligible for registration
In August 2006, a questionnaire was sent to 170 supervising physicians of 158 facilities registered with
the CSPOR concerning patients currently receiving postoperative treatment with an aromatase inhibitor.
A response was obtained from 111 facilities.
Responses detailed approximately 3700 patients in total in all facilities who had received initial treatment
with ANA after surgery and would complete 5 years of ANA treatment in the next 2 years. Approx. 60
facilities showed interest in the study and stated consent for participation could be obtained, which wasdeemed to account for over 2000 patients. No survey was taken of the number of patients who had
switched treatments, but after adding an estimated figure for those patients to the previous total it was
supposed that in a 2-year period between 2000-3000 patients could be registered to the study. It wasestimated that a scheduled number of 2500 patients could be obtained.

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2.4

Summary of anticipated benefits and risks (disadvantages) to study participantsProtocol treatment in the STOP group will consist of ending anastrozole treatment 5 years after surgery
identical to normal medical care, and in the CONTINUE group will consist of extending ANA treatment
by a further 5 years. The effect of treatment observed in the CONTINUE group is expected to be superior
to that in the STOP group, but since there is currently no evidence relating to administration of 10 yearsof postoperative treatment in support of this hypothesis the medical benefits of study participation are
not clear. In addition, all medical costs in this study, including drugs and investigations, will be paid
under the health insurance of the patient or as patient out-of-pocket expenses. Medical examinations
and investigations will be performed during the study period at a frequency similar to that of normal
medical care, so the consequent burden posed by medical examinations and investigations (including
invasive investigations) will not increase by participation in this study. However, this study does require
surveys pertaining joint symptoms, QOL and medical economics be performed in some patients, which
may be an additional burden faced by those patients.
The environment created by the regular medical examinations and investigations and contact withattending physicians and CRCs, amongst other parties, performed during the period of study
participation will make consultation and advice easier to obtain for patients, and the resulting intimatelevel of medical care may be an overall benefit of study participation when compared with nonparticipation in the study.

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2.5

Significance of this study
Determining the effects of extended endocrine therapy and the optimum period of postoperative
anastrozole treatment
Since the publication of the 2001 ATAC trial, 5-year ANA treatment has become a common
postoperative therapy in Japan in patients with postmenopausal, hormone responsive breast cancer.
Japanese patients who have completed the 5 years of ANA treatment have therefore existed since
March 2007. Similarly, we expect to encounter increasing numbers of patients who have completed a
total of 5 years of endocrine therapy and switched to ANA treatment after 2-3 years of TAM treatment.
From this point on, data must be obtained on whether it is possible to control and what degree of control
is possible over late-stage recurrence after the completion of 5 years of treatment, including AI
treatments. Extending endocrine therapy with AI treatment has been cited as a way of improving on the
prognosis seen in patients after 5 years of TAM treatment, and it may be possible to further improve
prognosis in these patients by administering further additional AI treatment. This study is capable ofdemonstrating the efficacy and safety of continued ANA treatment for more than 5 years, and will
provide new information on the effect of extended adjuvant endocrine therapy and the optimum periodof postoperative ANA treatment. The results of this study will be immediately reflected in normal clinicalpractice and are of great importance.
Assuming this study is started in 2007, the results can be investigated as part of the 2015 EBCTCG
meta-analysis.
Significance of HRQOL evaluation
From the perspective of evaluating the total benefit a patient can obtain from a cancer treatment, it isvery important to obtain an evaluation of the HRQOL-based patient-reported outcome alongside the theevaluation of the objective indicator of survival time. It is normal that QOL be included as a primary or
secondary endpoint in large-scale trials of adjuvant chemotherapies performed in breast cancer patients.
Since a QOL evaluation is also essential in when considering the treatment objectives of postoperative
adjuvant endocrine therapy, this study will demonstrate the effects of extending anastrozole treatment
on QOL relative to untreated patient observations.
Significance of the evaluation of medical economics (cost-benefit performance)
The focus of interest of an evaluation of economy of medical care is not only to compare the costs ofthe therapeutic drugs, but also the drugs used to alleviate adverse drug reactions and the cost of
outpatient visits. A diverse evaluation of (disease-free) survival, QOL and economy of medical care,including a comparison of quality-adjusted life year (QALY) that is the cost of survival with good QOL
for one year and an estimation of the cost of extending one year of survival with good QOL (incremental
cost/QALY) relative to the untreated group can make a substantial contribution not only in terms ofpotential therapeutic options for clinical practice, but also in terms of social significance.
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2.6

Comprehensive Support Project for Oncology Research
In the year 2000, the Public Health Research Foundation commenced a “comprehensive support project
for the development of therapy including psychosocial intervention for the purpose of improving thequality-adjusted life years (QALY) of breast cancer patients”. The Public Health Research Foundation
is a designated public interest corporation that was established in 1984 with the Ministry of Health,Labour and Welfare as its supervisory government agency. It was established with the objective of“Making a contribution to the maintenance and improvement of public health by conducting research on
the impact of stress on physical and mental health and implementing the results of this research inareas of disease prevention and health promotion of the Japanese people”. While the prevalence ofbreast cancer is on the rise as a consequence of changes in lifestyle, patient awareness towards QOL
is also increasing. The biological characteristics of cancer are also being revealed and new therapies
are rapidly being developed in light of these new findings. The implementation of researcher-led clinicalstudies that include a QOL evaluation aspect is essential in the creation of an evidence-based systemof standard treatment, and in creating treatment choices that value the QOL of each individual patient.
However, the infrastructure to facilitate large-scale multicenter studies in Japan is immature. In light ofthese circumstances, the comprehensive support project will carry out the following operations aimed
at improving the quality of breast cancer clinical research and the QOL of breast cancer patients inJapan:
1)

Planning and implementation of researcher-led breast cancer clinical research.

2)

Investigative research pertaining to the QOL of breast cancer patients.

3)

Education of Clinical Research Coordinators (CRCs).

4)

Utilizing the Internet to provide information to breast cancer patients, physician
researchers and CRCs.

The English name of this project is the “Comprehensive Support Project for Oncological Research”,
abbreviated to CSPOR. The present study is conducted as part of the Comprehensive Support Project
for Oncology Research.

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2.7

N-SAS BCThe National Surgical Adjuvant Study of Breast Cancer (N-SAS BC) was inaugurated in 1993 and isaffiliated with the “Anti-Cancer Drug Post-Marketing Research Team” (leader at the time: Kaoru Abe,
National Cancer Center President), which belongs to the Ministry of Health’s (now Ministry of Health,Labour and Welfare) “Drug Epidemiological Technique Examination Project” Contract Research
Organization. Its English name is the National Surgical Adjuvant Study of Breast Cancer and isabbreviated to the N-SAS BC. The “N-SAS BC 01” multicenter study conducted by the National Surgical
Adjuvant Study of Breast Cancer included 732 registered patients from 45 medical facilities nationwide
between October 1996 and March 2001. Continuing form this study, the “N-SAS BC 02” study
commenced in December 2001, the “N-SAS BC 03” study in November 2002, and the “N-SAS BC 04”
study commenced in September 2003 and is currently ongoing. In order to make use of the knowledge,
experience and know-how developed during the N-SAS BC studies performed to date, and to continue
in the format of a national-scale multicenter study research group, the research group has adopted theEnglish name and abbreviation of “National Surgical Adjuvant Study of Breast Cancer” (N-SAS BC) withthe present study being named “N-SAS BC 05”.

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3 Criteria and definitions used in this study
3.1

Clinical stage classification“Breast Cancer Management (2004, 15th Ed.)” will be used.
The UICC-TNM classification (2002, 6th Ed.) is adopted for stage classification.
T: Primary tumorNote 1)
Chest wall
fixation Note 2)

Size (cm)TX

Not evaluable

Tis

Non-invasive carcinoma or Paget’s disease where notumor mass is observed

T0

No primary tumor observed Note 3,4)

T1 Note 5)

≤2.0
>2.0

T2

≤5.0

T3

>5.0
a
b

T4

Edema of the skin,ulcer/ satellite skinnoduleAny size

c
d

－

－

－

－

－

－

＋

－

－

＋

＋
Inflammatory breast carcinoma

＋
Note

6)

Note 1: T1 is determined comprehensively by clinical breast examination and diagnostic imaging.
Note 2: Chest wall refers to the ribs, sternum, intercostal muscle and serratus anterior muscle, anddoes not include the pectoral muscle.
Note 3: The primary tumor cannot be determined by clinical breast examination or diagnostic
imaging (mammography, ultrasound).
Note 4: Patients with nipple discharge, calcification on mammography, etc. will not be diagnosed
as T0 and instead classification will be deferred. These patients will be classified as Tis, T1
mic, etc. according to a final pathological diagnosis.
Note 5: Subclassification as “a” (≤0.5), “b” (>0.5, ≤1.0) and “c” (>1.0, ≤2.0).
Histological radius of invasion of ≤0.1 cm will be described as T1mic.
Note 6: Inflammatory breast carcinoma indicates diffuse redness, edema and induration when anormal tumor mass is not found.
Note 7: In the event of multiple tumor masses in the mammary gland, the highest T classification
will be used.

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N: Regional lymph nodes Note 1)

Ipsilateral axillary lymph node
Fixed
(in surrounding
tissue or between
lymph nodes)

MovableNX

Parasternal
lymph nodes
Note 2)

Ipsilateralsubclavicula
r lymphnode

Ipsilateralsupraclavicu
lar lymph
node

Not evaluable

N0

－

－

－

－

－

N1

＋

－

－

－

－

a

－

＋

－

－

－

b

－

－

＋

－

－

a

＋/－

＋/－

＋/－

＋

－

b

＋

＋

－

－

c

＋/－

＋/－

＋/－

＋

N2

N3

Or

＋
＋/－

Note 1: Diagnosis of lymph node metastasis is by palpation, diagnostic imaging, etc.
Note 2: Taken as (-) if parasternal lymph node metastasis not found.
M: Distant metastasis
MX Cannot be evaluatedM0

No distant metastasis

M1

Distant metastasis present

TNM classification

T0
N0
M0

M1

T1

T2

T3

T4

I

IIA

IIB

IIIB

N1

IIA

IIA

IIB

IIIA

IIIB

N2

IIIA

IIIA

IIIA

IIIA

IIIB

N3

IIIC

IIIC

IIIC

IIIC

IIIC

IV

IV

IV

IV

IV

Stage 0: Tis noninvasive cancer: Not applicable
State I-IV: Invasive cancer

White potion without shading is subject toexamination in this study

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3.2

Histological classification“Breast Cancer Management (2004, 15th Ed.)” will be used.
1

2

3
3.3

Non-invasive carcinoma
1a. Non-invasive ductal carcinoma
1b. Lobular carcinoma in situ
Invasive carcinoma
2a. Invasive ductal carcinoma
2a 1
Papillotubular carcinoma
2a 2
Solid-tubular carcinoma
2a 3
Scirrhous carcinoma
2b. Special-types
2b 1
Mucinous carcinoma
2b 2
Medullary carcinoma
2b 3
Invasive lobular carcinoma
2b 4
Adenoid cystic carcinoma
2b 5
Squamous cell carcinoma
2b 6
Spindle cell carcinoma
2b 7
Apocrine carcinoma
2b 8
Carcinoma with cartilagous and/or osseous metaplasia
2b 9
Tubular carcinoma
2b 10
Secretary carcinoma (Juvenile carcinoma)
2b 11
OthersPaget’s disease

Performance Status evaluation
The Japanese translation of the ECOG scale[16] will be used.
Grade

Performance Status

0

Symptomless, able to carry out social activities without restriction similarly
to pre-disease performance.

1

Mild symptoms, restricted in physically strenuous activity but ambulatory
and able to carry out light physical labor and sedentary work. For example,
light housework and office work.

2

Ambulatory and capable of all self-care but sometimes requires
assistance. Unable to carry out light labor but moving for more than 50%
of waking hours.

3

Capable of limited self-care but often requires assistance. Confined to bed
or chair more than 50% of waking hours.

4Completely incapable of self-care and requires constant assistance. Totallyconfined to bed or chair.

