Phase III randomized trial of toremifene versus tamoxifen for Japanese ...

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Sep 12, 2012 - ORIGINAL ARTICLE. Phase III randomized trial of toremifene versus tamoxifen for Japanese postmenopausal patients with early breast cancer.
Breast Cancer (2014) 21:275–283 DOI 10.1007/s12282-012-0394-6

ORIGINAL ARTICLE

Phase III randomized trial of toremifene versus tamoxifen for Japanese postmenopausal patients with early breast cancer Morihiko Kimura • Takeshi Tominaga • Izo Kimijima • Yuichi Takatsuka • Shigemitsu Takashima • Yasuo Nomura • Fujio Kasumi • Akihiro Yamaguchi Norikazu Masuda • Shinzaburo Noguchi • Nobuoki Eshima



Received: 15 March 2012 / Accepted: 19 July 2012 / Published online: 12 September 2012 Ó The Japanese Breast Cancer Society 2012

The names of institutions participating in this trial are shown in the Appendix.

with tamoxifen in respect of 5-year survival. Secondary endpoints were cumulative overall survival, cumulative disease-free survival, effects on lipid profiles, and adverse events. Results A total of 253 patients were enrolled. The baseline characteristics of the two treatment groups were wellbalanced. Median follow-up was 66.5 months. Five-year survival was similar for toremifene and tamoxifen (97.0 vs. 96.9 %; 90 % confidence interval -3.9 to 4.1), indicating that toremifene is not inferior to tamoxifen for postmenopausal Japanese patients with early breast cancer. Cumulative overall survival and cumulative disease-free survival were also very similar for toremifene and tamoxifen (97.5 vs. 97.3 %, log-rank test P = 0.9458; 88.4 vs. 90.6 %, logrank test P = 0.3359, respectively). Adverse events in both groups were similar and mostly mild or moderate. Thus, both are equally effective and well tolerated.

M. Kimura (&) Department of Surgery, Gunma Cancer Center, Ota, Japan e-mail: [email protected]

F. Kasumi Department of Breast Oncology, Cancer Institute Hospital, Tokyo, Japan

T. Tominaga Breast Cancer Center, Toyosu Hospital, Showa University, Tokyo, Japan

A. Yamaguchi Department of Surgery, Ogaki Municipal Hospital, Ogaki, Japan

Abstract Background Toremifene, a selective estrogen receptor modulator, is used as adjuvant therapy for postmenopausal patients with breast cancer in Japan. For Japanese patients, however, only limited data are available on the efficacy and safety profile of toremifene. To establish the long term efficacy and safety of toremifene for Japanese patients, we conducted a prospective, multicenter, randomized phase III trial comparing toremifene and tamoxifen. Patients and methods The subjects were postmenopausal Japanese patients who had undergone surgery for nodenegative breast cancer. Toremifene or tamoxifen was administered for 2 years. The primary endpoint was demonstration of the non-inferiority of toremifene compared

I. Kimijima Breast Center, Northern Fukushima Medical Center, Date, Japan

N. Masuda Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan

Y. Takatsuka Department of Surgery, Kansai Rosai Hospital, Amagasaki, Japan

S. Noguchi Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Suita, Japan

S. Takashima Department of Surgery, National Shikoku Cancer Center Hospital, Matsuyama, Japan

N. Eshima Department of Medical Information Analysis, Faculty of Medicine, Oita University, Yufu, Japan

Y. Nomura Department of Breast Surgery, Oikawa Hospital, Fukuoka, Japan

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Conclusion Our results suggest that the efficacy and safety of toremifene and tamoxifen are equivalent for postmenopausal Japanese patients with early breast cancer. Keywords Toremifene  Tamoxifen  Breast cancer  Postmenopausal  Adjuvant therapy  Dyslipidemia

