Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (5)
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Takashima, S
Right arrow Articles by Shimoyama, M
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Takashima, S
Right arrow Articles by Shimoyama, M
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Japanese Journal of Clinical Oncology Pages 325-330

A Phase II Study of High-dose Epirubicin (EPI) plus Cyclophosphamide (CPA) with G-CSF for Breast Cancer Patients with Visceral Metastases or Hormone-independent Tumors: A Trial of the Japan Clinical Oncology Group
Introduction
Materials and Methods
   Eligible Criteria
   Treatment Schedule
   Evaluation of Clinical Response
Results
   Patients' Characteristics
   Intervals of Treatment and Total Doses of EPI in a Phase II Study
   Clinical Response
   Relationship Between Prior Chemoendocrine Therapy and Response
   Survival
   Toxicity
Discussion
Acknowledgments
References

A Phase II Study of High-dose Epirubicin (EPI) plus Cyclophosphamide (CPA) with G-CSF for Breast Cancer Patients with Visceral Metastases or Hormone-independent Tumors: A Trial of the Japan Clinical Oncology Group

A Phase II Study of High-dose Epirubicin (EPI) plus Cyclophosphamide (CPA) with G-CSF for Breast Cancer Patients with Visceral Metastases or Hormone-independent Tumors: A Trial of the Japan Clinical Oncology Group Shigemitsu Takashima1, Toshiaki Saeki1, Isamu Adachi2, Toru Watanabe2, Yasutsuna Sasaki3, Hiroshi Murai4, Toshio Tabei5, Masami Ogita6, Muneaki Sano7, Kazuhiro Kanda8 and Masanori Shimoyama9

1Department of Clinical Research and Surgery, National Shikoku Cancer Center Hospital, Matsuyama, 2Department of Medical Oncology, National Cancer Center Hospital, Tokyo, 3Department of Medical Oncology, National Cancer Center Hospital, East, Kashiwa, Chiba, 4Department of Surgery, Aichi Cancer Center, Nagoya, 5Department of Endocrinology, Saitama Cancer Center, Urawa, 6Department of Surgery, National Sapporo Hospital, Sapporo, 7Department of Surgery, Niigata Cancer Center, Niigata, 8Department of Surgery, Hamamatsu Medical Center, Hamamatsu, Shizuoka, 9Nagoya National Hospital, Nagoya, Japan

To evaluate the efficacy and toxicity of high-dose epirubicin (EPI) plus cyclophosphamide (CPA) therapy, a phase II study of EPI, 130 mg/m2, plus CPA, 1000 mg/m2, with G-CSF every 3 weeks was carried out for 51 advanced or recurrent breast cancer patients by the Japan Clinical Oncology Group (JCOG). Fifty out of the 51 patients who were eligible for our criteria were treated with this regimen as first-line chemotherapy for visceral metastases or hormone-independent tumors. In this trial, 203 cycles were administered with an average of four cycles per patient. In 50 patients who were evaluable for response, there were 7 complete (CR) and 25 partial responses (PR) with an overall response rate of 64% (95% confidence interval, 50.1-75.9%). Symptomatic and hematological acute toxicity more than grade 3 occurred frequently; however, no treatment-related death occurred. The incidence of toxicities ( >= grade 3) was as follows: leukopenia 98%, thrombocytopenia 42%, nausea/vomiting 56% and hair loss 12%. In each cycle, daily administration of 2 µg/kg G-CSF (granulocyte-colony stimulating factor) was given on days 2-15 subcutaneously. The incidence of cardiotoxicity was low. Arrhythmia ( <= grade 2) was observed in 8% and a slight decrease of ejection fraction index ( <= grade 2) was observed in 2% in this trial. The median follow-up period for patients was 37.2 (24.6-51.5) months and the median survival period was 17.4 months. These data indicate that high-dose EPI + CPA combination chemotherapy was effective and well tolerated for breast cancer patients with visceral metastases or hormone-independent tumors. A randomized trial of high-dose EPI vs conventional chemotherapy is required to ascertain the usefulness of this regimen.