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4 Inclusion and exclusion criteria
4.1

Selection criteria
Patients who meet all the criteria below will be eligible for this study.
1)

Patient has been diagnosed histologically with invasive breast cancer, undergone
surgery on the primary female breast cancer, and is menopausal at time of registration
to this study.
The condition for being menopausal is to meet at least one of the criteria below.
a)≥55 years of ageb)≥45 years of age with amenorrhea for at least 2 years, and has not undergone a
hysterectomyc)2)

Has undergone bilateral oophorectomy

The patient has not used LH-RHa and any of the criteria below applies regarding adjuvant
endocrine therapy.
a)Initial therapy of anastrozole treatment for 5 years and ongoing (ANA)(At time of registration, anastrozole treatment that is ongoing and has been
received for between a full 4 years 9 months and 5 years 2 months will be
admissible)b)

Initial therapy of tamoxifen treatment followed by at least a full 2 years anastrozole
treatment, comprising adjuvant endocrine therapy of a total of 5 years that is also
ongoing (TAM→ANA)(At time of registration, adjuvant endocrine therapy that is ongoing and has been
received for between a full 4 years 9 months and 5 years 2 months will be
admissible)

3)

TNM staging at first examination (before surgery): T1-3, N0-2, M0 (3.1 Clinical stage
classification)

4)

Positive for at least either ER hormone receptor or PR hormone receptor.

5)

PS (ECOG) 0, 1 (3.3 Performance status evaluation)

6)

Aged ≤80 years at time of registration.

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7)Neither recurrence nor contralateral breast cancer found at examination within 6 months
prior to registration.
Only either a bilateral mammogram or breast ultrasound (one-sided in patients withmastectomy) is required for the examination. Examination of areas other than the breasts(chest, abdomen, bones, etc.) will be performed according to the normal examination
policies of each facility.

8)

Patient has adequate organ function.
Meets all the criteria below (according to clinical test results form within 3 months prior
to registration).

9)a)Leukocyte count:≥3,000/mm3b)Platelet count:≥100,000/mm3c)Hemoglobin:≥9.0 g/dl

d)Total bilirubin:≤1.5 mg/dle)

GOT and GPT ≤2.5 times the facility upper limit of normalf)Creatinine:g)

No history of myocardial infarction or congestive heart failure.

h)

No ischemic heart disease or valvular disease that requires treatment.

≤1.5 mg/dl

Consent obtained for study participation in document form from patient herself.

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4.2

Exclusion criteria
Patients who meet any of the criteria below will not be eligible for this study, regardless of whether all
selection criteria are met.
1)

Patient has a metachronous or synchronous bilateral breast cancer.

2)

Patient has invasive cancer of another organ within 5 years of the end of treatment.

3)

Medical history of deep vein thrombosis.

4)

Medical history of bone fracture attributed to osteoporosis, and has symptoms ofosteoporosis at time of registration.

5)

Patient is receiving ongoing treatment in the form of hormone replacement therapy or aselective estrogen receptor modulator (SERM).

6)

Currently participating in another clinical trial with the objective of preventing the
postoperative recurrence of breast cancer.

7)

Patient is deemed unsuitable for study participation by an attending physician.

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5 Registration and allocation
5.1

Registration procedure
Sending of patient registration forms
Attending physicians will confirm that patients meet the selection criteria (4.1) and do not meet any ofthe exclusion criteria (4.2), fill in all items to be investigated at registration (8.1.1) in the “patientregistration form” (Appendix B) and fax the “patient registration form” to the CSPOR Data Center.
CSPOR Data Center
Fax: 03-5298-8536
Tel: 03-3254-8029
Open: Weekdays 10 am to 5 pm (except on weekends and national holidays)
Registration and allocation
The CSPOR Data Center will confirm the eligibility of patients based on the “patient registration form”.
Eligible patients will be registered and allocated randomly (5.2).
Notification of registration and allocation results
The CSPOR Data Center will fax a “registration confirmation form” (Appendix B) to the fax number of
the attending physician noted on the “patient registration form”.
Initiation of protocol treatment
Attending physicians will check the allocation result (treatment group) noted in the “registration
confirmation form” received from the CSPOR Data Center and initiate the prescribed protocol treatment(6 Treatment plan).

5.2

Random allocation and allocation adjustment factors
Patients will be allocated randomly to the STOP group and CONTINUE group at a ratio of nearly 1-to1. Random allocation will be performed dynamically using the adjustment factors below. The allocation
algorithm will be determined by the person responsible for biostatistical analysis.
1)

Type

of

treatment

prior

to

study

(adjuvantendocrine(Anastrozole/Tamoxifen→Anastrozole)2)

Preoperative or postoperative chemotherapy(Yes/None)

3)

Axillary lymph node metastasis(Yes/None)

Negative for isolated tumor cells (ITC)
4)

Facility(By facility)

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5.3

Registration confirmation and reporting commencement of the study
After the CSPOR Data Center has faxed the “registration confirmation form” (Appendix B) to theattending physician, it will also be posted to the attending physician in the mail. The CSPOR Data Center
will register eligible patients for electronic data capture (EDC).
An attending physician or CRC, etc. will submit a “commencement of study report” (Appendix B) to the
CSPOR Data Center via EDC within one month of initiation of protocol treatment.
Study registration will take place at the CSPOR Data Center according to the prescriptions below.
1)

Patients will not be registered if their patient registration form is not fully complete.

2)

Once registered, patient registration may not be rescinded (erased from the database).

3)

In the event of a duplicate registration, the prior registration information will be used(patient registration number, allocation group).

4)

Because a special procedure is required for dealing with an erroneous or duplicate
registration in the database, when an erroneous or duplicate registration comes to lightat a facility it will promptly be reported to the Data Center.

5.4

Discontinuation prior to commencement of the study
Following registration, a “commencement of study report” and “progress report” will be collected forevery patient, even patients for whom participation is discontinued prior to the initiation of protocoltreatment. For patient discontinuations that occur prior to the initiation of protocol treatment due towithdrawal of consent or cancelled visits, background information and the progress report at the time ofwithdrawal will be collected, and no further observations, examinations or investigations will be carriedout.

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6 Treatment plan
6.1

Definition of study periods
Study periods are defined as shown below.

Date ofsurgery

Between 4 years 9 months and5 years 2 months

Until the end of the study

Registration and random allocation

Pre-study treatment, adjuvant
endocrine therapy

Discontinuation or completion of protocol treatment
Protocol treatment (complete after 5 years)

Once/year

Observed untreated orwith extended ANA treatment

Recurrence andsurvival survey

Observation phase (6.3)

Follow-up phase

ANA or TAM→ANA

Pre-study treatment phase (6.2)
Date of starting prestudy treatment

6.2

Date of random
allocation(6.4)

Pre-study treatment phase
In this study the 5 years of adjuvant endocrine therapy initiated after surgery will be called “pre-study
treatment”, and this period will be termed the “pre-study treatment phase”.
Pre-study treatment and registration
Attending physicians will register patients to this study who are receiving ongoing pre-study treatment
and who are at a point between a full 4 years 9 months and 5 years 2 months into the pre-study
treatment phase (5.1). Pre-study treatment will not include use of LH-RHa and will apply to the use of
any of the postoperative endocrine therapies shown below (4.1 Selection criteria). Registration will,
whenever possible, be carried out at the time of completion of 5 years of pre-study treatment and will
be followed by the immediate initiation of protocol treatment (6.3.1).
1)

Initial therapy of 5 years of anastrozole treatment that is ongoing (ANA)(At time of registration, anastrozole treatment that is ongoing and has been received for
between a full 4 years 9 months and 5 years 2 months)

2)

Initial therapy of tamoxifen treatment followed by at least a full 2 years of anastrozole
treatment, comprising adjuvant endocrine therapy of a total of 5 years that is ongoing.
(TAM→ANA)(At time of registration, adjuvant endocrine therapy that is ongoing and has been received
for between a full 4 years 9 months and 5 years 2 months)

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Ending pre-study treatment
Attending physicians will end pre-study treatment in patients according to the provisions below.
1)

When the period of pre-study treatment is between 4 years 9 months and less than 5
years at time of registration:
Pre-study treatment will be continued until the full 5 years then ended.

2)

When the period of pre-study treatment is between a full 5 years and 5 years 2 months
at time of registration:
Pre-study treatment will be ended at time of registration.

6.3

Observation phase
The “protocol treatment” described below will be initiated after the end of pre-study treatment andobservations will be continued for 5 years from the date of initiation. The immediate initiation of protocoltreatment after the end of pre-study treatment is desirable, though transition to protocol treatment will
be completed within 90 days of the end of pre-study treatment.
The prescribed observations, examinations and evaluations (8.1) will be performed during theobservation phase and reported in a “progress report” (Appendix B).
Protocol treatment
Protocol treatment is defined as the treatment administered to the two groups below, into which patientsare allocated randomly at registration.
STOP group: 5 years of observation without treatment
CONTINUE group: Extension of anastrozole treatment for 5 years (1 dose/day, 1 mg/day, oral
administration)
The date of initiation of protocol treatment will be reported in a “commencement of study report”(Appendix B).

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End of protocol treatment
Reasons for ending protocol treatment will be classified as shown below.
The end date and reasons will be reported in a “progress report” (Appendix B).
1)

Completion of 5 years of protocol treatment. (Also reported as completion of observation(6.3.6).)2)

Discontinuation of protocol treatment due to an event (recurrence)3)

Discontinuation of protocol treatment due to an event (death). (Also reported as
discontinuation of observation (6.3.6).)
This classification will not be applicable in the event protocol treatment is ended foranother reason prior to patient death4)

Protocol treatment discontinued by an attending physician due to an adverse event

5)

Discontinuation of protocol treatment due to the wishes of the patient (for reasons related
to the occurrence of adverse events)

6)

Discontinuation of protocol treatment due to the wishes of the patient (for reasons not
related to the occurrence of adverse events)
This classification will only be applicable in the event a relationship with an adverse event
can be ruled out.

7)

Discontinuation of protocol treatment due to medical facility transfer

8)Discontinuation of protocol treatment due to other reasons (initiation of a prohibitedconcomitant treatment, protocol violations, etc.)

Note: The prescribed observations, examinations and evaluations (8.1) will continue in the event of
discontinuation of protocol treatment. If observation becomes impossible to perform simultaneous to
the end of protocol treatment, it will be reported as “discontinuation of observation (6.3.6)”.
Only investigations of survival, HRQOL (EQ-5D only) and economy of medical care will be continued
after a recurrence occurs.
Concomitant treatments prohibited during participation in the study
Concomitant use of the treatments below is prohibited. If a prohibited concomitant treatment is used,the date the treatment was initiated and details of the treatment will be reported in a “progress report”(Appendix B).
1)

Anticancer treatments other than the protocol treatment (chemotherapy, endocrine
therapy, antibody therapy, surgery, irradiation, etc.).

2)

Hormone replacement therapy.

3)

Treatment with a selective estrogen receptor modulator (SERM).

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Concomitant treatments during study participation: Treatment for reduced bone density
Attending physicians will advise patients to take care to take in calcium everyday as part of a balanced
diet. Treatment will be performed as described below in the event of reduced bone density during
protocol treatment.
(1) Criteria for initiation of treatment
Treatment will be administered if the young adult mean (YAM) or T score of the bone mineraldensity (BMD) of the lumbar vertebra (mean of L1-4, or mean of L2-4), femur, radius or second
metacarpal meets the criteria below.
Initiation of treatment will be recommended regardless of the T score if a previous vertebral body
fracture that is suspected to be non-traumatic is observed at X-ray examination of the thoracic
vertebra or lumbar vertebra at the time of registration.
1)

T score of ≤-2.5 or YAM of <70% (osteoporosis) → Initiate treatment (required)2)

T score ≤-2.0 or YAM of <80% (decrease in bone mass) → Recommend treatment (ifpossible)(2) Treatment method
See the treatment methods described below.
1)

First choice:Bisphosphonate preparation (any of the preparations noted below is recommended)• Alendronate (35 mg, once/week)• Risedronate (17.5 mg, once/week)

2)

Second choice: If a bisphosphate preparation cannot be administered
Active vitamin D (0.25 μg, once/day, taken after evening meal is recommended)3)

Concomitant use of 1) and 2) will be recommended if patient is 70 years of age or older

Treatment after the end of protocol treatment
This study does not prescribe any treatment to be given after the end of protocol treatment.

