0/l/L‘0106Y
`
`Oncology 1999;56:283—290
`
`Clinical Study
`
`
`
`
`A Randomized Controlled Comparative Study of
`Oral Medroxyprogesterone Acetate 1 .200 and
`600 mg in Patients with Advanced or Recurrent
`Breast Cancer
`
`HirokiKoyamaa TakeshiTominagab KazuakiAsaishiC Rikiya AbeCI
`
`Yuichi linoe Kohji Enomotof Shigeto Miurag Yasuo Nomurah
`Hiroaki Nakazatoi Osahiko Abel
`
`Study Group for the Chemo—Endocrine Therapy of MPA for Breast Cancer
`
`aDepartment of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, bDepartment of
`Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, CFirst Department of Surgery, Sapporo Medical College,
`Sapporo, dSecond Department of Surgery, Fukushima Medical College, Fukushima, eSecond Department of
`Surgery, School of Medicine, Gunma University, Maebashi, fDepartment of Surgery, School of Medicine,
`Keio University, Tokyo, 9Department of Breast Surgery, Aichi Cancer Center, Nagoya, “Department of Breast
`Surgery, National Kyushu Cancer Center Hospital, Fukuoka, iDepartment of Surgery, Aichi Cancer Center, Nagoya,
`and JDepartment of Surgery, St. Luke's Internal Hospital, Tokyo, Japan
`
`KeyWords
`Dose comparison study ~ Randomized controlled
`trial ~ Breast cancer, advanced or recurrent ~
`
`Medroxyprogesterone acetate
`
`Abstract
`
`A randomized controlled comparative study of oral me-
`droxyprogesterone acetate (MPA) 1,200 mg (arm I) and
`600 mg (arm II) was conducted in 80 patients with ad-
`vanced or recurrent breast cancer. There were no signifi-
`cant differences between arm I and arm II
`in terms of
`
`response rate, duration of response and survival, or in
`terms of incidence and severity of adverse reactions. The
`lowest serum MPA concentration in responders tended
`to be higher than that in nonresponders. In the cohort of
`this study, the lowest concentration in partial response
`was 17.4 ng/ml, suggesting that this level may be the
`required minimum serum concentration.
`
`Introduction
`
`Medroxyprogesterone acetate (MPA) is a progesterone
`analogue synthesized in 1958. MPA is characterized not
`only by its excellent direct effect on tumors such as breast
`and endometrial cancer, but also by its favorable effects,
`such as improvement of performance status and stimula-
`tion of appetite [1]. Pannuti et a1. [2] first reported the
`clinical activity of MFA in breast cancer in the 1970s. The
`usefulness of this agent in single use and in combination
`chemotherapy has since been confirmed [3, 4].
`In clinical studies carried out in Europe and the US a
`Wide range of daily dosages of MPA (500—3,000 mg) was
`used, but the optimal dosage has yet to be defined [5]. A
`dose comparison study conducted in Japan at the dosage
`range of 600—2,400 mg documented a higher response
`rate in the 1,200-mg group compared with the lower and
`higher dosage groups [6]. These results cannot be regarded
`as confirmatory, however, as this was not a randomized
`controlled study. Other studies subsequently reported
`
`
`
`KARO E R
`Fax+416130612 34
`E—Mail karger@karger. ch
`WWW. karger. com
`
`© 1999 S. Karger AG, Basel
`0030—2414/99/0564—0283$17.50/0
`
`Accessible online at:
`http:// BioMedNet.com/ karger
`
`Hiroki Koyama, Department of Surgery
`Osaka Medical Center for Cancer and Cardiovascular Diseases
`3-3 Nakamichi 1-chome, Higashinari—ku
`Osaka 537-8511 (Japan)
`Tel. +81 6 972 1181, Fax +816 9818055
`
`
`
`
`
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`AstraZeneca Exhibit 2147 p. 1
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`

`

`that an effect comparable to that achieved at 1,200 mg
`was obtained with MPA at dosages of 600 and 800 mg
`and suggested that lower dosages be considered to mini-
`mize the risk of adverse events [7—9].