Introduction Tamoxifen is a non-steroidal anti-estrogen agent used as standard adjuvant endocrine therapy for breast cancer [1]. Tamoxifen is classified as a selective estrogen receptor modulator (SERM); the different activity of tamoxifen on each of the estrogen receptors results in a variety of tissuespecific pro and anti-estrogenic effects. Toremifene is an anti-estrogen agent that was developed to improve upon the risk–benefit profile of tamoxifen [2]. Toremifene is also a non-steroidal anti-estrogen SERM and received approval from the Japanese government in 1995 for use in first-line treatment of postmenopausal patients with breast cancer. Toremifene and tamoxifen have similar efficacy in the treatment of advanced breast cancer [3–5], although their effects on lipid metabolism differ slightly [6–8]. However, there have been few clinical studies directly comparing the safety and efficacy of toremifene and tamoxifen in breast cancer patients. Although clinical trials conducted in Western countries show that toremifene and tamoxifen are equally effective, this has not yet been confirmed for Asian populations. In randomized trials toremifene and tamoxifen have been compared as adjuvant therapy for treatment of advanced stage breast cancer; however, no trials have been conducted on patients in the early stage of the disease. Therefore, we in the Japan Toremifene Cooperative Study Group conducted a multicenter, cooperative, randomized controlled phase III clinical trial to specifically compare the efficacy of toremifene and tamoxifen as postoperative adjuvant therapy for postmenopausal Japanese patients with early-stage breast cancer.

Patients and methods Ethics review and patients The study protocol was approved by the Ethics Committee/ Institutional Review Board of each participating institution and was conducted in accordance with the Helsinki Declaration of 1975. Before enrollment, all patients were provided with written information about the study design and written informed consent was obtained. The following inclusion criteria were used:

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1. 2. 3. 4. 5.

postmenopausal primary breast cancer; B75 years of age; tumor stage T1-2, N0, M0; estrogen receptor status either positive or unknown; and underwent mastectomy or breast conserving resection.

The TNM classification (1978 version) was used for staging of the breast cancer. Patients for which estrogen receptor status was unknown were included because the assay for estrogen receptors was not available in some institutions at the time of trial planning. Randomization and treatment Enrolled patients were randomly assigned to receive either toremifene or tamoxifen therapy. The toremifene treatment group received toremifene citrate tablets (40 mg/day) and the tamoxifen group received tamoxifen citrate tablets (20 mg/day). Medication was begun within 6 weeks of surgery and continued daily for 2 years. At the time of trial planning, the standard duration of treatment with toremifene and tamoxifen in Japan in the adjuvant setting for early breast cancer was 2 years. Patients receiving treatment for other malignancies were excluded from the study. Assessment and statistical methods The primary endpoint used to demonstrate the non-inferiority of toremifene compared with tamoxifen was 5-year survival. Five-year survival of Japanese patients in this trial was expected to be 90–95 %. The primary endpoint of our study was 5-year survival, thus expected survival was set at 90 %, by excluding survival-unknown cases from the total number of cases evaluated. On the basis of the Japanese phase II trial [10], toremifene and tamoxifen have similar efficacy. The number of patients for each agent, denoted by n, was estimated by use of the formula: n ¼  pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi2 z1a 2p0 ð1p0 Þþz1b p1 ð1p1 Þþp2 ð1p2 Þ where z1-P is the ðp p dÞ2 1

2

100(1 - P)th percentile of the standard normal distribution, a is one-sided type I error of 5 %, 1 - b is the power of 80 %, d is the non-inferiority margin of 10 %, 5-year survival for both agents is 90 %, denoted by p1 and p2, respectively, and combined survival is given as (p1 ? p2)/ 2. For each group, 112 cases were required to establish non-inferiority. Therefore, the number of target cases was a group of 125. The secondary endpoints were cumulative overall survival, cumulative disease-free survival, effects on lipid profiles, and safety. Kaplan–Meier methods were used to calculate overall and disease-free survival. Efficacy was determined on the basis of the full analysis set (FAS)

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population. The FAS population was all randomized patients who satisfied the major entry criteria, took at least one dose of the trial medication, and for whom data were available post randomization. Safety was assessed throughout the study by physical examination, hematology, and biochemical examination. Adverse events were assessed by using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE, v3). For blood tests, blood samples were collected on the defined day. Time points for blood collection were before administration of adjuvant drugs, then 3, 6, 12, and 24 months after their administration. Serum lipid analysis consisted of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Concentrations of serum lipids were measured by standard enzymatic methods. When an enzymatic method was not used, LDL-C values were calculated by use of the equation of Friedewald et al. [9]. All patients who took at least one dose of study medication (safety population) were included in the safety analysis.