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Completion or discontinuation of observations
Performance of the prescribed observations, examinations and evaluations (8.1) during the protocoltreatment phase for the prescribed 5 years will be termed “completion of observation”, and if they cannot
be performed for the prescribed 5 years will be termed “discontinuation of observation”. Prescribed
observations, examinations and evaluations will be performed in the event of either completion or
discontinuation of observations, and the date of final observation and reasons for ending observation(following categories) will be reported in a “progress report” (Appendix B).
1)

Completion of 5 years of observation:
The follow-up phase (6.4) occurs after the completion of observation.

2)

Discontinuation of observation due to an event (recurrence):
Also reported as recurrence (8.2).
Only investigations of survival, HRQOL (EQ-5D only) and economy of medical care will
be continued after a recurrence occurs.

3)

Discontinuation of observation due to an event (death):
This classification is not applied if observation is discontinued for another reason prior todeath:
The cause of death will be described.

4)

Discontinuation of observation by an attending physician due to adverse events.

5)

Discontinuation of observation due to the wishes of the patient (for reasons related to theoccurrence of adverse events):
The reasons will be described.

6)

Discontinuation of observation due to the wishes of the patient (for reasons not related
to the occurrence of adverse events).
This classification will only be applied in the event a relationship with the adverse event
can be ruled out:
The reasons will be described

7)

Discontinuation of observation due to medical facility transfer:
The destination medical facility will be recorded.

8)

Discontinuation of observation due to other reasons

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6.4

Follow-up phase
The period between the completion of observation and the end of the study (completion of the overall
study) will be defined as the “follow-up phase”. During the follow-up phase, attending physicians will
examine patients once per year whenever possible to performed prescribed observations, examinations
and evaluations (8.1.4).
If a patient cannot be examined, the attending physician will investigate from the facility by whatevermeans possible (by phone, by documents sent through the post, etc.), in particular, obtaining
information on survival and recurrence whenever possible.
The date of follow-up investigations and investigation results will be recorded in a “follow-up report”(Appendix B) for each follow-up examination performed. If follow-up is ended, the date of the final followup investigations, reasons for ending follow-up and results will be reported.

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7 Treatment Drug
A summary of the drugs used in this study based on the drug package inserts is shown below. See thepackage inserts (Appendix D) for details. The latest information on each drug will always be used andthe latest version of the package inserts of each drug can be found on the Pharmaceutical and Medical
Devices Agency web site (http://www.info.pmda.go.jp/).
7.1

Anastrozole (Arimidex® tablet 1 mg)
Generic name: Anastrozole, ANA
Product name: Arimidex tablet 1 mg (AstraZeneca K.K.)
Contraindications and careful administration(1) Contraindications
Pregnancy, possible pregnancy, or breast-feeding.
A history of hypersensitivity to drug ingredients.
(2) Careful administration
Severe liver or kidney damage.
Main adverse drug reactions(1) Severe adverse drug reactions
1)

Stevens-Johnson syndrome (<0.1%)

2)Anaphylactic reaction, angioedema, hives(2) Other adverse drug reactions
1)≥10%: Hot flush2)

1 to <10%: Headache, asthenia, fatigue, malaise, nausea, alopecia, genital bleeding

3)<1%: Anorexia, vomiting, diarrhea, somnolence, rash, arthralgia, stiffness, vaginal
dryness

4)

Unknown frequency: GOT/GPT/AL-P/γ-GTP increased, carpal tunnel syndrome,
osteoporosis, fracture, hypercholesterolemia

Drug interactions
Anastrozole inhibits activity of CYP1A2, CYP2C9 and CYP3A4 in in vitro tests, but during clinical trials
that investigated interaction with antipyrine, warfarin and tamoxifen this inhibitory action was confirmed
to be clinically non-problematic.

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Metabolism and excretion
The main metabolites on single oral administration of the drug in healthy, postmenopausal women weretriazole, glucuronic acid conjugates, and glucuronic acid conjugates of anastrozole hydroxide. By 336
hours after administration at least 70% of the drug was excreted in urine and at least 75% of the drug
was deemed to have disappeared due to hepatic metabolism.

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8 Observation, examination and evaluation
8.1

Observation, examination and evaluation schedule

3○

After 1 year

4○

After 1 year 6 months

5○

After 2 years

6○

After 2 years 6 months

7○

After 3 years

8○

After 3 years 6 months

9○

After 4 years

10○

After 4 years 6 months

11

○

12

○

13
14

＊
＊

●‡

●

●

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○§

○§

○§

△

△

△

○
○

○
○

○

○

○

○
○

○

○

○
○

○

○

○
○

○

○

△

△

△

△

△

△

Investigated during all phases/periods

At completion of observation(after 5 years)
Or at discontinuation ofobservation
After 6 years(1 year after start of followup)
After 7 years(2 years after start of followup)＊＊

Economy of medical care

6 months after initiation

○

HRQOL

○

○

Joint symptoms(patient survey form)○

Bone density and urinary NTx

2○Adverse events

At initiation of protocoltreatment†◎

X-ray of lumbar and thoracic
vertebra○

Laboratory tests○

Mammography

1

Palpation andvisual examination

HeightClinical examination

Visit

At registration＊

Breast exam◎：Recurrence and contralateral breast cancer not observed in examinations performed within 6months before registration (4.1 Selection criteria).
Only bilateral mammography or breast ultrasound (one-sided in patients with mastectomy) is
required.
Examination of areas other than the breasts (chest, abdomen, bones, etc.) will be performed
according to the normal examination policies of each facility.
●：Performed after consent is obtained and before faxing the patient registration form.
△：Performed whenever possible.
＊
Data at registration will refer to data obtained within 3 months prior to registration (8.1.1).
†
Data at initiation of protocol treatment will refer to data obtained within 3 months prior to initiation
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of protocol treatment (8.1.2).
‡
Patient investigations will be carried out at registration, and physician evaluation will be carriedout by the initiation of protocol treatment (8.5).
§
Only survival, HRQOL (EQ-5D only) and economy of medical care will continue to be investigatedafter recurrence.
＊＊ See “11 Evaluation of HRQOL and economy of medical care”.

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Investigations at registration (Visit 1 in Table 8.1)
The matters below will be investigated at registration. If no other specific provisions apply, data will be
used from examinations within 3 months prior to registration.
1)

Height, body weight, date of surgery, date of initiation of pre-study treatment, scheduled
date of initiation of protocol treatment

2)

Selection criteria check (4.1 Selection criteria)a)Menopausalb)Type of pre-study treatment (adjuvant endocrine therapy); ANA / TAM→ANAc)

TNM staging at first examination (before surgery) (3.1 Clinical stage classification)d)Hormone receptors (estrogen receptor, progesterone receptor)e)PS (3.3 Performance Stats evaluation)f)

Age at time of registrationg)

Recurrence and contralateral breast cancer (based on examination within 6months prior to registration)h)Organ function: Laboratory tests (leukocyte count, platelet count, hemoglobin, total
bilirubin, GOT, GPT, creatinine), medical history of and complicating heart diseasei)3)Consent obtained in document form

Exclusion criteria check (4.2 Exclusion criteria)a)Metachronous and synchronous bilateral breast cancerb)

Invasive cancer of another organ within 5 years of the end of treatmentc)Medical history of deep vein thrombosisd)Medical history of bone fracture attributed to osteoporosis (symptoms present attime of registration)

4)e)Receiving ongoing hormone replacement therapy or a SERM

f)

Deemed unsuitable for study participation by an attending physician

Presence/absence of axillary lymph node metastasis (number of metastases if present)
Negative for isolated tumor cells (ITC).

5)

Use/nonuse of (preoperative or postoperative) chemotherapy

6)

X-ray examination of thoracic vertebra and lumbar vertebra (check for vertebral fracture)

7)

Joint symptoms (patient survey form), HRQOL, economy of medical care.
Investigations at registration will be performed after consent is obtained and before faxing
the patient registration form. After completion will be entered into the registration form.

Investigation at initiation of protocol treatment (Visit 2 in Table 8.1)
The matters below will be investigated at initiation of protocol treatment. Data obtained within 3 months
prior to initiation of protocol treatment will be used for test values (the same data may be used as thatused at time of registration if the test was performed within 3 months prior to initiation of protocol
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treatment).
In the event of patient discontinuation after registration and prior to initiation of protocol treatment,
background information will be collected and investigations at discontinuation will be carried out but nofurther observation, examination or investigation will be performed.
1)

Date of initiation of protocol treatment

2)

Confirmation of discontinuation prior to initiation of treatment

3)

Patient background4)

Surgical findings

5)

State of breast cancer prior to registration

6)

Concomitant treatments

7)

Recurrences, metastases and secondary cancers

8)

Bone evaluation: PS, height, bone density test, urinary NTx, bone fracture

9)Complications: Presence/absence of chronic rheumatism, joint symptoms, symptoms,
signs and diseases that are not the primary disease that are present prior to the start ofthis study

Investigation between 6 months and 5 years after initiation of protocol treatment (Visits 3-12 inTable 8.1)
According to the schedule (8.1), the following items will be investigated.
1)

Date of observation: Date of final observation and reasons at discontinuation orcompletion of observation (6.3.6)

2)

Protocol treatment: Date of ending treatment and reasons if protocol treatment has been
ended since the previous investigation (6.3.2)

3)

Concomitant treatments

4)

Survival status

5)

Recurrences, metastases and secondary cancers

6)

Bone evaluation: PS, height, bone density test, urinary NTx, bone fracture

7)

Adverse events

8)

Joint symptoms (patent survey form), HRQOL, economy of medical care

Only survival, HRQOL (EQ-5D only) and economy of medical care will continue to be investigated afterrecurrence.

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Investigation during follow-up phase (Visits 13 and 14 in Table 8.1)
The matters below will be investigated once/year during the follow-up phase. If a medical examination
is not feasible the attending physician will report details of investigations performed by remote contact
with the patient.
1)

Discontinuation and continuation of follow-up: Date of the final follow-up investigation
and reasons if follow-up was ended

2)

Survival status

3)

Recurrences, metastases and secondary cancers

4)

Adverse events
Adverse events that occur anew during the follow-up phase, and the outcome of adverse
events that occurred during the observation phase.

In addition to the above, whenever possible HRQOL, economy of medical care and joint symptoms(patient survey form) will be investigated only after 1 year of follow-up (Visit 13 in Table 8.1). Also, only
survival, HRQOL (EQ-5D only) and economy of medical care will be investigated after recurrence.

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8.2

Evaluation of recurrence
Tests for recurrence
Tests for recurrence will be carried out after the commencement of observation according to theprescribed schedule (8.1). If recurrence is suspected the necessary examinations will be performed toobtain a definite diagnosis (8.2.3 Diagnosis of recurrence).
Definition and classification of recurrence (parts 1-18 of Breast Cancer Management, 15th edition)
Recurrence refers to a re-emergence of cancer after temporary clinical disappearance due to breast
cancer treatment (surgery, radiotherapy, chemotherapy, etc.) that is confirmed histologically (cellularly).
Multiple cancers are excluded from this definition. Recurrence is classified as follows according to the
site.
1)

Conserved breast recurrence2)

Local recurrence (affected breast wall)
The breast wall refers to an area contained by the lower edge of the clavicle as upperboundary, the costal arch as lower boundary, the midline of the sternum as innerboundary and the anterior border of the latissimus dorsi as outer boundary. Cases that
occur close to a boundary that are difficult to determine will be included under cases of
local recurrence.