Key words: intensive chemotherapy - epirubicin - cyclophosphamide - G-CSF - breast cancer

Introduction

Chemoendocrine therapy for advanced or recurrent breast cancer providing either tumor reduction or improvement of quality of life has failed to prolong the survival of these patients. The main cause of the poor prognosis may be a low incidence of complete responses in the responding patients treated with the conventional chemotherapy such as CAF (C, cyclophosphamide; A, doxorubicin; F, 5-FU), CMF (M, methotrexate) and CA (1 -4 ). Moreover, the conventional chemotherapy regimens have been ineffective in patients with visceral metastases or hormone-independent tumors. The usefulness of dose-intensive chemotherapy to increase curability in patients with advanced or recurrent breast cancer has recently been discussed and several trials with intensive chemotherapy have been carried out to improve prognosis (5 -9 ). These combinations usually include doxorubicin which is considered to be one of most effective anti-cancer agents for breast cancer (1 ). To reduce the incidence of specific toxicity such as cardiotoxicity and hair loss seen with doxorubicin, some analogs of doxorubicin have been introduced. Epirubicin (EPI) has been shown to have lower cardiotoxicity than doxorubicin (10 ,11 ). Carmo-Pereira et al. (12 ) using single agent administration of EPI, 120 mg/m2, demonstrated a 65% response rate with tolerable toxicity, indicating that EPI might play a role in high-dose chemotherapy regimens. In a previous combination phase I trial, to define the maximum tolerated dose of epirubicin with a fixed dose of CPA (1000 mg/m2), dose escalations from 70 to 140 mg/m2 of EPI have been tested. The recommended dose from this study of EPI was 130 mg/m2 , which was the dose used in this study (13 ). In addition, G-CSF was included in this study to avoid severe hematological toxicity since, in the phase I study, neutropenia ( >= grade 3) was frequently observed. To ascertain if high-dose EPI + CPA with G-CSF might be a useful treatment for breast cancer patients with visceral metastases or hormone-resistant tumors, we analyzed efficacy and toxicity using this combination chemotherapy in a multi-institutional phase II study conducted by the Japan Clinical Oncology Group (JCOG).

Materials and Methods

Eligible Criteria

Eligible patients should have histologically diagnosed advanced or recurrent breast cancer with visceral metastases. The patients must have estrogen receptor negative in primary cancer or hormanally refractory cancer. No previous chemotherapy was allowed with the exception of adjuvant therapy. In addition, they were required to have adequate cardiac function confirmed by echocardiography and adequate hepatic function. Patients with CNS (central nervous system), bone or bone marrow metastases were also included but those with lower or abnormal renal (creatinine clearance <= 60 ml/min), hepatic (bilirubin >1.5 mg/dl, SGOT >80 IU/l), pulmonary (PaO2 <70 mmHg), cardiac (abnormal ECG, ejection fraction <50%) and/or bone marrow function (leukocyte counts <4000/mm3, hemoglobin <10/dl, thrombocyte counts <150 000/mm3) were excluded. This protocol was accepted as JCOG9107 by the clinical trial reviews committee of JCOG. Informed consent was obtained from all patients.

Treatment Schedule

On day 1, 130 mg/m2 of EPI (Pharmacia and Upjohn KK, Tokyo, Japan) was administered for 1 h infusion, and sequentially1000 mg/m2 of CPA (Shionogi Pharmaceutical, Tokyo, Japan) was given for 1 h. These drugs were given i.v. every 3 weeks. From day 2, 2 µg/kg recombinant G-CSF (Chugai Pharmaceutical, Tokyo, Japan) was injected subcutaneously (Fig. 1 ). G-CSF administration was suspended on day 15 or when leukocyte counts increased to 10 000/mm3. Dose and intervals of G-CSF administration were defined in a phase II study of G-CSF described previously (14 ). When more than grade 4 neutropenia or thrombocytopenia occurred at the time treatment was due, the administration of anti-cancer agents was deferred for 1 week and a 25% dose reduction was applied. In the absence of tumor progression or intolerable toxicity, patients received at least five cycles (Table 2 ). In case of NC (no change), the treatment could be achieved after three cycles.