`The aim of the present multicenter randomized con-
`trolled study was to compare the clinical efficacy of MPA
`1,200 and 600 mg in patients with advanced or recurrent
`breast cancer.
`
`Patients and Methods
`
`Patients
`
`The study was performed in 34 centers in Japan (Appendix 1)
`between January 1992 and June 1993. Patients included in the study
`were females with advanced or recurrent breast cancer and with mea-
`
`surable or evaluable lesions who had not received previous treat-
`ment, who had failed to respond to previous treatment or who were
`unaffected by previous treatment. Patients who had undergone sur-
`gery within 1 month before the start of study or those with complica-
`tions or a past history of hypertension, diabetes or arteriosclerosis
`were excluded, because they were considered at high risk for MPA-
`induced thrombosis.
`
`Methods
`Patients were registered over the telephone by a central registra-
`tion method and were randomly assigned to treatment groups at the
`Case Registration Center. Prior to case registration, details of treat-
`ment were fully explained to patients or their families and informed
`consent was obtained either verbally or in writing.
`Patients received oral therapy with MPA at a dosage of either
`1,200 mg/day (arm I) or 600 mg/day (arm II) for as long as possible
`with the aim of continuing administration beyond 12 weeks. Thera-
`peutic efficacy was assessed in accordance with the Standards for
`Assessment of the Therapeutic Effects in Advanced and Recurrent
`Breast Cancer Patients (Japan Breast Cancer Society, 1992) and the
`Criteria for the Evaluation of the Clinical Effects of Solid Cancer
`
`Chemotherapy (Japan Society for Cancer Therapy, 1986). These cri-
`teria are essentially the same as the WHO criteria except for minor
`revisions made for Japanese patients. Assessment of the effect was
`reviewed extramurally by an evaluation committee organized by
`members of the protocol committee.
`Duration of survival and treatment response were assessed at
`final follow-up made in June 1996. The median duration from case
`registration to the end of follow-up was 201.4 weeks. Serum concen-
`trations of MPA were measured by high-performance liquid chroma-
`tography [10] at 8 weeks after the start of the treatment. Plasma corti-
`sol levels were measured before the start of the treatment and at
`8 weeks thereafter.
`
`To test for blood coagulation and fibrinolytic activity, the fibrin
`degradation products D-dimer, rig-plasmin inhibitor plasmin com-
`plex, antithrombin III, protein C and plasminogen activator inhibi-
`tor I were measured before the start of the treatment and 2, 4, 8,
`12 weeks after the start of the treatment.
`
`Patient Eligibility
`Of the 80 patients registered in the study, 10 were considered
`ineligible for inclusion, because of an insufficient duration of with-
`
`Table 1 . Patients’ characteristics
`
`Arm 1
`Arm II
`Total
`p value
`
`(I1 = 37)
`(n = 32)
`(II =70)
`(7:2 test)
`
`
`Mean age, years
`55.6
`55.9
`55.8
`0.93403
`Menopausal status
`16
`8
`8
`Pre
`8
`5
`3
`Peri
`Post
`20
`17
`37
`
`Castrated
`6
`3
`9
`Advanced/recurrent
`Advanced
`4
`3
`7
`0.9999
`
`Recurrent
`33
`30
`63
`
`0.6777
`
`Disease-free interval, years
`7
`3
`4
`0
`9
`6
`3
`< 1
`19
`9
`10
`< 2
`< 3
`6
`3
`9
`
`2 3
`14
`12
`26
`
`0.7123
`
`Histology
`19
`9
`10
`Pap. tub.
`10
`4
`6
`Solid tub.