3)

Regional lymph node recurrence

4)

Distant recurrence

The following symbols will be used for distant organs in accordance with the TNM classification.
Contralateral breast :CBR

Lymph node

:LYM

Lung

:PUL

Bone marrow :MAR

Bone

:OSS

Pleural

:PLE

Liver

:HEP

Skin

:SKI

Brain

:BRA

Other

:OTH

Diagnosis of recurrence
Below are stipulated the criteria for a definite diagnosis of recurrence.
1)

Conserved breast recurrence
Determined as recurrence when definite diagnosis is obtained from biopsy or cytologicalexamination.

2)

Local recurrence (affected breast wall)
Determined as recurrence when definite diagnosis is obtained from biopsy or cytologicalexamination.

3)

Regional lymph node recurrence (LLYM)
Determined as recurrence when definite diagnosis is obtained from biopsy, cytological
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examination or diagnostic imaging.
4)

Distant organ metastasisa)Contralateral breast (CBR)
Determined as recurrence when definite diagnosis of breast cancer fromcytological examination or biopsy is obtained and diagnosed as clearly ametastasis either clinically or pathologically. A diagnosis of metachronous bilateralbreast cancer will be referred to as secondary cancer (double cancer) and notrecurrence.

b)

Distant lymph node (DLYM)
Determined as recurrence when definite diagnosis is obtained from biopsy,
cytological examination or diagnostic imaging.

c)Lung (PUL)
Determined as recurrence when multiple nodular shadows consistent with lungmetastasis are observed in diagnostic imaging (plain chest x-ray, CT, etc.).
Determined as recurrence when a solitary nodule difficult to differentiate fromprimary lung cancer appears afresh, appropriate differential diagnosis is carriedout and the results show metastasis.
The onset of primary lung cancer will be treated as a “secondary cancer
complication” rather than “recurrence”.

d)Bone marrow (MAR)
Determined as recurrence when definite diagnosis is obtained from bone marrowaspiration.

e)Bone (OSS)
Determined as recurrence when osteolytic or osteoblastic changes are observedin bone x-ray or when abnormalities are observed in bone scintigraphy or bone
MRI, etc. and other conditions can be ruled out.

f)Pleural (pleural effusion) (PLE)
Determined as recurrence when positive cytological examination or pleural biopsy
results are obtained.

g)Meninges
Determined as recurrence when definite diagnosis is obtained from cytologicalexamination.

h)Ascites (peritoneal), pericardial effusion
Determined as recurrence when definite diagnosis is obtained from biopsy or
cytological examination.

i)

Eye
Determined as recurrence when diagnosis is obtained from fundoscopy, CT or MRI.
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j)Liver (HEP)
Determined as recurrence when diagnosis is obtained from ultrasonography, CT
or MRI.

k)Skin (SKI)
Determined as recurrence when definite diagnosis is obtained from biopsy or
cytological examination.

l)Brain (BRA), spinal cord
Determined as recurrence when diagnosis is obtained from CT or MRI.

m)Other (OTH)
Determined as recurrence when definitive diagnosis is obtained from biopsy or
histological examination or non-definitive diagnosis from biopsy or histologicalexamination where other conditions are ruled out.

5)

Diagnosis of recurrence from tumor markersa)An increase in tumor markers alone will not result in a diagnosis of recurrence.

b)

The likelihood of recurrence is extremely high in cases where there is an increasein multiple tumor markers above a certain proportion during the same period or acontinuous increase in a single tumor marker over time and therefore appropriate
diagnostic imaging shall be carried out in such cases to properly diagnose
recurrence.

Determination of the date of recurrence
The date of recurrence will be the date recurrence was first confirmed, that is, either the date specimens
were collected for biopsy and cytological examination or the date of the imaging exam (determinedbased on the “First Evidence Principle”).

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8.3

Evaluation of adverse events
In this study adverse events will be all undesirable signs and symptoms that occur in a patient (including
abnormal laboratory test values) regardless of causal relationship to the study drug. However, therecurrence of breast cancer during the study period will be deemed worsening of the primary disease
and not an adverse event. When an adverse event occurs attending physicians will promptly takenecessary measures (examinations, treatment of adverse event, discontinuation of protocol treatment,etc.) and endeavor to ensure patient safety.
Adverse events will be named and Grade determined according to Common Terminology Criteria for
Adverse Events (CTCAE) v3.0 - August 9, 2006 (Japanese translation JCOG/JSCO Edition – March 8,2007) (Appendix F).
Timing of evaluation and adverse events subject to evaluation
1)

All adverse events that occur during the observation phase will be investigated (including
exacerbation of complications).
Adverse events subject to evaluation will be grouped as shown below in the progress
report. Determination of grade and the naming of adverse events that are “other” will be
carried out according to the CTCAE.
CTCAE
Major
classification

Hot flashes/flushes

Fracture

Fracture

Osteoporosis

Osteoporosis

Joint function

Joint-function

Arthritis (nonseptic)

Arthritis（non-septic）⇒ PainPain-choice: Joint

Pain-Select: Joint⇒ PainPain-choice:HeadachePain-Select: Head/headache⇒ Endocrine

Fracture⇒

Stiffness
Arthritis
ArthralgiaHeadacheOther
2)

Hot flush(flushed face)

Hot flush

Osteoporosis

Name of adverse event

Musculoskeletal/Soft tissue
Musculoskeletal⇒/Soft tissue
Musculoskeletal⇒/Soft tissue
Musculoskeletal⇒/Soft tissue⇒ According to CTCAE

Adverse events that occur anew during the follow-up phase, and the outcome of adverse
events that occurred during the observation phase will be investigated.

Known and unknown adverse events
Adverse events that appear as adverse drug reactions on drug package inserts will be known adverse
events, and those that do not appear will be unknown adverse events.

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8.4

Evaluation of bone density
Periodic observation of bone condition is recommended as an important basic precaution on theanastrozole package insert (Appendix D). Since all patients of this study will be exposed to anastrozole,an evaluation of bone density is deemed necessary and the tests below will be performed.
Attending physicians will measure bone density at visits made at the initiation of protocol treatment, at
1 year after initiation of protocol treatment and at 2 years, 3 years, 4 years and 5 years. The
measurement method, measurement site and results will be reported in a progress report (Appendix B).
Measurement will be carried out according to the items below and treatment in the event of reducedbone density will be carried out according to “6.3.3 Treatment for reduced bone density”.
1)

Bone density measurements will, whenever possible, be carried out by dual X-ray
absoptiometry (DXA). If a facility is unable to perform DXA the next-preferredmeasurement methods are CXD (MD) and DIP. (CXD: computed X-ray densitometry,
MD: microdensitometry, DIP: digital image processing). Measurement results obtained
from other medical institutions are permitted, but the same measurement method will be
used for the same patient for the duration of the study.

2)

Measurement sites in order of preference are lumbar vertebra>femur>radius>second
metacarpal.
The mean of L1-L4 or the mean of L2-L4 will be used for the lumbar vertebra.

3)

DXA measurement results will be recorded as BMD (g/cm2) and percentage relative to Tscore or YAM. CXD (MD) and DIP measurement results will be recorded as (mm AI) andpercentage relative to YAM.

4)

Urinary NTx (urinary cross-linked N-telopeptides of type-I collagen) will be measured asa predictive factor of bone fracture independent of BMD. NTx will be measured by anoninvasive method of urine collection as opposed to blood collection.
Although the collection of second morning urine is optimal, whenever possible urine will
be collected during at same time period (morning or afternoon) in the same patient, given
what is feasible.

In addition, considering that height loss may be related to reduced bone density, height will be measured
at each visit.

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8.5

Evaluation of joint symptoms
The below investigations will be performed since anastrozole treatment is reported to cause arthalgia
and stiffness.
Attending physicians will use CTCAE v3.0 to evaluate arthralgia as an adverse event at visits in all
patients, and report the results in a progress report (Appendix B).
In addition, patients subject to HRQOL investigations will be requested to fill in a patient survey form
(Appendix C) pertaining to joint symptoms with the same schedule as the HRQOL investigations (atregistration, after 1 year, 2 years, 3 years, 4 years, 5 years and 6 years [1 year after starting follow-up])(investigation of joint symptoms will end in the event of breast cancer recurrence). The patient survey
form will include the following.
1)

Presence/absence and grade of arthralgia (CTCAE v3.0 modified for patient use).

2)

Figures to identify sites of arthralgia in the body and a VAS scale showing the severity ofpain at the site where it is most severe.

3)

Presence/absence and grade of joint stiffness (CTCAE v3.0 modified for patient use).

4)

Figures to identify sites of joint stiffness in the body and a survey of timing of onset andchange in symptoms.

8.6

Evaluation of HRQOL and economy of medical care
(See “11 Evaluation of HRQOL and economy of medical care”.)

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9 Data collection
9.1

Data submission
In this study most data collection will be carried out via electronic data capture (EDC). The attending
physician or Clinical Research Coordinator (CRC) will submit data to the CSPOR Data Center inaccordance with the progress of the study up until its completion for all patients registered to this clinicalstudy. When a CRC completes a form or enters data he/she will obtain confirmation from the attending
physician.
Types of survey forms, means of sending and submission of survey forms and timings are shown below.

No.

Type

1

Normal laboratory test values

2

Patient registration form
(Appendix B)

3

Commencement of study
report (Appendix B)

45Progress report (Appendix B)
Protocol treatment,
concomitant treatment,
survival, recurrence,evaluation of bone,adverse events
Follow-up report (Appendix B)
Recurrence,state of survival

Method and timing ofsending form
Posting of EDC
Immediately after facility
registration
Mailed in advance toparticipating facilities

Method and timing ofsubmitting form
EDC entry
1 week prior to start ofregistration
Faxed at time of registration(Included in EDC)

EDC entry
Within 1 month after
initiation of protocoltreatment(Included in EDC)

EDC input
Within 1 month of timing ofeach survey(Included in EDC)
Mailed in advance tofacilities performing theinvestigation
Mailed in advance tofacilities performing theinvestigation

EDC input
Within 1 month after
implementation
MailedWithin 1 month after
implementation
MailedWithin 1 months after
implementation

6

Patient survey form; joint
symptoms (Appendix C)

7Lifestyle and costquestionnaire(Appendix C)

8Copies of statements ofmedical expenses and outsideprescription (paper orelectronic media)

Stipulated for each facility
performing theinvestigation

Submitted once/year

9

Adverse event emergency
contact form (Appendix B)

Medical facility’s style ofform can also be used
Mailed in advance toparticipating facilities

Faxed within 72 hours oflearning of occurrence

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9.2

Data management
The CSPOR Data Center will, in accordance with a separately prescribed data management plan (SOPand manual), send reminders concerning unsubmitted data, scrutinize submitted data and makeinquiries, amend data based on the results of said inquiries and manage the database. In addition, theData Center will also create documents based on the input data for monitoring purposes, which theData Center will conduct together with the Executive Committee. The Data Center will also create
analysis data sets for statistical analysis.

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10 Reporting of adverse events
If any of the following adverse events that must be reported occur, the physician in charge will make areport to the secretariat. Note that when a serious adverse event (serious according to the definition of
ICH E2A) with a causal relationship to the drug that cannot be ruled out occurs, reports made according
to the Safety Information Report System for Drugs, etc. (Pharmaceutical Affairs Law Article 77-4 No.22) and communications with the relevant marketing authorization holder with the purpose of obtaining
cooperation in spontaneous reports of adverse drug reactions by the marketing authorization holder(Pharmaceutical Affairs Law Article 77-4 No.2-1) will be carried out appropriately in accordance with theprovisions of each medical facility and under the responsibility of the physician in charge.
10.1 Adverse events requiring emergency reporting
The following adverse events will be subject to emergency reporting via the adverse event emergency
contact form (Appendix B).
1)

All deaths during the protocol treatment or within 30 days following the date of the final
protocol treatment
Deaths will be subject to emergency reporting regardless of causal relationship to theprotocol treatment. In addition, in the event protocol treatment is discontinued andposttreatment has already begun, deaths within 30 days after the date of the final protocoltreatment will also be subject to emergency reporting.

2)

Unknown grade 4 non-hematological toxicity (adverse events that are not classified
under the blood or bone-marrow classification according to CTCAE).
“Unknown adverse events” refer to events not described on the drug package insert.