Figure 1. Treatment schedule of high-dose EPI and CPA. i.v., Intravenous infusion; s.c., subcutaneous injection.

Evaluation of Clinical Response

The efficacy of treatment was assessed by International Union Against Cancer Criteria and extra-mural review for responding patients was also carried out (15 ). The grading of toxicity was determined according to the Common Toxicity Criteria by ECOG (Eastern Cooperative Oncology Group) (16 ).

This trial was designed as a prospective study and the first endpoint is response rate. According to the response rate in a phase I study [ORR 70%; 95% confidence interval (C.I.) 53-82%], for the phase II study the minimun number of patients who might be needed to prove statistically the usefulness of our regimen compared with the standard therapy (ORR 50%) was estimated (1 -3 ,13 ). We estimated that at least 50 eligible patients have to be entered (17 ).

Statistical evaluations were performed by a chi-squared test or Kaplan-Meier life table analysis using statistical evaluation software from SAS. These statistical analyses were performed by the JCOG Statistical Center in Tokyo.

Results

Patients' Characteristics

Between October 1991 and November 1993, 51 patients were entered in this trial but one patient was considered ineligible since she did not have any measurable lesions for clinical evaluation. Finally, 50 of 51 patients were eligible for evaluation (Table 1 ). The mean age of the 50 eligible patients was 47.5 (28-60) years; 45 (90%) patients had recurrent breast cancer and 5 (10%) had primary advanced cancer. None of these patients had had previous irradiation therapy. Patients' characteristics for the eligible patients are listed in Table 1 . The mean disease-free interval of the 50 eligible patients was 21.5 months. The estrogen receptor status (ER) was positive in 11 (22%) primary lesions while 27 (54%) lesions demonstrated negative ER, whereas the ER status was unknown in 12 (24%) patients. Thirty-eight (76%) patients had received adjuvant chemoendocrine therapy and 12 (24%) were previously untreated. With regard to the number and sites of lesions, 76.5% of the patients had more than two metastatic sites including 22 local or soft tissue, 21 bone, 20 lung and 16 liver.

Intervals of Treatment and Total Doses of EPI in a Phase II Study

The accumulative dose of EPI was 505 mg/m2. In this trial, 27 patients had five cycles of chemotherapy and 23 patients were treated with less than five cycles because of tumor progression, intolerable toxicity or refusal of patients. The treatment was suspended in eight patients with no change of disease after administration less than five cycles (Table 2 ).

Clinical Response

The overall clinical response rate (ORR) was 64% [7 complete response (CR) + 25 partial response (PR), 95% C.I. 50.1-75.9%], whereas 9 (18%) were NC and 9 (18%) were progressive disease (PD) (Table 3 ). The response rate in each metastatic site was 65% in lung metastasis, 66.7% in pleural metastasis, 62.5% in liver metastasis, 23.8% in bone metastasis and 63.6% in soft tissues. The mean response duration in soft tissues was 428.9 days, whereas that in pleural metastasis was 148 days. Among the responding patients, the overall mean time to response from the first treatment was 43.6 (10-87) days and the response duration after PR or CR was 356.6 (65-1145) days. In the eligible patients, the mean time to progression from the first treatment was 318.4 (18-1197) days.

Relationship Between Prior Chemoendocrine Therapy and Response

In the 38 patients who had received adjuvant therapy, there were 4 CR and 21 PR (ORR 65.8%), whereas 3 CR and 4 PR (ORR 58.3%) were obtained in 12 patients who were not treated with adjuvant therapy. In the 12 patients who were treated with anthracyclines, there were 2 CR and 7 PR (ORR 75.0%), whereas 5 CR and 17 PR (ORR 60.5%) were obtained in the 38 patients who had not had any prior anthracycline administration. With reagrd to the prior hormone therapy, 3 CR and 19 PR (ORR 66.7%) were obtained in the 33 patients with a history of tamoxifen failure, but there were 4 CR and 6 PR (ORR 58.8%) in the 17 patients without any prior treatment with TAM. There was no significant difference in overall response rate (ORR) between the patients with or without the prior adjuvant therapy, anthracycline administration or TAM treatment.

