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Journal of Clinical Oncology, Vol 20, Issue 11 (June), 2002: 2689-2694
© 2002 American Society for Clinical Oncology

First-Line Treatment With Epirubicin and Vinorelbine in Metastatic Breast Cancer

By Patrizia Vici, Giuseppe Colucci, Vittorio Gebbia, Antonella Amodio, Francesco Giotta, Franca Belli, Francesca Conti, Nicola Gebbia, Giuseppe Pezzella, Maria Rosaria Valerio, Mario Brandi, Salvatore Pisconti, Ernesto Durini, Diana Giannarelli, Massimo Lopez

From the Division of Medical Oncology B, Biostatistic Unit, Regina Elena Institute for Cancer Research, Rome; Oncologic Scientific Institute, Bari; Oncologic Center, Catania; Clinical Oncology, Policlinic University, Palermo; Oncologic Unit, SS Annunziata Hospital, Taranto; and Oncologic Day Hospital, G. Panico Hospital, Tricase (Lecce), Italy.

Address reprint requests to Patrizia Vici, MD, Division of Medical Oncology B, Regina Elena Institute for Cancer Research, Via E. Chianesi, 53, 00144 Rome, Italy; email: lopez{at}ifo.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: This phase II multicenter trial was aimed at investigating the activity of epirubicin-vinorelbine combination as first-line chemotherapy in metastatic breast cancer patients.

PATIENTS AND METHODS: Ninety-seven patients with metastatic breast cancer and no prior exposure to anthracyclines received the following regimen: epirubicin 100 mg/m2 by intravenous (IV) bolus infusion on day 1 plus vinorelbine 25 mg/m2 by 30-minute IV infusion on days 1 and 5, every 3 weeks for up to eight cycles. All patients also received granulocyte colony-stimulating factor (G- CSF) on days 7 to 12 of every cycle.

RESULTS: Objective responses, confirmed at least 4 weeks after the first documentation, were observed in 65 out of 92 assessable patients (70.6%; 95% CI, 62% to 80%). Disease remained stable in 17 patients (18.5%). Responses were observed in all disease sites, being 94% in soft tissue, 60% in bone, and 66% in visceral disease. Median time to response, median duration of response, median time to progression, and median overall survival were 2, 9, 10, and 26 months, respectively. The dose-limiting toxicity was neutropenia, which was grade 4 in 36% of the patients, and was accompanied by fever in 26% of the cases. Grade 3 to 4 mucositis was encountered in 28% of the patients. Other toxicities were mild to moderate. No cardiotoxicity was observed.

CONCLUSION: The epirubicin-vinorelbine combination with G-CSF support has been shown in this study to be highly active as first-line treatment of metastatic breast cancer patients, with significant although transient toxicity. This justifies further evaluation in the neoadjuvant setting and in early-stage breast cancer.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
ANTHRACYCLINES are among the most active drugs in advanced breast cancer, with single-agent response rates in untreated patients of 35% to 50%.1 Because of their high rates of activity, these agents have served as the basis for several combination chemotherapy regimens. Perhaps the most commonly used of these combinations is fluorouracil, doxorubicin, and cyclophosphamide, which has yielded response rates in 40% to 70% of the patients.2 In Europe, doxorubicin has been often replaced by epirubicin without loss of efficacy and with decreased toxicity.3,4 Nevertheless, anthracycline-containing regimens have not substantially prolonged survival in patients with metastatic breast cancer because only 16%5 can be rendered free of detectable disease with a short median duration of response. Therefore, there is clearly a need for new therapeutic strategies and new combination regimens.