10.2 Adverse events requiring normal reporting
Adverse events subject to normal reporting are shown in “8.3 Evaluation of adverse events”.

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10.3 Reporting obligations of the physician in charge and reporting procedures
Emergency reporting
If an adverse event requiring emergency reporting (10.1) occurs, the attending physician will promptly
inform the physician in charge. In the event the physician in charge cannot be contacted, the attending
physician must assume the responsibilities of the physician in charge. If an adverse event requiring
emergency reporting is observed, the physician in charge must immediately report the situation to thehead of the medical facility, and report the situation to the secretariat orally within 24 hours. The
physician in charge must also fill in the prescribed items of an “adverse event emergency contact form”(the medical facility’s own style of form can also be used) and fax it to the CSPOR Data Center (fax:03-5298-8536) within 72 hours of knowledge of the adverse event. In addition, the physician in charge
will create a case report (A4 free format) as a separate document that describes the adverse event infurther detail and fax it to the CSPOR Data Center within 15 days of both parties becoming aware of
the adverse event.
Normal reporting
The physician in charge will fill out the prescribed items in a “progress report” (Appendix B) that
corresponds to the timing of onset of the adverse event and send it to the CSPOR Data Center within
the time of submission for the progress report.
10.4 Responsibilities of the secretariat
Determination of the necessity to suspend registration and emergency notification of participating
medical facilities
In the event the secretariat receives a report from a physician in charge, he/she will seek the judgmentof the principal investigator (or the person acting on his/her behalf) with regard to the degree of urgency,
importance and effects of the report and, if necessary, take measures such as temporary suspensionof registration (by contacting the CSPOR Data Center and all participating medical institutions) andurgently inform participating facilities of the matters in the report.
In addition, the secretariat will also strongly encourage the physician in charge at the reporting facility
to cooperate in making a report according to the Safety Information Report System for Drugs, etc. andspontaneous reports of adverse drug reactions by marketing authorization holders based on the
Pharmaceutical Affairs Law.

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Reporting to the Independent Monitoring Committee
If the principal investigator deems an adverse event that has been reported by a medical facility via
normal reporting or via emergency reporting is an “adverse event that requires reporting”, the principal
investigator will make a report in document form to the Independent Monitoring Committee within 15
days after learning of the adverse event. At the same time, the principal investigator’s opinion
concerning the relevant adverse event and a review of the appropriateness of the response to theadverse event will also be requested.
10.5 Investigation by the Independent Monitoring Committee
The Independent Monitoring Committee will review the content of reports and recommend an ongoing
response to the principal investigator in document form that will cover the handling of the subject andwhether to continue registration.

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11 Evaluation of HRQOL and economy of medical care
11.1 Evaluation of HRQOL
Objectives
HRQOL from the subjective perspective of the patient will be evaluated and compared as a secondary
endpoint of this study.
1)

HRQOL will be compared over a period of disease-free survival in patients who havecompleted 5 years of adjuvant endocrine therapy for postmenopausal breast cancer after
either ending treatment or after extension of anastrozole treatment for 5 years.

2)

An investigation of utility, used to evaluate economy of medical care (11.2) will also be
carried out at the same time.

Measures (survey form)
The survey forms below will be used as measures to evaluate HRQOL (Appendix C).
1)

SF-36 (Medical Outcome Study Short-Form 36-Item Health Survey): The Japanesetranslation of SF-36v2™[17, 18], a survey form and comprehensive measure of HRQOL,
will be used.

2)

FACT-ES[19, 20] subscale: Additional measure for evaluation of endocrine-related
symptoms (subscale only)3)

EQ-5D (EuroQol 5 Dimension)[21-23]: This is a scale based on preference and will be used
to measure utility for evaluation of economy of medical care (5th only, excluding VAS).

Investigation schedule
Investigations will be undertaken at the time of registration, 1 year after registration, 2 years, 3 years, 4
years, 5 years and 6 years (1 year after start of follow-up). Investigation at time of registration will takeplace between after obtaining consent and before faxing the patient registration form. The acceptablewindow for conduct of other investigations will be within ±6 months of each time point. The investigation
at 6 years after initiation of observation (1 year after starting follow-up) will be performed wheneverpossible. Investigations will continue as long as a patient is alive and does not refuse the investigation.
In the event of recurrence the SF-36 and FACT-ES surveys will end and only the EQ-5D survey will be
continued.

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Investigation methods
Attending physicians will obtain the survey forms by post in advance. Attending physicians will distributethe survey form to patients subject to the HRQOL investigation and request the patient fill in and submit
the survey form at each time point. Submission of survey forms will take place by the retrieval of survey
forms by the attending physician and postage to the Data Center within the prescribed window of time.
Patients may submit forms by post directly to the Data Center, in which case the attending physician
will check compliance with submission.
If a patient is unable to fill in a survey form due to exacerbation of an illness or the like, a third party that
may be a family member or a CRC may read the survey form to the patient and fill it in on the patient’s
behalf. In this case the fact this method has been used will be described on the survey form. See
Appendix C for precautions during the completion of the survey by third parties and how to respond in
the event of missing data and the like.
Number of patients
From the experience of the N-SAS BC 03 study, the number of patients required for HRQOL analysis
is deemed to be approx. 150 in each group. In this study the planned number of patients for use in theevaluation of HRQOL is 150 patients in each group starting from the first enrolled patient, with a total of
300 patients in all.
Data analysis method
The SF-36, FACT-ES and EQ-5D scores obtained will be collected by treatment group to produce apattern of change over time, summarized by a few statistical variables as necessary and compared
between treatment groups using an analysis of variance technique. The EQ-5D score will be used to
calculate the QALY and QADFY for an evaluation of economy of medical care (11.2). Note that thedetails of the analytical plan will be described in detail in a separate analysis plan.
11.2 Evaluation of economy of medical care
Objective
To compare the economics of ending treatment and of a 5-year extension of anastrozole treatment inpatients who have completed 5 years of adjuvant endocrine therapy for postmenopausal breast cancer.

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Variables subject to evaluation(1) Direct medical costs
1)

Facilities subject to evaluation
Participating medical institutions that are capable of implementing the HRQOL
investigation and a survey of statements of medical expenses (medical practitioners’
receipts for health insurance claim). This will be approx. 10 facilities.

2)

Number of patients
Approx. 100 patients.

(2) Indirect costs and direct non-medical costs
The same 300 patients participating in the HRQOL investigation will be surveyed.
Method1)Analytical method
A cost-utility analysis (Note 1) will be performed.
If outcomes are equivalent, a cost minimization analysis will be performed.

2)

Frame of reference
Analysis will be from a societal perspective (Note 2).

3)

Outcome indicators
Quality adjusted life year (QALY)
The survival time (overall survival, OS) and QOL (evaluated using a scale where 1 isfull health and 0 is death) are required to calculate QALY. The secondary endpoint overall
survival will be used for survival time and QOL will be obtained from the HRQOL
investigation.
Quality adjusted disease free year (QADFY)QADFY will be calculated using the primary endpoint disease-free survival (DFS) andQOL.

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4)

Cost variables (Note 3)
Costs will be summarized from a societal perspective in terms of direct cost and indirect
cost.
Direct costDirect medical cost
Medical cost associated with treatment and intervention for treatment of adverse
drug reactions.
Direct non-medical cost
Travel cost of medical examination
Disease-related adaptive devices (supportive devices, pads, wigs, etc.).
Indirect cost
Work loss associated with treatment.

5)

Discounting (Note 4)
Discounting will be implemented at a yearly rate of discount of 3% of costs andoutcomes[24].

6)

Presentation of results (Note 5)
Cost-utility ratio (CUR)
The CUR is the cost of obtaining 1 QALY (or 1 QADFY) in either the untreated groupor the extended anastrozole treatment group. The cost of obtaining the same unit of
QALY (or QADLY) will be compared and the group with the smaller cost-utility ratio
determined as the more efficient method of treatment. If outcomes are equivalent
between the groups, a cost-minimization analysis will be performed by comparison of
cost only and the cost-utility ratio will not be calculated.
Incremental cost-utility ratio (ICUR)The ICUR is the cost required to obtain an additional 1 QALY (or 1 QADFY) in theextended anastrozole treatment group relative to the untreated group. This will determine
whether introducing a 5-year extension of anastrozole treatment corresponds withadditional cost.
If the therapeutic effect is higher in the extended anastrozole treatment group relative tothe untreated group and cost is lower, the extended anastrozole treatment group is“dominant” and the incremental cost-utility ratio will not be calculated.

7)

Sensitivity analysis
A sensitivity analysis will be performed that changes the values of parameters using tocalculated both cost and outcome. A sensitivity analysis will also be carried out using a
discount rate of between 0%-7%.

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Data collection
1)

Outcome
Disease-free survival (DFS)The primary endpoint of this study and as such used in the clinical trial results.
QOL (Note 6)
Investigated using a QOL survey form. Evaluation of economy of medical care will use
the QOL evaluation results calculated based on the EQ-5D form.

2)

Cost
Direct medical costDirect medical cost will use data from medical practitioners’ receipts for healthinsurance claims (receipts) and data from outside prescriptions for facilities that issue
prescriptions to be filled at external pharmacy services. Copies of receipts printed forinvoicing purposes and outside prescriptions that are issued will be collected on anannual basis. Electronic data pertaining to direct medical cost is allowed. The standard
data collection procedure will be as described below. Since receipts occur in two types,
paper receipts and electronic receipts, the procedure for submission of receipts will bedecided in advance after discussion between the relevant medical institution and theData Center.
a) Request for cooperation is made to a medical institution.
b) Provisions are created pertaining to the facility and data collection methods.
c) Commencement of data collectiond) Copies are made of the receipts and outside prescriptions of relevant patients, andafter redacting patient names and other information the study registration number isadded to the copies and the copies are sent to the Data Center.
e) The receipts and outside prescriptions are checked at the Data Center and data isentered.
Direct non-medical cost
To investigate direct non-medical cost, a questionnaire survey (Appendix C) will be
implemented in patients subject to the HRQOL investigation with the same schedule as
HRQOL investigations (at time of registration, 1 year after registration, 2 years, 3 years,
4 years, 5 years and 6 years [1 year after start of follow-up]). The acceptable window oftime for surveys is within ±6 months of each time point. Investigations will continue aslong as a patient is alive and does not refuse the investigation, and in the event ofrecurrence the investigation will continue to be implemented using the same survey form.
Indirect cost
The investigation of indirect cost will be included in the investigation of direct nonmedical cost.
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Data processing
1)

OutcomeQALY will be calculated for each relevant patient using survival time and QOL evaluation
results.

2)

Cost
Direct medical cost will be entered with costs grouped by type as clinical exams,
administered drugs, injections, medical procedures, surgeries, tests, diagnostic imaging,hospitalizations and diet. The medical cost of each medical practice will be calculated aswell as overall medical cost.
Direct non-medical cost and indirect cost will be calculated per relevant patient for eachtreatment method after the data has been entered at the Data Center.

3)

Statistical analysis
Details of the analytical plan will be prescribed in a separate analysis plan.
An analysis of the years of disease-free survival can be performed using only the datacollected in this study. An analysis of the overall years of survival will require additional
information on cost after occurrence of metastasis and the like, and is difficult to performusing only the data obtained in this study. Because of this, analysis will be conductedusing a medical treatment model.