Table 1 . Patient's characteristics
Eligible patients 50
Median age in years: all patients 47 (28-60)
ER status
Positive 11
Negative 27
Unknown 12
Adjuvant therapy
+ 38
- 12
Metastatic sites
Lung 20
Pleura 6
Liver 16
Bone 21
Local/lymph node 22
Others 6
Disease free interval in month 21.5 (0-165)
Numbers in parentheses show the range.

Table 2 . Number of cycles and patients treated with this regimen
No. of cycle No. of patients Cause of suspended treatment*
1 1 Disease progression
2 6 Disease progression
3 9 Intolerable toxicity (1), NC (6), disease progression (2)
4 7 Refusal of patient (1), intolerable toxicity (1), NC (2), disease progression (3)
5 27  
*No. of patients in parentheses; NC, no change.

Table 3 . Clinical response
  Characteristic
  CR PR NC PD %CR ORR
Metastatic sites
Lung (20) 3 10 5 2 15 65.0
Pleura (6) 0 4 1 1 0 66.7
Liver (16) 1 9 3 3 6.2 62.5
Bone (21) 0 5 13 3 0 23.8
Soft tissue (22) 9 5 4 4 40.9 63.6
Adjuvant
+ (38) 4 21 6 7 10.5 65.8
- (12) 3 4 3 2 25.0 58.3
ADM
+ (12) 2 7 1 2 16.7 75.0
- (38) 5 18 8 7 13.2 60.5
TAM
+ (33) 3 19 5 6 9.1 66.7
- (17) 4 6 4 3 23.5 58.8
ORR, overall response rate.

Survival

The median survival period was 17.36 (SE 2.104) months. In addition, the 2-year survival rate was 40.0% and the 3-year survival rate was 35.4% (Fig. 2 ).


Figure 2. Kaplan-Meier life table analysis. Number of censored = 15. 50% survival time in months = 17.36.

Toxicity

Symptomatic and/or hematological acute toxicity >grade 3 often occurred. The incidence of leukocytepenia, thrombocytopenia and hair loss was 98, 42 and 12%, respectively (Table 4 ). In this study, 2 µg/kg G-CSF was routinely administered from day 2 in each cycle. The mean duration of grade 4 neutropenia was ~2 days regardless of the number of cycles. Grade 4 thrombocytopenia was not observed (Table 5 ). The incidence of cardiotoxicity was low, that is, arrhythmias ( <= grade 2) were observed in 8% and a slight decrease in ejection fraction index ( <= grade 2) was found in 2% in this trial. Other adverse effects were GI toxicity such as nausea, vomiting and stomatitis, but these symptoms were controlled by appropriate medication.

Discussion

The goal of the present phase II study for advanced breast cancer patients with visceral metastases or hormone-independent tumors was to clarify the efficacy of high-dose epirubicin (EPI) plus cyclophosphamide (CPA) as an intensive chemotherapy and also to compare the toxicity of this regimen with other regimens including doxorubicin (ADM). Intensive chemotherapy regimens usually include ADM and CPA since both agents have been proved to be key drugs against advanced breast cancer (1 ,2 ). In addition, a steep dose-response relationship with these agents was observed in a prospective randomized trial and equimolar serum concentrations of EPI showed the same efficacy as ADM with less toxicity, suggesting that a combination of high-dose EPI and CPA might be a candidate combination for intensive chemotherapy (12 ,18 -20 ). In the previous phase I trial, a high frequency of grade 4 neutropenia was observed. In the phase II study, G-CSF administration was therefore routinely required as a hematopoietic rescue (13 ). However, the benefits of G-CSF in high-dose chemotherapy have still to be proved (21 ). Hansen et al. (22 ) reported a significant reduction in nadir duration of neutropenia in a prospective randomized study with and without GM-CSF administration after high-dose EPI (130 mg/m2) + CPA (2.5 g/m2) therapy.