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A total of 9 violations of the patient protocol, on the basis of the selection criteria, occurred as a result of the inclusion of pre-menopausal patients (toremifene group 3, tamoxifen group 2), patients with treatment history for breast cancer (tamoxifen group 2), a patient with node-positive breast cancer (tamoxifen group 1), and a patient with ER-negative (tamoxifen group 1). As shown in Table 1, there were no significant differences in background characteristics of the patients between the two treatment groups. Five patients in the toremifene group and 3 in the tamoxifen group had histories of angina pectoris. Among eligible patients, 1 in the toremifene group and 2 in the tamoxifen group had histories of myocardial infarction. One patient in the tamoxifen group had a history of cerebral infarction. Fourteen patients in the toremifene group (11 received statins and 3 received fibrates) and 13 in the tamoxifen group (12 received statins and 1 received fibrate) were on medication for dyslipidemia. Efficacy was analyzed in the FAS population, n = 243 patients (123 in toremifen group, and 120 in tamoxifen group). There was no bias in the background characteristics between the two groups. Treatment efficacy

Results Patients Between December 1998 and November 2001, 253 patients were enrolled. Patient disposition is summarized in Fig. 1.

Median follow-up was 66.5 months (range 1.6–89.7 months) at the time of data lock. Five-year survival was 97.0 % in the toremifene group (98 out of 101 cases) and 96.9 % in the tamoxifen group (95 out of 98 cases). Six patients died within 5 years after the day of registration (3 in the toremifene group, 3 in the tamoxifen group); of

Fig. 1 Patient flow diagram

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Table 1 Patient characteristics in the safety population Variable

Toremifene (n = 126)

Tamoxifen (n = 126)

0.172a

Age (years) Median

64.0

62.0

Range

49–74

47-75 0.173a

Body mass index (BMI) (kg/m2) Median

22.5

23.6

Range

16.9–32.1

15.8-37.2

Performance statusb

0.561c

0

124

125

1

2

1

Histologic subtypeb

0.517c

Papilotubular carcinoma

42

40

Solid-tubular carcinoma

30

26

Scirrhous carcinoma

46

47

Other

8

13

Tumorb

0.709a

T0

2

T1a

63

62

T1b

1

0

57

58

T2a Surgery

P value

0

b

0.914c

Mastectomy

60

63

Breast conservation surgery

66

63

Estrogen receptorb Positive

Fig. 2 Kaplan–Meier curves for overall survival (a) and disease-free survival (b) 0.356c

123

119

Negative

0

1

Unknown

3

6

a

Wilcoxon’s rank-sum test

b

Number of patients

c

v2 test

these, 5 were due to breast cancer (2 in the toremifene group and 3 in the tamoxifen group). One death in the toremifene group was due to subarachnoid hemorrhage that was unrelated to the experimental drug. There were 33 survival-unknown cases (17 in the toremifene group and 16 in the tamoxifene group) for whom survival could not be confirmed at a point 5 years after registration. The difference in 5-year survival between the treatment groups was 0.1 %, and the 90 % confidence interval was -3.9 to 4.1; because the lower limit of the confidence interval did not exceed 10 %, these data indicate non-inferiority of toremifene compared with tamoxifen. In Fig. 2, survival curves for the toremifene arm and the tamoxifen arm are plotted by use of the Kaplan–Meier method and compared by use of the log-rank test. Six deaths were confirmed by the final

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observation date (3 in the toremifene group, 3 in the tamoxifen group), resulting in cumulative overall survival of 97.5 % in the toremifene group and 97.3 % in the tamoxifen group. These data indicated there was no significant difference between the two treatments (log-rank test; P = 0.9458). Thirteen patients in the toremifene group and 8 in the tamoxifen group relapsed before the end of follow-up, resulting in cumulative disease-free survival of 88.4 and 90.7 %, respectively. Thus, there were no significant differences between the two groups as determined by these secondary endpoints (log-rank test; P = 0.3359). Effects on lipid profiles The effects of the two agents on lipid profiles differed as described in detail elsewhere [11]. Compared with baseline, at 24 months, the toremifene group had significantly reduced TC and LDL-C levels, and significantly increased HDL-C levels. Their TG levels were not affected. The tamoxifen group (N = 120) also had significantly reduced TC and LDL-C levels; no significant changes occurred in HDL-C (P = 0.297) or TG levels (P = 0.120). Overall,