Note 1: Cost-utility analysis
Normal methods of evaluating the economy of medical care include cost-minimization analysis (CMA),
cost-effectiveness analysis (CEA), cost-utility analysis (CUA) and cost-benefit analysis (CBA). Each ofthese involves a comparison of multiple treatment methods and uses data both on cost and outcome toinvestigate efficiency, and is classified as a full economic evaluation[25].
The CMA is used when outcome is identical between the treatment methods being compared. The CMA
only compares cost where the method of least cost is determined the most efficient. The CEA is themost commonly deployed analytical method and defines one primary outcome indicator and compares
the calculated cost of obtaining a single unit of outcome. Life years gained is often used as the outcome
indicator for CEA. The CUA uses a utility value as an indicator of outcome, which is a measure thattakes into account extension of years of survival and the relative QOL between those years. QALY isoften used as the unit of reference for CUA. QALY is evaluated using a scale that takes total health as“1” and death as “0”. Consequently, 1 QALY refers to one year of survival in a fully healthy state. The
CBA converts all the effects obtained from treatment into a monetary value and evaluates the results.
In addition to comparing the calculated benefit obtained per input cost, the CBA also compares thecalculated net benefit that is the benefit minus cost.
Note 2: Analytical perspective
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When conducting an evaluation of the economy of medical care, it is important to define from whose
perspective the evaluation is being performed. In terms of outcome the objective is an improvement in
the health status and QOL of the patient, but changing from whose perspective analysis is performed
will result in differing scopes of costs that must be included in the analysis. Potential perspectives
include the patient, medical institution, insurance-paying party and government. For example, from theperspective of the patient, costs will include payments made at the medical institution and travel costs
incurred due to clinical exams. From the perspective of the medical institution, cost will include the laborcosts, materials costs, expenditures, etc. incurred in providing medical care for the illness. From theperspective of the party paying the insurance claim, costs will include remuneration paid to the medical
institution. A societal perspective includes all these perspectives and in so doing encompasses all
perspectives that pertain to a disease.
Note 3: Classification of cost
There are various methods of classifying cost for the evaluation of economy of medical care. Whatfollows is an explanation of the difference between direct and indirect cost. Direct cost is the cost paid
to receive treatment for a particular disease while items included in the direct cost will vary from ananalytical perspective. Normally, direct cost is divided in to the costs incurred at the medical institution
and pharmacy (direct medical cost) and other payments (direct non-medical cost). Indirect cost is
calculated as the opportunity cost of loss of work that arises from the change in becoming unable toperform activities of daily living associated with a disease or treatment. No actual payments are made,but indirect cost is important for an evaluation of economy of medical care from the perspective of lossof resources.
Note 4: DiscountDiscounting is a method of converting cost arising across a number of years into a valuation at a single
point in time. People generally have a time preference, where a sum of money has a higher valuationin the present time relative to its valuation at a point of time in the distant future. Discounting is carriedout to convert a future cost into a current valuation. A number of discount rates have been proposed.
There is a dispute about whether to also discount for outcomes, with many suggesting that outcome
should be discounted to the same extend as cost.

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Note 5: Cost-utility ratio and incremental cost-utility ratio
The results of evaluations of economy of medical care are often represented as the cost of obtaining asingle unit of outcome. This is the cost-utility ratio (called the cost-utility ratio or cost-benefit ratio
depending on the analytical method). The cost-utility ratio is calculated by taking the cost of eachtreatment method as the numerator and the effect obtained as the denominator.
Taking the respective cost of treatments A and B as cost(A) and cost(B) and the respective effects aseffectiveness(A) and effectiveness(B), the cost-effectiveness ratio is calculated as:

Compared to this, the incremental cost-effectiveness ratio is calculated using the incremental cost or
effect of a treatment method relative to the more common treatment method or the lower cost treatmentof the treatments being compared:

This represents the cost incurred to obtain an additional single unit of effect relative to the treatment
method taken as the control method.
Note 6: QOL evaluation for an evaluation of economy of medical care
The QOL evaluation used in the cost-utility analysis uses a scale between 1 and 0 where 1 represents
full health and 0 represents death. Direct methods of QOL evaluation include the visual analogue scale,time trade-off and standard gamble. An indirect method of QOL evaluation includes calculating a QOL
evaluation value using a conversion formula obtained from a scale based on preference (for example,
the ED-5Q that evaluates a scale of 5 dimensions and 3 stages, and the HUI of 8 dimensions).

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12 Endpoints
12.1 Primary endpoint
Disease-free survival (DFS)(1) Definition
Period of time from date of random allocation to the date when the first event occurs.
(2) EventAn event will be defined as occurrence of any of the below.
1)

A diagnosis of conserved breast recurrence, local (affected chest wall) recurrence,
regional lymph node recurrence or distant organ metastasis (8.2)

2)

A diagnosis of metachronous breast cancer or secondary cancer (not including
cutaneous basal cell carcinoma, squamous cell cancer or endometrial intraepithelial
carcinoma)3)

All deaths (regardless of cause)(3) Cut-off
1)

The last confirmed date of an absence of the above events2)

For surviving patients, the last confirmed date of survival

12.2 Secondary endpoints
Overall survival (OS)(1) Definition
Period of time from date of random allocation to the date of death, regardless of cause of death(2) EventAll deaths (regardless of cause)(3) Cut-off
1)

For surviving patients, the last confirmed date of survival2)

For patients lost to follow-up, the last confirmed date of survival

Distant disease-free survival (DDFS)(1) Definition
Period of time from date of random allocation to the date when the first event occurs(2) EventAn event will be defined as occurrence of any of the below.
1)

A diagnosis of distant organ metastasis (8.2)2)

All deaths (regardless of cause)(3) Cut-off
1)

The last confirmed date of an absence of the above events2)

For surviving patients, the last confirmed date of survival
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Adverse events
Adverse events will be termed and classified by Grade according to the JCOG Edition Japanesetranslation of CTCAE v3.0 (Appendix F).
The rate of occurrence of adverse events will be calculated by taking the total number of patients inwhom observation is initiated (patients evaluable for safety) as the denominator and the number ofpatients in whom one or more adverse events is observed after commencement of observation as thenumerator. In addition, the rate of occurrence of the most severe Grade of each adverse event will becalculated for each group.
Evaluation of HRQOL and economy of medical care
(See “11 Evaluation of HRQOL and economy of medical care”.)
12.3 Other endpoints
Evaluation of bone density
Bone density will be evaluated in registered patients in whom the mean BMD (g/cm2) is measured in
L1-L4 or in L2-L4. Taking the commencement of observation as baseline, the mean rate of change(percentage change) in BMD and the T score in each year will be compared in the CONTINUE groupand the STOP group. The temporal change in urinary NTx will be evaluated in patients in whom urinary
NTx is measured.
Bone density results obtained by methods other than DXA will be used for evaluating adverse eventsand determining the commencement of treatment (6.3.3 Treatment for reduced bone density).

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Evaluation of joint symptoms
Joint symptoms will be valuated in patients in whom the below items are investigated according to theprovisions of section “8.5” of this protocol. CTCAE v3.0 evaluation results will be used to calculate rateof occurrence of each Grade and a comparison made between the CONTINUE group and STOP group.
The pain score measured in terms of distance from a zero score indicating no pain according to the
VAS evaluation, will be used to calculate basic statistics and make a comparison between the groups.
1)

Joint pain-related CTCAE v3.0 (pain-musculoskeletal-joints) evaluation (patient andphysician)2)

Sites of joint pain throughout body (patient)3)

VAS evaluation of site of strongest joint pain (patient)

4)

Joint stiffness-related CTCAE v3.0 (musculoskeletal-joint function) evaluation (patientsand physician)5)Sites of joint stiffness (patient)

6)

Duration of joint stiffness (patient)

7)

Change in joint stiffness (patient)

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13 Statistical matters13.1 Rationale for primary hypothesis and the number of patients
The hypothesis for this study is that “If the rate of disease-free survival is 91% in patients who complete
5 years of endocrine therapy (ANA or TAM→ANA) followed by no treatment for 5 years, the rate of
disease-free survival in patients who receive a 5-year extension of ANA treatment will be 94% or higher”.
An EBCTCG meta-analysis[13] of 15 years of long-term follow-up including 5 years of TAM treatment in
ER positive (including unknown) breast cancer patients reports that patients who transitioned tountreated observation after 5 years of TAM treatment had a cumulative rate of breast cancer recurrenceof 15.1% after 5 years, 24.7% after 10 years, and 33.2% after 15 years. In addition, an ATAC trial thatobtained 68 months of data reports a difference of a little under 3% in recurrence rate between patientstreated with ANA or TAM after 5 years of endocrine therapy. Even considering the carry over effect,
based on the previously mentioned EBCTCG results the estimated recurrence rate for a grouptransitioned to 5 years of no treatment after receiving ANA treatment will be 9%.
Consequently, the results observed in patients who receive TAM→ANA treatment are assumed to bealmost identical to those who receive ANA monotherapy, and the estimated rate of recurrence in the
STOP group of this study is estimated at 9%.
Although no results are available from direct investigations into the potential recurrence rate in the
CONTINUE group, the results of the MA17 trial[15] of an additional 4 years of LET treatment after 5 years
of TAM treatment showed a difference in DFS of ≥4%. Consequently, it has been assumed that an
improvement in DFS of ≥3% will be evidence of clinical effectiveness.

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13.2 Scheduled number of patients and follow-up period
With a DFS rate of 91% for untreated observation (STOP group) and 94% in the population that receives
a 5-year extension of ANA treatment (CONTINUE group), an enrollment period of 2 years is chosen, afollow-up period of 5 years, a type I error of 5%, and a statistical power of 80%.
The number of patients required has been calculated assuming a patient dropout rate of 0%, 5% and
10% in the STOP group and 0% and 5% in the CONTINUE group (according to the SAS 9.1.3 STAT
Power procedure).
STOP group

Number ofpatients/group

Dropout rate

CONTINUE
group
Dropout rate

0

0

1002

0

0.05

1098

0.05

0

1068

0.05

0.05

1159

0.1

0

1144

0.1

0.05

1231

In this study of the 5 years that follow standard treatment, assuming slightly more dropouts in the STOP
group compared to the CONTINUE group with respective dropout rates of 10% and 5%, the required
number of patients is 1231. For reference purposes only, when the required number of patients wascalculated using the Freedman and Schoenfeld formulae, not taking into account a dropout rate orregistration period, the two methods gave results of 1214 and 1178 patients, respectively.
Consequently, the required number of patients will be 1250 per group.
13.3 Handling of patients and analysis sets
The analysis set will include all patients who are allocated randomly after consent is obtained.
13.4 Aggregation of patient registration status
Patients who discontinue or drop out from the study will be aggregated in accordance with the handlingguidelines and the cumulative discontinuation and drop out rate will be calculated using the KaplanMeier method. Aggregation of patient registration status in terms of a scoring of each patient
background factor will be carried out and the difference between the groups will be tested with the
purpose of examining the balance amongst the groups with regards to distribution of discontinuationand dropout cases.

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13.5 Aggregation and comparison of treatment complianceAggregation of treatment compliance will be carried out in accordance with the handling guidelines, andthe reasons for treatment discontinuation will be gathered and summarized.
13.6 Analyses of each survival times
Rates of DFS will be compared amongst the groups by constructing a Kaplan-Meier curve and applying
a Log-rank test. The test will be two-sided with a significance level of 5% and the two-sided 95%
confidence interval will be calculated.
Interaction between the factors used during allocation will be examined using a chi-square test and adiagrammatic representation of confidence intervals for subgroups. In particular, since patients eligible
for this study will have received an endocrine therapy of either ANA or TAM→ANA, whether a differencein treatment method on entry has an effect on prognosis will be examined.
In addition, this study will evaluate whether to continue or discontinue ANA treatment. Since patients
have already received 5 years of treatment, analysis (sensitivity analysis) will take into account carryover effects of the prior treatment and results will be examined for corresponding influences.
See the separately prepared analysis plan for more details.
13.7 Supplemental analysis of each survival time
Cox regression analysis will be performed to examine each survival time with the use of adjustment
factors.
13.8 Analysis of adverse events
The rate of adverse events in each group will be summarized and evaluated.
13.9 Other analyses
Other analyses will be decided during the period until the conduct of data analysis, and included on
preparation of the analysis plan.