`32
`17
`15
`Scirrhous
`Others
`4
`3
`7
`
`Unknown
`2
`0
`2
`
`0.6446
`
`Site
`
`4
`2
`2
`Breast
`16
`9
`7
`Skin and subcutaneous
`20
`8
`12
`Lymph node
`12
`6
`6
`Lung
`12
`3
`9
`Pleura
`Liver
`2
`2
`4
`
`Bone
`19
`16
`35
`
`0.7874
`
`Number of sites
`45
`22
`23
`1
`2
`9
`9
`18
`
`2 3
`5
`2
`7
`
`0.5 819
`
`ER
`
`36
`18
`18
`+
`—
`8
`8
`16
`
`Unknown
`11
`7
`18
`
`0.7180
`
`PgR
`
`23
`13
`10
`+
`—
`10
`6
`16
`
`Unknown
`17
`14
`24
`
`0.4824
`
`PS
`
`0.4296
`
`43
`21
`22
`0
`18
`10
`8
`1
`2
`1
`1
`2
`3
`4
`1
`5
`
`4b
`2
`0
`2
`Previous treatment
`40
`19
`21
`Yes
`7
`3
`4
`Chemotherapy
`24
`11
`13
`Chemotherapy + Endo.
`9
`5
`4
`Endo.
`
`
`
`16 14No 30
`
`0.9999
`
`ER = Estrogen receptor status; PgR = progesterone receptor status; PS =
`performance status; Endo = endocrine therapy.
`a
`ttest.
`
`b Pain because of bone metastases.
`
`
`
`
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`Oncology 1999;56:283—290
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`Table 2. Response rates (complete cases)
`
`CR PR NC PD CR + PR
`p value
`
`()8 test)
`
`0.9999
`6/31 (19.4,7.5—37.5)
`13
`12
`6
`0
`ArmI
`
`
`
`
`
`10 1233Arm II 6/28 (21.4, 8.3—41.0)
`
`Figures in parentheses represent percentage followed by 95 % con-
`fidence interval.
`
`drawal from previous therapy (2 patients), previous radiotherapy (4
`patients), bone lesion not identified as metastatic from breast cancer
`(1 patient), active double cancer (1 patient), complication with
`hypercalcemia and performance status 4 (1 patient) and previous
`treatment with MPA (1 patient). Of the remaining 70 eligible cases,
`59 were judged as ‘complete’ and 11 as ‘incomplete’. Incomplete
`cases included 1 patient who was diagnosed as having a venous
`return disorder during MPA administration and whose treatment
`was discontinued (discontinuation case), 2 patients with protocol
`violation and 2 patients lost to follow-up (dropout cases), and 6
`patients whose bone lesions were inadequately studied with x-ray (in-
`complete observation cases). The response rate and duration of sur-
`vival were assessed in all complete cases. Adverse reactions were
`assessed in all evaluable cases (i.e. complete cases, discontinued cases
`and incomplete observation cases).
`
`Patient Details
`The demographic characteristics of the eligible patients are
`shown in table 1. There were no significant differences between treat-
`ment groups in terms of age, menopausal status, advanced or recur-
`rent cancer, disease-free interval, histology, sites of tumor, number of
`tumor sites, estrogen receptor status, progesterone receptor status,
`performance status or numbers of patients with or without previous
`treatment.
`
`Statistics
`
`Demographic characteristics, tumor response rate and the inci-
`dence of adverse reactions were compared between treatment groups
`by the )8 test, t test and Fisher’s direct probability test. Duration of
`response and survival were compared by the generalized Wilcoxon
`test and log-rank test.
`
`Results
`
`Therapeutic Results
`Response rates for complete cases are given in table 2.
`The response rate [complete response (CR) + partial
`response (PR)] was 19.4% (6/31) in arm I and 21.4%
`(6/28) in arm II, with no significant differences noted
`between the two treatment groups. By comparison, the
`response rate for 70 eligible cases was 16.2% (6/ 37) in arm
`
`I and 18.2% (6/33) in arm II; again, no significant differ-
`ences were noted between treatment groups.