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the effects of toremifene on lipid profile were more beneficial than those of tamoxifen. Adverse events The incidence of side effects (including subjective symptoms and objective opinions) was 31.7 % in the toremifene group and 33.3 % in the tamoxifen group. The most frequent treatment-related adverse events are shown in Table 2. Hot flashes and vaginal discharge were observed at high frequency in both groups. There were 2 patients of grade 4 in the toremifene group (endometrial cancer and uterine leiomyoma) and 1 in the tamoxifen group (cryptogenic organizing pneumonia). No coronary heart disease was observed; cataracts and endometrial cancers were rare, and there were no deaths due to adverse events. In clinical laboratory tests liver function was significantly worse in patients treated with toremifene than in those treated with tamoxifen.

Discussion Before this study no randomized clinical studies had been conducted on Japanese patients comparing the clinical efficacy of toremifene and tamoxifen for postoperative adjuvant therapy of early breast cancer. We therefore conducted a phase III trial to demonstrate non-inferiority, with a 10 % non-inferiority margin, for a toremifene group against a tamoxifen group, using 5-year survival as the primary endpoint among Japanese patients. Our results verified the non-inferiority of toremifene compared with tamoxifen. The outcomes from this study also showed no significant differences between both groups for cumulative overall survival and cumulative disease-free survival, which were secondary endpoints. These results indicate that toremifene was as effective as tamoxifen in the adjuvant setting. We used a 2-year treatment duration because this was the standard treatment duration in Japan for using tamoxifen in adjuvant settings for early breast cancer, although there have been reports concerning the optimum duration of tamoxifen treatment in European and North American trials [12, 13]. SERMs have been the major adjuvant therapy for postmenopausal breast cancer worldwide for decades. Holli et al. [14] first reported the clinical utility of toremifene, showing that overall survival and cumulative disease-free survival were equivalent to those for tamoxifen in the interim results of a trial on adjuvant therapy for postmenopausal stage II-IIIB breast cancer patients (459 in the toremifene group and 440 in the tamoxifen group). In addition, others have shown no significant differences between toremifene and

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tamoxifen, including a double-blind randomized trial in postmenopausal women with estrogen receptor-positive advanced breast cancer [15] and an international collaborative randomized trial of endocrine therapy for earlystage breast cancer patients [16]. In the latter trial, 5-year survival for the toremifene and tamoxifen groups was 85 and 81 %, respectively (P = 0.83), and 5-year diseasefree survival was 72 and 69 %, respectively (P = 0.64). These results demonstrate that these two agents have equivalent efficacy. Recently, Lewis et al. [17] reported no significant differences in a randomized trial of toremifene and tamoxifen adjuvant therapy for 1813 North American patients with early breast cancer. After 59 months of follow-up, after 5 years of drug administration, median survival of the toremifene and tamoxifen groups was 98.6 and 98.1 months, respectively (P = 0.628) and median disease-free survival was 96.7 and 96.4 months, respectively (P = 0.790). Furthermore, a meta-analysis of five clinical trials of endocrine therapy as primary therapy for locally advanced and metastatic postmenopausal breast cancer [18] found that response and risk of death were identical for toremifene and tamoxifen. Taken together, these European and North American clinical trials convincingly demonstrate the equivalent treatment efficacy of toremifene and tamoxifen in Caucasians. In recent years, SERMs have also attracted attention for their beneficial effects on serum lipids [19]. Consequently, we included the effects on serum lipid profiles as a secondary endpoint in this trial. We observed beneficial changes in serum lipids in both treatment groups postadministration, for example significant decreases in levels of TC and LDL-C. In addition, HDL-C significantly increased in patients receiving toremifene, in accordance with previously published results [6, 20]. There have been several reports that tamoxifen increased serum TG levels, whereas toremifene had little or no effect [6, 7]. Similar effects were observed in an in-vitro study of intracellular concentrations of TG in HepG2 cells [21]. In postmenopausal breast cancer patients, the effects of medications taken long-term on lipid and bone metabolism are important to the quality of life and are becoming an important criterion for selecting treatment. Of all serum lipids, only the level of HDL-C is correlated with coronary artery disease risk. Robins et al. [22] measured an 11 % reduction in coronary heart disease risk because of a 5 mg/dL increase in HDL-C. Moreover, hypertriglyceridemia is a well-known risk factor of arteriosclerosis in the USA, Europe, and Asia, including Japan [23, 24]. Although LDL reduction remains the main target of intervention for lipid-lowering, Barzi et al. [25] showed that among patients of the Asia–Pacific region, TG and HDL were better predictors of coronary heart disease and