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13.10 Monitoring and review under blinding
The Executive Committee will conduct appropriate monitoring and review of the matters below.
・ Enrollment
・ Recurrence of beast cancer and occurrence of adverse events (examination of annual number of
events only)
The need to reexamine the number of patients and the timing of interim and final analyses will be
determined based on information gained through monitoring and review and new findings obtained untilthat point in time. This information will also be examined for the appropriateness of the timing of
publication of results.
The Executive Committee will also provide recommendations to the Clinical Study Sub-Committee andthe Independent Monitoring Committee in the event the protocol requires amendment, and amendments
will require review and approval by the Clinical Study Sub-Committee and the Independent Monitoring
Committee.
Note the blind review required to determine the particulars of the analysis plan, such as to examine thevariables used in the Cox regression analysis, will be performed prior to interim analysis.
13.11 Interim analysis
Calculation of the rate of DFS in the STOP group will be performed based on the EBCTCG metaanalysis. In addition, an interim analysis will be performed due to a lack of evidence in Japanese patients.
To maintain a two-sided type I error of 5% for the whole study at interim analysis, the Lan & DeMets α
consumption function will be used to adjust for redundancy in analysis of the primary endpoint. The
O’Brian & Fleming α consumption function will be used.
Interim analysis will be carried out by the Independent Monitoring Committee. The prospective numberof events according to the Freedman equation is 232. Interim analysis will be carried out when 50%60% of events have occurred.
If the therapeutic effects are sufficient and rate of cancer recurrence is higher than supposed in the
STOP group according to results at interim analysis, the disbenefit of not receiving treatment will havebeen demonstrated adequately. Recalculated based on therapeutic effects evidenced up to the point ofinterim analysis, if the number of required patients differs substantially from the initial calculation the
discontinuation or change of the study will be examined from a statistical viewpoint and arecommendation will be made to the Executive Committee.
In addition, the Independent Monitoring Committee will carry out an interim analysis of safety at 1 yearand 2 years after commencing registration. The Independent Monitoring Committee will examine
treatment compliance and occurrence of adverse events, and if it deems discontinuation or change ofthe study necessary will make a recommendation to the Executive Committee.

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14 Ethics
14.1 Patient Protection
All researchers involved with this study will conduct this study in conformance with the Declaration of
Helsinki(Appendix

E)

and

the

“EthicalGuidelinesforClinicalResearch”(http://www.imcj.go.jp/rinri/index.html) of the Ministry of Health, Labour and Welfare.
14.2 Informed Consent
Explanation to patients
Prior to registration, the attending physician will provide the patient with explanatory documents(Appendix A explanatory documents revised by each facility) approved by the facility’s Ethical Review
Committee (or Institutional Review Board; IRB) and give the patient a detailed oral explanation of thefollowing content.
1)

An explanation of the disease2)

That the study is a clinical trial

3)

The study design and rationale (study significance, scheduled number of patients,
necessity, objectives, etc.).

4)

Details of the protocol treatment
Drug names, treatment methods, doses, phases, etc.

5)

Expected effects of protocol treatment

6)

Anticipated adverse events and treatment methods

7)

Burden of cost and compensation
The burden of cost and compensation will be equivalent to normal medical care. I.e., thecost of treatment will be covered by the patient’s system of insurance and in the event ofdamage to patient health compensation will be consistent with normal medical care.

8)

Alternative methods of treatment
Alternative methods of treatment that are currently common treatments.

9)

The anticipated benefits and possible disadvantages of participation in the study

10)

Checking of the patient’s medical history by auditors
Explanation of the patient’s acceptance of audit

11)

Refusal of consent and withdrawal of consent
That the patient is free to refuse consent before participating in the study, and once
consent has been given the patient is still free to withdrawal consent, and will be put at
no unreasonable medical disadvantage as a result.

12)

Human rights
Utmost efforts will be made to protect the name and personal information of the patient.

13)

Secondary use of data
Data may be put to secondary uses in such a way that it may not be linked to personally
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identifying information.
14)

Freedom to ask questions
The patient will be given a document with the contact details of the attending physician
and principal investigator (or study secretariat), and given the freedom to ask questions
about the study or treatment.

Consent
Patients will be asked to participate in this study after having the study explained to them and after it
has been confirmed they fully understand the content of the study. In the event a patient consents toparticipation in the study, a consent form in a format prescribed by the facility will be used to record thename and signature of the physician who provided the explanation, the patient who received the
explanation and consents to participation in the study, and the date of consent.
Two copies of this consent form will be made, one copy given to the patient and one copy retained by
the facility. The original will be stored in the patient’s medical record.
Timing of obtaining consent
Consent will be obtained prior to registration.
14.3 Patient identification and protection of privacy
The names of registered patients will not be made known to the Data Center by participating facilities.
Identification of and queries regarding registered patients will be carried out using their patientregistration number issued at the time of registration, initials and date of birth and no information thatwould allow a third party to directly identify patients such as patient names, etc. will be registered in the
database of the Data Center.
To maintain confidentiality of patient information the “day” section of the date and patient initials may
be masked, but an “x” mark will be placed next to the affected place.
Exchange of patient data between facilities, the Data Center and the secretariat will be conducted by
the methods described below.
1) Patient registration, queries to be expedited, emergency adverse event reporting: By fax.
2) EDC system: Electronic data transfer employing encryption.
3) Paper survey forms: Mailed through the post or passed hand-to-hand.
14.4 Protocol compliance
The researchers participating in this study will comply with this study protocol insofar as compliancedoes not compromise patient safety and human rights.

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14.5 Facility Ethical Review Committee (or Institutional Review Board: IRB) approval
Approval at commencement of study participation
Upon commencing participation in this study, each facility’s Ethical Review Committee or IRB must
approve this study protocol and the patient explanatory documents. If IRB approval is obtained, a copyof the IRB approval form will be sent to the CSPOR Data Center. The original IRB approval forms will
be retained by each facility and copies retained by the CSPOR Data Center.
Yearly re-approval by the IRB
The regulations of each facility will dictate whether yearly review and re-approval of this study protocol
and the patient explanatory documents by their Ethical Review Committee or IRB will be necessary.

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15 Monitoring and auditing
15.1 Monitoring
Objective
To confirm whether the study is being conducted safely and in accordance with this protocol andwhether data is being collected accurately.
Central monitoring (in-house monitoring)
The Executive Committee and Data Center will cooperate in monitoring the content of EDC data and
HRQOL survey forms collected at the CSPOR Data Center using the processing results of digitizeddata as a reference. There is no plan to carry out monitoring by visiting participating facilities.
Items (on patient basis)
1)

Eligibility

2)

Protocol treatment status

3)

Adverse events; serious adverse events and their reporting status in particular4)

Follow-up status after completion of the protocol treatment; survival in particular

5)

Other items

Items (on by-group accumulated results basis)
1)

Patient accumulation status

2)

Eligibility

3)

Protocol treatment status

4)

Incidence of adverse events

5)

Follow-up

6)

Other items

15.2 Auditing
Objective
To confirm whether this study is being conducted appropriately and verify the reliability of the dataobtained.
Auditing Committee
An Auditing Committee will be established within the Japan Clinical Research Support Unit (J-CRSU)
in order to conduct auditing. The Auditing Committee will be composed of physicians or professionals
with similar qualifications who possess experience and insight in clinical trial research and are notdirectly responsible for patients that are subject to auditing. A chairperson will be selected from amongst
the members.
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Duties of the Auditing Committee
1)

The Auditing Committee will conduct audits to verify whether the registration of eligible
patients, drug administration, observation and follow-up examinations, etc. are being
carried out in accordance with the provisions of this clinical study protocol.

2)

The Auditing Committee will create auditing plans (SOP and manual) and visit the
CSPOR Data Center and participating medical facilities to conduct audits in accordancewith these auditing plans.

3)

Visit and audit of medical facilities
The Auditing Committee will sequentially visit all participating medical facilities to inspectclinical study-related documents and source documents related to registered patients(medical records, diagnostic images, etc.) with the purpose of confirming whether thisstudy is being conducted in adherence with the principles of ICH-GCP and this clinicalstudy protocol.

4)

CSPOR Data Center auditing
The auditing team will conduct auditing to confirm whether duties of the CSPOR Data
Center are being carried out in accordance with the SOP and provide guidance.

5)

Creation of audit reports
The Auditing Committee will perform their duties, create audit reports to record mattersconfirmed in audits that have been conducted, create audit certificates to prove that
audits have been conducted and submit these documents to the principal investigator.

Protection of privacy
Attention will be given to the protection of records that disclose the identity of the patients in this study
and confidential medical information.
Extramural review by the Auditing Committee
The Auditing Committee will conduct an extramural review of cases of recurrence, death and serious or
unexpected adverse events and report their results to the principal investigator. The principal
investigator and Executive Committee will examine the necessity of facility monitoring based on theseresults and conduct facility monitoring if necessary.

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16 Announcement of research results
Research results will be published in line with policy created by the Clinical Study Sub-Committee.
Study-related announcements will be made at the study planning report, interim report, and final reportstages of the study. These announcements will be within the format of academic conferences and article
submissions to journals. The study planning report will be announced at an appropriate time as an
outline of this study that will be based on this protocol. The interim report will be announced promptly
at the first opportunity if results are obtained from an interim analysis performed according to theprevious study plan that should be announced. As long as the study does not end early, the final report(report of results of primary endpoint confirmatory analysis) will be made at the completion of the followup phase.
The listing of authors and their listing order will be carried out in accordance with the above-mentioned
Clinical Study Sub-Committee policy and be reviewed and authorized by the Clinical Study SubCommittee and Independent Monitoring Committee prior to announcement of the relevant results at
both academic conference presentations and in submissions to journals.

17 Conflicts of interest and research funding
There are no potential conflicts of interest relating to the planning, conduct or announcement of thisstudy. A conflict of interest refers to a vested interest that affects research results and includes financial
and personal relationships.
The conduct of this study is funded by the Comprehensive Support Project for Oncology Research(CSPOR). The secretariat of the CSPOR will undertake clerical activities but will have no part indecisions related to the planning, conduct or announcement of the study. Decisions relating to theplanning, conduct and announcement of the study will be undertaken by the Executive Committee.

18 Clinical trial registration
This study will be registered to and information published on the UMIN Clinical Trials Registry (UMINCTR, http://www.umin.ac.jp/ctr/index-j.htm). Registration will occur prior to enrollment of the first patientto the study, and registration will be carried out by the CSPOR.
UMIN-CTR is a registry organization that meets the requirements of the internationally supported clinical
trial registration system. The necessity for the registration of clinical trials has been debated since the1970s. In September 2004, the International Committee of Medical Journal Editors (ICMJE) declares apolicy that made the advance registration of clinical trials a condition of their publication[26, 27], advancing
the establishment of a system of registration. In addition, the World Health Organization (WHO)launched the International Clinical Trials Registry Platform, and in April 2005 implemented a system of
WHO guidance that stipulated standards for registration[28]. In light of this, in June 2005 the UMIN-CTR
was initiated as Japan’s first clinical trial registration organization. UMIN-CTR is recognized as an
acceptable registry by the ICMJE, and cooperates with the WHO.
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19 Accompanying research
The “Breast cancer patient multipurpose cohort study 05” will be carried out as accompanying research.
The study protocol will be prescribed separately.