`There were no significant differences between the two
`treatment groups in terms of the response rate as a func-
`tion of tumor sites (table 3). CRs were obtained in the
`breast and lymph node only in arm I patients, while CRs
`were obtained in the skin and subcutaneous tissue only in
`arm II patients. PRs in the pleura occurred only in arm I
`patients.
`The median overall duration of response was 66.9
`weeks (range 23.6—106. 1) in arm I and 46.0 weeks (range
`246—1206) in arm II, and there were no significant dif-
`ferences between the two treatment groups. Kaplan-Meier
`survival curves initiated from the start of treatment
`
`showed no significant differences in survival between the
`two treatment groups (fig. 1).
`
`Adverse Events
`
`The incidences and types of adverse events occurring
`during the study were similar irrespective of MPA dosage
`and, again, no significant differences were noted between
`treatment groups (table 4). MPA treatment was discontin-
`ued in 1 patient receiving 1,200 mg/day because of ten-
`derness and purple coloration of the limbs; a venous
`return disorder was subsequently diagnosed at the vascu-
`lar surgery department.
`
`Laboratory Results
`There was a considerable interpatient variation in
`serum concentrations of MPA in both of the treatment
`
`groups. Nevertheless, the median serum concentration of
`MPA was nearly 2-fold higher in arm I compared with
`arm II (63.5 vs. 35.9 ng/ml; fig. 2a). Median serum MPA
`concentrations by response were 49.7 ng/ml
`in CR,
`47.2 ng/ml in PR, 56.9 ng/ml in no change (NC) and
`39.0 ng/ml in progressive disease (PD), showing no signif-
`icant difference between responders (CR + PR) and non-
`responders (NC + PD) (fig. 2b). The lowest serum MPA
`concentrations by response were 44.4 ng/ml
`in CR,
`17.4 ng/ml in PR, 22.0 ng/ml in NC and 8.0 ng/ml in
`PD.
`Plasma cortisol levels decreased after MPA adminis-
`
`tration in nearly all patients in both treatment groups
`(fig. 3). However, there was no correlation between the
`extent of this decrease and the antitumor effect of MPA.
`
`Levels of antithrombin III and protein C increased signifi-
`cantly in both treatment groups, but there were no signifi-
`cant changes in other test items of blood coagulation and
`the fibrinolytic system.
`
`
`
`
`
`MPA in Advanced or Recurrent Breast
`Cancer
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`Oncology 1999;56:283—290
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`

`

`(%)
`100
`
`-
`
`.
`
`Arm I (1200)
`
`Arm 11 ( 600)
`
`n
`
`31
`
`28
`
`2 years
`Median survival
`duration(weeks) survival rate(%)
`
`79.1
`
`101.0
`
`41.9
`
`46.4
`
`9:037?
`(g. wilcoxcm)
`
`9:0-43‘5‘
`(Iogrank)
`
`vival rates are shown by the Kaplan-Meier
`
`Fig. 1 . Survival curves. The cumulative sur-
`
`method. — 2 Cumulative survival rate of
`arm I; —— — = cumulative survival rate of arm
`11.