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Table 2 Treatment-related adverse events Event

Toremifene (n = 126) Grade 1

Grade 2

Grade 3

Tamoxifen (n = 126) Grade 4

Total (%)

Grade 1

Grade 2

Grade 3

P value Grade 4

Total (%)

Metabolic and nutritional disorders Reduced appetite (anorexia) Nervous system disorders Dizziness Headache

3

1

4 (3.2)

4

1

2

3 (2.4)

5

2 (1.6)

2

0 (0)

3

2

Other

1

4 (3.2)

0.991

6 (4.8)

0.321

2 (1.6)

1.000

3 (2.4)

0.082

0 (0)

0.317

Gynecological disorders Endometrial cancer

1

1 (0.8)

Uterine leiomyoma

1

1 (0.8)

Uterine polyps

1

1 (0.8)

1 1

1 (0.8)

0.996

0 (0)

0.317

8 (6.3)

0.791

Vaginal discharge

7

2

9 (7.1)

7

Genital hemorrhage

3

1

4 (3.2)

5

5 (4.0)

0.745

1 (0.8)

2

2 (1.6)

0.562

Visual impairment

0 (0)

2

2 (1.6)

0.157

Other

0 (0)

2

2 (1.6)

0.157

Cardiac disorders Palpitations

1

Eye disorders

Vascular disorders Hot flashes Peripheral coldness

15

2

1

1

1

Flushing

18 (14.3)

12 (9.5)

0.243

2 (1.6)

10

2

0 (0)

0.157

2 (1.6)

0 (0)

0.157

Skin and subcutaneous disorders Hyperhidrosis

6

6 (4.8)

2

2 (1.6)

0.152

Rash

3

3 (2.4)

1

1 (0.8)

0.314

Other

3

3 (2.4)

2

2 (1.6)

0.652

4 (3.2)

6

6 (4.8)

0.540

3 (2.4)

0.082

7 (5.6)

0.031

1 (0.8)

0.317

Gastrointestinal disorders Nausea

2

2

Gastritis Other

1

0 (0)

2

1 (0.8)

7

1

Respiratory disorders Cryptogenic organizing pneumonia

0 (0)

1

General disorders Malaise

3

1

Feeling hot

4 (3.2)

2

2 (1.6)

0.406

0 (0)

1

1 (0.8)

0.317

Clinical laboratory tests GOT

12

9

4

23 (20.2)

5

5

10 (8.1)

0.006

GPT

9

10

5

24 (19.4)

2

7

9 (7.3)

0.005

ALP

1

1

0 (0)

0.157

2 (1.6)

GOT glutamic oxaloacetic transaminase, GPT glutamic–pyruvic transaminase, ALP alkaline phosphatase

cardiovascular disease risk than TC alone. Recently, Anan et al. [26] reported that toremifene is more beneficial than anastrozole, a widely used non-steroidal aromatase inhibitor, on lipid profiles and bone metabolism in Japanese

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postmenopausal females with early breast cancer. Therefore, toremifene is regarded as suitable for adjuvant therapy of breast cancer patients with dyslipidemia requiring long-term medication.