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20 Study organization
This study is one of the clinical studies carried out as part of the Public Health Research Foundation’sComprehensive Support Project for Oncological Research. The first committee listed here is the
Executive Committee, which is an organization unique to this study. Next, committees, etc. that arecommon across the support project are listed.
20.1 N-SAS BC05 Executive Committee
Chairperson (principal investigator)
Takuji Iwase (Department of Breast Oncology, The Cancer Institute Hospital of JFCR Ladies
Center)Study statistician (person responsible for biostatistical analysis)
Hiroshi Ohtsu (Department of Clinical Trial Data Management, Graduate School of Medicine,
The University of Tokyo)
Committee members (in order of Japanese syllabary)
Yoshifumi Komoike (Department of Breast and Endocrine Surgery, Osaka Medical Center for
Cancer and Cardiovascular Diseases)
Shigehira Saji (Department of Oncology, Saitama Medical University International Medical
Center)Hiroyuki Takei (Department of Breast Surgery, Saitama Cancer Center)
Hiroshi Yagata (Department of Breast Surgery, St. Luke’s International Hospital)
Adviser
Toshitaka Nakamura (Bone Metabolism Adviser: Department of Orthopaedic Surgery,
University of Occupational and Environmental Health)Mission of the N-SAS BC05 Executive Committee

To carry out coordination work related to the implementation of the study with thesecretariat and Data CenterTo report the study implementation status to the Clinical Research Committee

Matters necessary for quality control and quality assurance of the entire studyQuality evaluation of the facilities participating in the studyTo support the Data Center in data managementTo support the study statistician in statistical analysis

Report creation



Other matters necessary for the smooth and efficient implementation of the study

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20.2 Management Committee
Chairperson
Yasuo Ohashi (Graduate School of Medicine, The University of Tokyo)
Vice chairperson
Kojiro Shimozuma (College of Life Sciences, Department of Science and Engineering,
Ritsumeikan University)
Management Committee members
Toru Watanabe (Hamamatsu Oncology Center)
Tadashi Ikeda (Department of Surgery, School of Medicine, Teikyo University)
Masakazu Toi (Department of Breast Surgery, Kyoto University Hospital)
Takuji Iwase (Department of Breast Oncology, The Cancer Institute Hospital of JFCR Ladies
Center)Yuichi Takatsuka (Department of Surgery, Japan Labour Health and Welfare Organization
Kansai Rosai Hospital)
Shinzaburo Noguchi (Department of Breast and Endocrine Surgery, Faculty of Medicine,
Osaka University)
Shinji Ohno (Department of Breast Oncology, National Hospital Organization Kyushu Cancer
Center)Hiroji Iwata (Department of Breast Oncology, Aichi Cancer Center Central Hospital)
Seiichiro Yamamoto (Center for Cancer Control and Information Services, National Cancer
Center)Mission of the Management Committee

To formulate long-term project plans and annual project plans and report activities to the
Public Health Research Foundation

To formulate budget proposals for project implementation and report balance sheets to
the Public Health Research Foundation

To establish/abolish various sub-committees in order to carry out the project and appoint
sub-committee members

To oversee the activities of sub-committees

Any other matters necessary to achieve the aims of the project20.3 Advisory Committee
Members
Shigemitsu Takashima (Department of Breast and Endocrine, National Hospital Organization
Shikoku Cancer Center)
Hiroki Koyama (Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular
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Diseases)
Tomoo Tajima (Breast Clinic, Department of Surgery, Tokai University Tokyo Hospital)
Hiroshi Obata (Public Health Research Foundation)
Mission of the Advisory CommitteeTo oversee the activities of the Management Committee and respond to inquiries of the
Public Health Research FoundationTo advise the Management Committee and sub-committees

Other matters necessary to ensure transparency of the project and guarantee consistency
with its purpose

20.4 Clinical Study Sub-Committee
Chairperson
Masakazu Toi (Department of Breast Surgery, Kyoto University Hospital)
Vice chairperson
Tetsuya Taguchi (Department of Breast and Endocrine Surgery, Osaka University Hospital)
Members
Toru Watanabe (Hamamatsu Oncology Center)
Takuji Iwase (Department of Breast Oncology, The Cancer Institute Hospital of JFCR Ladies
Center)Takuhiro Yamaguchi (Department of Clinical Trial Data Management, Graduate School of
Medicine, The University of Tokyo)
Shinji Ohno (Department of Breast Oncology, National Hospital Organization Kyushu Cancer
Center)Hiroji Iwata (Department of Breast Oncology, Aichi Cancer Center Central Hospital)
Observers
Yasuo Ohashi (Graduate School of Medicine, The University of Tokyo)
Kojiro Shimozuma (College of Life Sciences, Department of Science and Engineering,
Ritsumeikan University)
Hirokuni Amari (Visiting Researcher, Public Health Research Foundation)
Mission of the Clinical Study Sub-CommitteeTo make decisions on new clinical studies and associated research and, in the event a
public appeal for research is made, make decisions on the guidelines of the public appeal
and adopt research

To appoint Executive Committee members for each clinical study and associatedresearch
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

To oversee the implementation of each clinical study and associated research

To approve oral presentations and the publication of papers related to clinical studies andassociated research

Any other matters necessary for the smooth implementation of the clinical studies andassociated research conducted under this project and coordination between studies

20.5 Epidemiological Study Sub-Committee
Chairperson
Katsumasa Kuroi (Department of Surgery, Tokyo Metropolitan Komagome Hospital)
Vice chairperson
Hiroji Iwata (Department of Breast Oncology, Aichi Cancer Center Central Hospital)
Members
Motoki Iwasaki (Research Center for Cancer Prevention and Screening, National Cancer
Center)Kojiro Shimozuma (College of Life Sciences, Department of Science and Engineering,
Ritsumeikan University)
Tomotaka Sobue (Center for Cancer Control and Information Services, National Cancer
Center)Kaoru Hirose (Aiichi Prefectural Institute of Health)
ObserverYasuo Ohashi (Graduate School of Medicine, The University of Tokyo)
Mission of the Epidemiological Study Sub-CommitteeTo make decisions on new epidemiological studies, and in the event a public appeal for
research is made, make decisions on the guidelines of the public appeal, select research,and report the selected research to the Management CommitteeTo appoint Executive Committee members for each apidemiological study

To oversee the implementation of each epidemiological studyTo approve oral presentations and the publication of papers related to epidemiologicalstudies

Any other matters necessary for the smooth implementation of the epidemiologicalstudies conducted under this project and coordination between studies

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20.6 Education and Training Sub-Committee
Chairperson
Toru Watanabe (Hamamatsu Oncology Center)
Vice chairperson
Kojiro Shimozuma (College of Life Sciences, Department of Science and Engineering,
Ritsumeikan University)
Members
Yasuo Ohashi (Graduate School of Medicine, The University of Tokyo)
Keiichi Fujiwara (Department of Gynecologic Oncology, Saitama Medical University
International Medical Center)
Yuko Saito (Clinical Study Support Laboratory, Shizuoka Cancer Center)
Hirofumi Mukai (Department of Chemotherapy, National Cancer Center Hospital East)
Noriyuki Katsumata (Department of Internal Medicine, National Cancer Center Hospital)
Eriko Aotani (Research Center for Clinical Pharmacology, The Kitasato Institute)
Miki Fukutani (Research Center for Clinical Pharmacology, The Kitasato Institute)
Noriko Yamashita (Division of Clinical Trials and Treatment Development, National Cancer
Center Hospital)
Tatsuhiko Ichiki (EPS Corporation)
Shigeru Takagi (TAIHO PHARMACEUTICAL CO., LTD.)
Yoshitake Tamaoka (Novartis Pharma K.K.)
Mission of the CRC Support/Education Sub-CommitteeTo plan and implement seminars for physician and CRC education

To collaborate with internal and external organizations conducting physician and CRC
educationTo report activities to the Management Committee

Other matters necessary for the improvement in quality and vitalization of physician and
CRC education

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20.7 Public Relations Sub-Committee
Chairperson
Atsushi Fukuuchi (Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital)
Vice chairperson
Seigo Nakamura ((Department of Breast Surgery, St. Luke’s International Hospital)
Members
Kojiro Shimozuma (College of Life Sciences, Department of Science and Engineering,
Ritsumeikan University)
Shigeru Murakami (Department of Breast Surgery, Hiroshima University Hospital)
Mitsuru Miyauchi (BREAST SERVICE Co., Ltd.)
Mission of the Public Relations Sub-Committee

To provide information for the implementation of clinical studies supported by the projectTo examine the content of the Japan Comprehensive Cancer Network, Breast (JCCNB)

To establish working groups for the actual provision of information and oversee theiractivities



Public relations activities related to the project (media, academia, patient groups)To report activities to the Management Committee

Other activities that contribute to the provision of useful information to breast cancer
patients and the smooth implementation of breast cancer research

20.8 Independent Monitoring Committee (Clinical Study Protocol Review Committee)
Chairperson
Tomoo Tajima (Breast Clinic, Department of Surgery, Tokai University Tokyo Hospital)
Members
Suketami Tominaga (Aichi Cancer Center)
Fujio Kasumi (Breast Center, Juntendo Universtiy Hospital)
Eiko Uchida (NPO Bougainvillea)
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20.9 Data Management Committee
Chairperson
Yasuo Ohashi (Graduate School of Medicine, The University of Tokyo)
MemberYuko Saito (Clinical Study Support Laboratory, Shizuoka Cancer Center)
Katsumasa Kuroi (Department of Surgery, Tokyo Metropolitan Komagome Hospital)
Koji Oba (Kyoto University Graduate School of Medicine)
Hiroshi Ohtsu (Department of Clinical Trial Data Management, Graduate School of Medicine,
The University of Tokyo)
Harumi Kaba (National Cancer Center)
Shigeru Hayase (Japan Clinical Research Support Unit)
Naohito Fukui (Japan Clinical Research Support Unit)
Akio Ohta (Japan Clinical Research Support Unit)
20.10 CSPOR Data Center
The CSPOR Data Center carries out patient registration, clinical study progress management,
monitoring and data management.
NPO Japan Clinical Research Support Unit (J-CRSU)
Representative (Head of Data Center)Yasuo Ohashi (Graduate School of Medicine, The University of Tokyo)
Address: 5F Nishiyama-kogyo Ochanomizu Building. 1-2-13 Yushima, Bunkyo Ward, Tokyo
113-0034
Tel.: 03-3254-8029
Fax: 03-5298-8536
E-mail: support@csp.or.jp
20.11 Comprehensive Support Project for Oncological Research Secretariat
Department Chief
Hitoshi Masuda
Address: 3F 1-7-7 Nishiwaseda, Shinjuku Ward, Tokyo 169-0051
Public Health Research Foundation
Tel.: 03-5287-2633
Fax: 03-5287-2634
E-mail: info@csp.or.jp

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21 Amendment of the study protocol / discontinuation of the study
21.1 Change to the protocol
Classification of protocol content changes
Changes to the study protocol following approval by the Clinical Study Review Committee will beclassified as either “amendments” or “revisions”. The definition and treatment of “amendments” and“revisions” are as follows.
(1) Amendment
Amendments include partial changes to the protocol that may increase risk to the patients
participating in this clinical study or changes that are related to the primary endpoint.
Review and approval of the Independent Monitoring Committee and Ethical Review Committee of
each facility is required for amendments.
The date of Independent Monitoring Committee approval will be listed on the cover page of the
protocol.
(2) Revision
Revisions include changes to the protocol that do not increase risk to the patients participating inthis clinical study and are not related to the primary endpoint.
Independent Monitoring Committee review is not required for revisions; however approval of thechairperson of the Executive Committee and reporting to the Independent Monitoring Committee
is required. The regulations of each facility will dictate whether review and approval by their
Ethical Review Committee is required.
The date of Executive Committee chairperson approval will be listed on the cover page of the
protocol.
Approval of the of the Ethical Review Committee of each facility at the time of protocol
amendment/revision
In the event this study protocol or the patient explanatory documents are amended during this study
with the approval of the Independent Monitoring Committee, the amended study protocol and/or theamended patient explanatory documents must also be approved by each facility’s Ethical Review
Committee (or IRB).
In the event a revision, not an amendment, is made, the regulations of each facility will dictate whether
review and approval by their Ethical Review Committee (or IRB) is required.
In the event IRB approval is obtained for an amendment, the facility coordinator of each facility shallsend a copy of the IRB approval form to the secretariat. The original IRB approval form will be retainedby the CRC and a copy retained by the secretariat.

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21.2 Discontinuation of the study
The Independent Monitoring Committee will examine the validity of continuing the study based oninterim analyses of safety and efficacy. If continuation of the study is not deemed to be appropriate, theIndependent Monitoring Committee will recommend the discontinuation or suspension of the study to
the Executive Committee. If the Executive Committee decides to discontinue the study in accordancewith this recommendation, the principal investigator will inform the physicians in charge of the
discontinuation, reason for the discontinuation and method of supporting patients participating in the
study as soon as possible. Physicians in charge will report the circumstances surrounding thediscontinuation to their IRB and provide appropriate support for patients participating in the study inaccordance with the directions of their IRB and the principal investigator.

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22 List of participating medical facilities
Facility name

Department

Physician in charge

See http://www.csp.or.jp/ for the most recent list of participating medical institutions.

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