`
`0
`
`25
`
`50
`
`75
`
`100
`
`1 25
`
`150
`
`175
`
`200(weeks)
`
`Table 3. Response rates as a function of
`tumor site (complete cases)
`
`CR
`PR
`NC
`PD
`CR + PR
`FEMS
`x es
`
`
`
`
`Breast
`
`Arml
`1
`0
`1
`0
`1/2 (50.0, 13—987)
`1000
`
`Arm II
`0
`1
`0
`1
`1/2 (50.0, 1.3—89.7)
`'
`Skin and subcutaneous tissue
`
`Arm I
`0
`1
`4
`2
`1/7 (14.3, 0.4—57.9)
`0 3602
`
`Arm II
`3
`1
`2
`2
`4/8 (50.0, 15.7—84.3)
`'
`
`Lymph node
`
`Arml
`2
`2
`4
`3
`4/11(36.4,10.9—69.2)
`0 6314
`
`Arm II
`0
`1
`4
`2
`1/7 (14.3, 0.4—57.9)
`'
`
`Lung
`
`Arml
`0
`1
`2
`3
`1/6 (16.7, 0.4—64.1)
`0 9999
`
`Ann 11
`0
`1
`2
`1
`1/4 (25.0, 06—806)
`'
`Pleura
`
`Arm I
`0
`2
`4
`3
`2/9 (22.2, 2.8—60.0)
`0 999
`
`Arm II
`0
`0
`1
`2
`0/3 (0.0, 0.0—70.8)
`'
`Liver
`
`Arm I
`0
`0
`1
`0/1 (0.0, 0.0—70.8)
`
`Arm II
`0
`0
`0
`1
`0/1 (0.0, 0.0—70.8)
`_
`Bone
`
`09999
`2/13(15.4,1.9—45.5)
`3
`8
`0
`Arml
`
`
`
`
`
`0 1 5 4 1/10 (10.0, 0.3—44.5)Arm II '
`
`
`
`Figures in parentheses represent percentage followed 95% confidence interval.
`
`
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`

`

`(ng/ mi)
`100
`
`90
`80
`7o
`50
`50
`
`4O
`30
`20
`10
`
`l—— p<0.01-l
`
`g 0
`
`(63.5)
`
`019/ ml)
`100
`90
`80
`70
`60
`50
`40
`30
`20
`
`amum].-uc22-
`
`
`
`I
`
`
`
`.
`
`§
`
`—-O— (49.7)
`.
`
`C
`T (47.2)
`.
`
`.
`
`3
`4— (55.9)
`.
`g
`.
`
`:
`o
`
`.
`u
`
`439.0)
`
`b
`
`31
`
`N
`N
`O
`
`N
`N
`.
`'
`
`Arm I
`
`Arm II
`
`CR
`
`PR
`
`NC
`
`PD
`
`Fig. 2. Serum MPA concentration 8 weeks after the start of the treatment. a Concentration by arm. b Concentration
`by response.
`
`Discussion
`
`(us/d1)
`
`A multicenter randomized controlled trial was con-
`
`ducted to compare the efficacy and safety of MPA at dos-
`ages of 1,200 and 600 mg/day in patients with advanced
`or recurrent breast cancer.
`
`There were no differences noted in this study between
`the two dosage groups in terms of the response rate to
`MPA treatment (arm I: 19.4%; arm 11: 21.4%). These
`results correspond with findings obtained in other dose
`comparison studies performed elsewhere. For example,
`no significant differences in response rates were reported
`by Hortobagyi et al. [11] at MPA dosages of 800 and
`400 mg, by Gallagher et al. [12] at dosages of 1,000 and
`300 mg, by Davila et al.
`[13] at dosages of 800 and
`400 mg, and by Langecker et al. [14] at dosages of 1,400
`and 400 mg [14]. Enomoto et al. [15] reported that the
`response rate of MPA 1,200 mg was somewhat superior to
`600 mg but there were no significant differences between
`the two doses in combination with cyclophosphamide and
`epirubicin. Ganzina [16] reported that the response rate
`in patients treated with MPA at 200 mg or less was 17%
`and thus concluded that so-called ‘low dose MPA therapy’
`cannot achieve a satisfactory response rate. However,
`‘high dose MPA therapy’ using higher doses appears to
`produce no marked difference in the response rate of dif-
`ferent doses.
`
`CR was obtained in the skin in the MPA 600-mg treat-
`ment group (3 responses), and in the breast (1 response)
`and lymph node (2 responses) in the 1,200-mg treatment
`
`
`
`Pre
`
`8 weeks
`
`Pre
`
`8 weeks
`
`Arm 1
`
`Arm ll
`
`Fig. 3. Plasma cortisol concentration before the start of the treat-
`ment and 8 weeks later.