Table 4 . Toxicity
Type of Grade* Incidence Incidence of
toxicity 0 1 2 3 4 (%)grades 3 and 4 (%)
Anemia 3 2 24 21 - 94.0 42.0
Leukopenia 1 0 0 3 46 98.0 98.0
Neutropenia 2 0 1 1 46 96.0 94.0
Thrombo-
cytopenia		 9 7 13 11 10 82.0 42.0
Nausea/
vomiting		 2 3 17 27 1 96.0 56.0
Stomatitis 31 6 12 1 0 38.0 2.0
Micro-
hematuria		 40 6 2 2 0 20.0 4.0
Skin 46 2 1 1 0 8.0 2.0
Hair loss 3 1 40 6 0 94.0 12.0
Arrhythmia 46 2 2 0 0 8.0 0
Cardiac function 48 1 1 0 0 2.0 0
* Common Toxicity Criteria by ECOG.

Table 5 . Nadir of neutropenia and thrombocytepenia
    Neutropenia Thrombocytopenia
Cycle Case Nadir
(cells/mm3)		 Days of grade 4 Nadir
(×10 000 cells/mm3)
1 50 333.9 (0-5216) 2.14 (0-7) 9.95 (1.9-25.4)
2 49 483.7 (0-3848) 1.84 (0-5) 9.21 (1.2-20.5)
3 43 590.8 (0-5518) 2.35 (0-6) 7.62 (0.8-17.3)
4 34 364.7 (0-3180) 2.27 (0-5) 6.78 (1.0-19.2)
5 27 439.0 (0-1888) 2.04 (0-4) 5.34 (0.9-11.1)
Numbers in parenthesis show the range.

The duration of leukopenia in the present study was shortened by G-CSF administration. In addition, no treatment-related death was observed with this regimen, suggesting that G-CSF might contribute to the reduction of severe adverse effects in high-dose chemotherapy. With regard to other toxicities, GI toxicity was relatively frequent, but it was controlled by appropriate medication. Nielsen et al. (23 ) reported that accumulative doses of EPI between 500 and 1000 mg/m2 increased the risk of congestive heart failure. The incidence of cardiotoxicity was low in the present study, with an accumulative dose of EPI of ~500 mg/m2. The first trial of a combination chemotherapy with EPI (120 mg/m2) + CPA (600 mg/m2) demonstrated a 78% response rate (37.5% CR, 40.5% PR) (24 ). The response rate in the present study was lower than those reported previously. This might be due to a higher frequency of visceral metastases in our patients. In addition, in the present study patients who had not responded to endocrine therapy were eligible. A similar population to the recurrent breast cancer patients in our study was also reported by Dunphy et al. (25 ). In their study, super-high-dose combination chemotherapy with cyclophosphamide, VP-16 and cisplatin for estrogen receptor-negative or hormonally refractory breast cancer demonstrated an 84% response rate and a 25 month median survival time. In spite of bone marrow support, they lost 9% of the patients with treatment-related death; in addition, the patients who were treated with these super-high-dose regimens had less visceral metastases, suggesting that it might be difficult to compare the benefit between their results and ours. However, we were satisfied with the efficacy of our regimen since, in spite of poor-responder patients who had hormonally refractory and viceral metastases, the response rate and survival time might be slightly improved. Marschner et al. (26 ) reported that high-dose EPI (120 mg/m2) + CPA (600 mg/m2) therapy resulted in a better clinical response (64%) than a conventional-dose EPI regimen (60 mg/m2 of EPI), but there was no statistically significant difference in survival between the two regimens. In the present study, both the clinical response rate and median survival time for responding patients were similar to those reported by Marschner et al. The response rate in patients who were treated with ADM as adjuvant therapy was 75% and there was no significant difference between patients with or without adjuvant therapy, suggesting that the adjuvant therapy was not a major predictive factor to response with this regimen. Moreover, Bonneterre and Mercier (27 ) reported that efficacy and time to failure were less in patients who had received adjuvant therapy than in those who were not treated with any prior therapy. Taken together, this regimen may be effective in patients with recurrence even though they had prior chemotherapy.