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Regarding drug safety and tolerance, the incidence of subjective and objective side effects was similar in both groups in our study. Both groups had a high frequency of known treatment-related adverse events, for example hot flashes and vaginal discharge, most likely because of the weak pro-estrogen effect of these SERMs. In the adjuvant setting, second non-breast primary cancers are very important concern. One endometrial cancer was observed. No significant difference between those taking toremifene or tamoxifen in the occurrence of endometrial cancer has been reported in previous trials [17]. No serious treatmentrelated adverse events, for example coronary artery disease associated with dyslipidemia, were observed. Although cataracts and endometrial cancers were reported in the European and American clinical trials [27, 28], these adverse events were rare in our study. These results suggest there may be ethnic differences between Japanese and Caucasians in the metabolism and effects of SERMs. The frequencies of abnormal findings in clinical tests were 31.7 and 39.7 % in the toremifene and tamoxifen groups, respectively. The most common adverse event in either group was an increase in liver function test values. Our results showed that liver function was significantly worse in patients treated with toremifene than in those treated with tamoxifen. For most patients, elevated levels of transaminases were promptly restored to baseline levels after stopping the treatment with toremifene. The difference between toremifene and tamoxifen in the effects on liver function has not been reported after previous studies. There might be ethnic differences in the metabolism of toremifene between Japanese and Caucasians. Further research is required to confirm this. Recently, meta-analysis performed by Zhou et al. [29] indicated that toremifene is as effective and as safe as tamoxifen in the adjuvant setting. Although our results are in general agreement with this, our results suggested some differences among the two agents. One limitation of this study is the relatively small number of patients enrolled, although the study outcome confirmed the non-inferiority of toremifene to tamoxifen. Another is the treatment duration; throughout the world the standard duration of treatment with SERMs is currently 5 years, although no Japanese randomized study has shown the advantages of using tamoxifen for 5 years over 2 years. Sequential treatment (e.g., 2–3 years treatment with tamoxifen followed by aromatase inhibitors) is also widely used today. Because the optimum duration of treatment with SERMs in sequential treatment has not yet been established, the outcomes of this study should contribute to current clinical practice of breast cancer management. Further large-size investigation is necessary to substantiate the optimum treatment for Japanese patients in an adjuvant setting.

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In conclusion, we have shown that the efficacy and safety of toremifene are equivalent to those of tamoxifen for postmenopausal Japanese patients with early breast cancer; however, toremifene may be more beneficial for patients with dyslipidemia, because of its effects on the serum lipid profile. Acknowledgments The authors wish to acknowledge the patients, physicians, nurses, and clinical research coordinators who participated in the trial. This study was sponsored by Nippon Kayaku Co. Ltd. The study sponsor had no role in the study other than providing information relevant to proper use of the study drugs. All decisions concerning the planning, implementation, and publication of this study were made by the executive committee of this study. Conflict of interest interest.

The authors indicated no potential conflict of

Appendix See Table 3.

Table 3 Participating institutions Hokkaido University Hospital

Cancer Institute Hospital

Osaka University Hospital

NHO Hokkaido Cancer Center

NHO Yokohama Medical Center

Osaka City General Hospital

Sapporo Medical University Hospital

Kanagawa Cancer Center

Kansai Rosai Hospital

NHO Sendai Medical Center

Fukui Red Cross Hospital

Kinki University Hospital

Tohoku Kosai Hospital

Shinshu University Hospital

Kobe University Hospital

Fukushima Medical University Hospital

Ogaki Municipal Hospital

Kinki Central Hospital

Gunma University Hospital Gunma Prefectural Cancer Center

Shizuoka General Hospital

Okayama University Hospital Kawasaki Medical School Hospital

Nagoya University Hospital

Saitama Cancer Center

Nagoya City University Hospital

Tokushima University Hospital

Chiba Cancer Center

NHO Nagoya National Hospital

NHO Shikoku Cancer Center

Juntendo University Urayasu Hospital

Yokkaichi Municipal Hospital

Kitakyushu Municipal Medical Center

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Table 3 continued Keio University Hospital

Kyoto Prefectural University of Medicine Hospital

Fukuoka University Hospital

St Luke’s International Hospital

NHO Osaka National Hospital

NHO Kyushu Cancer Center

Mitsui Memorial Hospital

Osaka General Medical Center

Kurume University Hospital

Surugadai Nihon University Hospital

Osaka Kouseinenkin Hospital

Oita Prefectural Hospital

Showa University Toyosu Hospital

Osaka Medical Center for Cancer and Cardiovascular Diseases

NHO National Hospital Organization

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