`
`Table 4. Adverse events (evaluable patients)
`
`Adverse event
`Arm I
`Arm II
`p value
`(x2 test)
`
`
`12/30 (40)
`12/36 (33)
`Increase in body weight
`4/30(13.3)
`6/36 (16.7)
`Increase>5 kg
`0.5105
`6/30 (20)
`4/36(11)
`Vaginal bleeding
`Moon face
`7/36 (19)
`4/30(13)
`0.7831
`
`Edema
`4/36(11)
`2/30 (7)
`0.8224
`
`0.8546
`
`Total
`22/36 (61)
`18/30 (60)
`0.9999
`
`
`Figures in parentheses represent percentage.
`
`
`
`
`
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`MFA in Advanced or Recurrent Breast
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`

`

`group. A PR was obtained in the pleura (2 responses) in
`the 1,200-mg treatment group. Pannuti et al.
`[17] re-
`ported that significantly higher serum MPA concentra-
`tions were measured in patients with visceral metastasis
`which responded to the treatment compared with serum
`concentrations in nonresponsive patients. It is therefore
`possible that the effective dose of MPA differs between
`tumor sites.
`
`In the present study serum concentrations of MPA
`were measured at 8 weeks after the start of the treatment,
`the time when steady state is achieved following consecu-
`tive daily oral administration [18]. The median serum
`concentration of MPA in the 1,200-mg treatment group
`was almost double that of the 600—mg group, but there was
`wide interpatient variation. This has also been reported in
`pharmacokinetic studies of measuring serum concentra-
`tions [19, 20]. The variation may be explained by individ-
`ual differences in MPA absorption and metabolism.
`With regard to a correlation between serum concentra-
`tiopn and tumor response, Etienne et al. [21] documented
`that 50—70 ng/ml were required to elicit a response. Simi-
`larly, Nishimura et al. [22] stated that the concentration
`was >55 ng/ml. According to Furukawa et al.
`[23], a
`tumor response was not expected at serum MPA concen-
`trations of < 17 ng/ml which was the mean serum concen-
`tration in patients with either NC or PD who had received
`MPA at the dosage of 600 mg.
`In our investigation, serum MPA concentration did
`not significantly differ between responders and nonre-
`sponders, but
`the lowest serum MPA concentration
`tended to be higher in responders than in nonresponders.
`This indicates that serum MPA concentration higher than
`a certain level is necessary to achieve tumor response. In
`the cohort of this study, the lowest concentration in PR
`was 17.4 ng/ml, suggesting that this level may be the
`required minimum serum concentration. On the other
`hand, there were those patients who did not respond to
`the treatment in spite of having a high serum concentra-
`tion, and the response rate was not different between the
`two groups in spite of a 2-fold difference in serum MPA
`concentrations. These findings suggest that a high serum
`MPA concentration is one of the requirements for achiev-
`ing response but not a sufficient condition.
`Endocrine inhibition of the pituitary-adrenal system
`has been suggested as one of the mechanisms of action of
`MPA [24], and an inverse correlation between serum con-
`centrations of MPA and plasma cortisol levels has been
`reported [25, 26]. Plasma cortisol levels decreased in
`almost all patients in the present study, reflecting a
`remarkable influence of MPA administration. Robustelli
`
`[27] reported that the response rate was high in patients
`with serum MPA concentrations greater than 80 ng/ml
`measured by the RIA method and plasma cortisol levels
`less than 5 ug/dl. In view of the wide interpatient varia-
`tion in pharmacokinetics [28], investigation of the hor-
`monal dynamics involving MPA concentrations and plas-
`ma cortisol levels seems necessary to determine the opti-
`mal dosage of MPA for an individual patient.