In conclusion, for breast cancer patients with visceral metastases or hormone-independent tumors, high-dose EPI + CPA therapy with G-CSF may be useful for obtaining a high response rate with acceptable toxicity, but may fail to prolong survival. A randomized trial of high-dose EPI vs conventional combination chemotherapy may be required to ascertain the benefit of this regimen for advanced or recurrent breast cancer patients.

Acknowledgments

The authors thank Dr S. Kvinnsland (Pharmacia and Upjohn) for his valuable advice and Ms Kinuko Tajima for her excellent technical support. This study was supported by a Grant-in-Aid for Cancer Research (#5-17, #2S-1, #5S-1 and #8S-1) from the Ministry of Health and Welfare, Japan.

References

1. Hoogstraten B, George S, Samal B, Rivkin S, Costanzi J, Bonnet J, et al. Combination chemotherapy and adriamycin in patients with advanced breast cancer: a South-West Oncology Group Study. Cancer 1976;38:13-20. MEDLINE Abstract

2. Traunum B, McDonald B, Thigpen T, Vaughn C, Wilson H, Maloney T, et al. Adriamycin combination in advanced breast cancer. Cancer 1982;49:835-9.

3. Paterson AHG, Szafran O, Cornish F, Lees AW, Hanson J. Effect of chemotherapy on survival in metastatic breast cancer. Breast Cancer Res Treat 1981;1:357-63.

4. Bonnadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. New Engl J Med 1976;294:405-10.

5. Hryniuk W, Figueredo A, Goodyear M. Application of dose intensity to problems in chemotherapy of breast and colorectal cancer. Semin Oncol 1987;14(Suppl 4):2-14.

6. Jones RB, Holland JF, Bhardwaj S, Norton L, Wilfinger C, Strashun A. A phase I/II study of intensive dose adriamycin for advanced breast cancer. J Clin Oncol 1987;5:172-7. MEDLINE Abstract

7. Peters WP, Eder JP, Henner WD, Schryber S, Wilmore D, Finberg R, et al. High-dose combination alkylating agents with autologous bone marrow support: A phase I trial. J Clin Oncol 1986;4:646-54. MEDLINE Abstract

8. Eddy DM. High-dose chemotherapy with autologus bone marrow transplantation for the treatment of metastatic breast cancer. J Clin Oncol 1992;10:657-70. MEDLINE Abstract

9. Bezwoda WR, Seymour I, Dansey RD. High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: A randomized trial. J Clin Oncol 1995;13:2483-9. MEDLINE Abstract

10. Lawton PA, Spittle MF, Ostrowski MJ, Young T, Madden F, Folkes A, et al. A comparison of doxorubicin, epirubucin and mitozantrone as single agents in advanced breast carcinoma. Clin Oncol 1993;5:80-4.

11. Perez DJ, Harvey VJ, Robinson BA, Atkinson CH, Dady PJ, Kirk AR, et al. A randomized comparison of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy in advanced breast cancer. J Clin Oncol 1991;9:2148-52. MEDLINE Abstract

12. Carmo-Pereira J, Costa FO, Henriques E, Richards MA, Rubens RD. A comparison of two doses of adriamycin in the primary chemotherapy of disseminated breast cancer. Br J Cancer 1987;56:471-3. MEDLINE Abstract

13. Watanabe T, Miya T, Fukutomi T, Okamoto R, Adachi I. Phase I study of high-dose epirubicin (EPI) and cyclophosphamide (CPA) with rG-CSF for metastatic breast cancer. Proc Am Soc Clin Oncol 1992;11:88.

14. Tominaga T, Ohota K, Yamaguchi S, Takashima S, Hirata K, Ogita M, et al. Clinical effect of recombinant G-CSF on neutropenia induced by adriamycin-containing chemotherapy in patients with advanced or recurrent breast cancer. Biotherapy 1993;7:1709-16 (in Japanese).