`Test for blood coagulation and the f1brinolytic system
`did not reveal any marker tendency for acceleration of
`coagulation with either dose of MPA. This result is consis-
`tent with the findings of a previous report [29], and MPA
`is thus considered not to directly accelerate coagulation.
`The present investigation showed no significant differ-
`ence in efficacy or safety between MPA 1,200 and
`600 mg. The serum MPA concentration was about 2-fold
`higher in the 1,200-mg group than in the 600-mg group,
`but showed no significant difference between responders
`and nonresponders. However, the fact that the lowest
`serum MPA concentration in responders tended to be
`higher than that in nonresponders suggests that a high
`serum MPA concentration is one of the requirements to
`achieve tumor response.
`
`Conclusions
`
`There were no significant differences between MPA
`600 and 1,200 mg in terms of the response rate, duration
`of response and survival, or in terms of incidence and
`severity of adverse reactions. There were considerable
`interindividual differences in the absorption of MPA
`from the gastrointestinal tract; however, the median se-
`rum concentration was about 2-fold higher in the 1,200-
`mg group than in the 600—mg group. The serum MPA con-
`centration showed no significant difference between re-
`sponders and nonresponders. However, the fact that the
`lowest serum MPA concentration in responders tended to
`be higher than that in nonresponders suggests that a high
`serum MPA concentration is one of the requirements to
`achieve tumor response.
`
`Acknowledgements
`
`The authors would like to thank all investigators in the Study
`Group for the Chemo-Endocrine Therapy of MPA for Breast Cancer
`for their cooperation.
`
`
`
`
`
`288
`
`Oncology 1999;56:283—290
`
`Koyama et al.
`
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`Appendix 1
`
`Study Centers
`
`First Department of Surgery
`Second Department of Surgery
`Department of Surgery
`Department of Surgery
`Department of Surgery
`Department of Surgery
`Second Department of Surgery
`Department of Surgery
`Department of Surgery
`Department of Surgery
`Department of Surgery
`First Department of Surgery
`First Department of Surgery
`Department of Surgery
`Second Department of Surgery
`Department of Surgery
`Department of Surgery
`Department of Surgery
`Department of Surgery
`Department of Oncologic Surgery
`Department of Surgery
`Department of Surgery
`Department of Surgery
`
`Second Department of Surgery
`Department of Surgery
`Department of Surgery
`
`School of Medicine
`School of Medicine
`
`School of Medicine
`School of Medicine
`
`School of Medicine
`
`School of Medicine
`
`School of Medicine
`
`Research Institute for
`
`Nuclear Medicine and Biology
`
`Hokkaido University
`Hokkaido University
`Sapporo National Hospital
`Miyagi Cancer Center
`Sendai National Hospital
`Keio University
`Jikei University
`Tokyo Metropolitan Komagome Hospital
`Cancer Institute Hospital
`St. Luke’s International Hospital
`Mitsui Memorial Hospital
`St. Marianna University
`National Defense Medical College
`Sakitama Hospital
`Gunma University
`Gunma Cancer Center
`
`Maebashi Red Cross Hospital
`Tochigi Cancer Center
`Niigata Cancer Center
`Osaka University Medical School
`Osaka Medical College
`Osaka National Hospital
`Osaka Medical Center for Cancer and
`Cardiovascular Diseases
`
`University of Tokushima
`Shikoku Cancer Center
`
`Hiroshima University
`
`Department of Endocrine Surgery
`Yamaguchi University
`First Department of Surgery
`Kyushu University
`Second Department of Surgery
`Kurume University
`First Department of Surgery
`National Kyusyu Cancer Center Hospital
`Department of Breast Surgery
`Kitakyusyu Municipal Medical Center
`Department of Surgery
`Oita Prefectural Oita Hospital
`Department of Surgery
`
`Department of Surgery Nakabaru Hospital
`
`School of Medicine
`Faculty of Medicine
`School of Medicine
`
`Kawasaki Medical School
`
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