15. Hayward JL, Carbone PP, Hewson JC, Kumaoka S, Segaloff A, Rubens RD. Assessment of response to therapy in advanced breast cancer. Cancer 1977;39:1289-94. MEDLINE Abstract

16. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55. MEDLINE Abstract

17. Bulpitt CJ. Confidence intervals. Lancet 1987;i:494-7.

18. Focan C, Andrien JM, Clson MT, Dicato M, Driesschaert P, Focan-Henrad D et al. Dose-response relationship of epirubicin-based first line chemotherapy for advanced breast cancer: a prospective randomized trial. J Clin Oncol 1993;11:1253-63. MEDLINE Abstract

19. Gasparini G, Fior SD, Panizzoni GA, Favretto S, Pozza F. Weekly epirubicin versus doxorubicin as second line therapy in advanced breast cancer. Am J Clin Oncol 1991;14:38-44. MEDLINE Abstract

20. Lopez M, Papaldo P, Lauro LD, Carpano PS, Conti EMS. 5-Fluorouracil, adriamycin, cyclophosphamide (FAC) vs 5-fluorouracil, epirubicin, cyclophosphamide (FEC) in metastatic breast cancer. Oncology 1989;46:1-5. MEDLINE Abstract

21. American Society of Clinical Oncology (Chairman Ozer H, Langdon L ed.). American Society of Clinical Oncology Recommendations for the Use of Hematopoietic Colony-stimulating Factors: Evidence-based, Clinical Practice Guidelines. J Clin Oncol 1994;12:2471-508.

22. Hansen F, Stenbygaard L, Skovsgaard T. Effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on hematologic toxicity induced by high-dose chemotherapy in patients with metastatic breast cancer. Acta Oncol 1995;354:919-24.

23. Nielsen D, Jensen JB, Dombernowsky P, Munck O, Fogh J, Brynjolf I, et al. Epirubicin cardiotoxicity: a study of 135 patients with advanced breast cancer. J Clin Oncol 1990;8:1806-10. MEDLINE Abstract

24. Nagel GA, Beyer JH, Holtkamp W. High-dose epirubicin + cyclophosphamide (HD-EC) in metastatic breast cancer: A dose-finding study. Oncologie 1988;11:287-8. MEDLINE Abstract

25. Dunphy FR, Spitzer G, Buzdar AU, Hortobagyi GN, Horwitz LJ, Yau, JC, et al. Treatment of estrogen receptor-negative or hormonally refractory breast cancer with double high-dose chemotherapy intensfication and bone marrow support. J Clin Oncol 1990;8:1207-16. MEDLINE Abstract

26. Marschner N, Kreienberg R, Souchon U, Eggeling B, Voigtmann R, Ruffert K et al. Evaluation of importance and relevance of dose intensity using epirubicin and cyclophosphamide in metastatic breast cancer: Interim analysis of a prospective randomized trial. Semin Oncol 1994;21(Suppl.1):10-6. MEDLINE Abstract

27. Bonneterre J, Mercier M. Response to chemotherapy after relapse in patients with or without previous adjuvant chemotherapy for breast cancer. The French epirubicin study group. Cancer Treat Rev 1993;19(Suppl B):21-30. MEDLINE Abstract

Received March 5, 1997; accepted April 18, 1997
For reprints and all correspondence: Shigemitsu Takashima, Department of Surgery, National Shikoku Cancer Center Hospital, 13 Horinouchi, Matsuyama 790, Japan
Abbreviations: EPI, epirubicin; CPA, cyclophosphamide; G-CSF, granulocyte colony stimulating factor; CAF, cyclophosphamide + doxorubicin + 5-fluorouracil; CMF, cyclophosphamide + methotrexate + 5FU; CA, cyclophosphamide + doxorubicin; CNS, central nervous system; SGOT, serum glutamic oxaloacetic transaminase; ORR, overall response rate; ER, estrogen receptor; TAM, tamoxifen; ADM, doxorubicin

This page is run by Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, as part of the OUP Journals
Comments and feedback: www-admin{at}oup.co.uk
Last modification: 19 May 1998
Copyright© Japanese Journal of Clinical Oncology, 1997.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (5)
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Takashima, S
Right arrow Articles by Shimoyama, M
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Takashima, S
Right arrow Articles by Shimoyama, M
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?