Vinorelbine is a new semisynthetic vinca alkaloid, which has gained increasing acceptance over other agents of this class because of its greater action on mitotic rather than axonal microtubules, leading to a reduction in the neurotoxicity typically observed with antimicrotubule agents.6 Used as single agent, at weekly doses of 30 mg/m2, vinorelbine has proved to be very active in advanced breast cancer, with response rates ranging from 41% to 60%7,8 as first-line treatment. Vinorelbine has been combined with doxorubicin in patients with advanced breast cancer, yielding a 74% response rate with a median duration of response of 12 months and a median survival of 27.5 months.9 The most frequently encountered side-effect was neutropenia, which was febrile in only 3% of the cycles. However, grade 2 to 4 World Health Organization (WHO) cardiotoxicity was observed in 10% of the patients. With the aim of reducing this effect and exploiting the dose-response relationship reported with epirubicin,10 while at the same time trying to improve treatment results by combining two highly active single agents, we first performed a phase I study of epirubicin and vinorelbine. The recommended phase II doses of these drugs were, respectively, 100 mg/m2 on day 1 and 25 mg/m2 on days 1 and 5, with G-CSF support and cycles repeated every 3 weeks. The choice of administering vinorelbine on days 1 and 5 instead of the more commonly used schedule of days 1 and 8 was to avoid the frequent eighth-day dose reduction or omission.

On the basis of the above reported results, since November 1997, the combination of epirubicin and vinorelbine has been used in a multicenter phase II study as first-line treatment in patients with metastatic breast cancer.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
Eligibility criteria included histologically confirmed carcinoma of the breast, a life expectancy more than 3 months, WHO performance status <= 3, measurable or assessable disease, adequate bone marrow (absolute neutrophil count >= 1,500/mL, platelet count >= 100,000/mL, and hemoglobin >= 11 g/dL), renal and liver (total bilirubin and creatinine < 1.25 times the upper normal limit) function, and a normal cardiac function, as demonstrated by ECG and left ventricular ejection fraction (LVEF) measurement.

Patients were excluded from the study if they had active cardiac disease or significant arrhythmia, preexistent neuropathy, a history of other malignancies, and previous exposure to anthracyclines or vinca alkaloids. Previous adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil or similar regimens was allowed, but an interval of 2 months since the end of therapy should have elapsed; prior hormonal therapy or radiotherapy must have been discontinued for at least 4 weeks before protocol entry. No other concomitant antineoplastic treatment was allowed. The protocol was approved by the ethical committees of each participating center; all patients gave their written informed consent to participate in the trial.

Treatment
Treatment consisted of epirubicin 100 mg/m2 by intravenous bolus infusion on day 1, and vinorelbine 25 mg/m2, diluted in 500 mL of normal saline and administered intravenously over 30 minutes on days 1 and 5, with cycles repeated every 3 weeks. Granulocyte colony-stimulating factor (G-CSF) was given subcutaneously on days 7 to 12 of each cycle. Antiemetic treatment consisted of an antiserotonin agent plus dexamethasone in a 15-minute infusion before starting chemotherapy.

Treatment was postponed by a maximum of 2 weeks if the absolute neutrophil count was less than 1,500/µL or the platelet count was less than 100,000/µL. A 25% drug dose reduction was planned in case of grade 4 neutropenic fever (absolute granulocyte count below 500/µL at the time of a documented temperature of 38°C or higher), as well as in case of grade 4 mucositis, or grade 3 to 4 neurotoxicity. Chemotherapy was administered for a maximum of eight cycles and was discontinued in case of unacceptable toxicity, treatment delay longer than 2 weeks, disease progression, or patient refusal.

Pretreatment and Follow-Up Studies
Pretreatment evaluation included clinical history and physical examination, automated blood cell count, biochemical profile, chest x-ray, liver ultrasound, bone scan, ECG, and resting LVEF determination by echocardiography or multigated radionuclide angiography scan. Blood counts were obtained on day 1 and at nadir; biochemical profile was repeated every 3 weeks. All measurable or assessable parameters of disease were reevaluated every 9 weeks. Cardiac monitoring was performed at baseline and after cycle 6 of the combination. In case of a LVEF decrease more than 10% and/or below the lower limits of normal, a repeat measurement in 3 months was required. Otherwise, during follow-up, cardiac toxicity was assessed only in case of clinical signs and symptoms of congestive heart failure (CHF).

Evaluation of Response and Toxicity
Patients were evaluated for response to chemotherapy every three cycles of treatment. Responses were assessed by at least two observers. Standard WHO criteria11 were used to evaluate clinical response. Duration of response was measured from initiation of treatment for partial response and from time when response was first documented for complete response. Time to progression and survival were calculated starting from the date of first chemotherapy cycle to the date of disease progression or the date of death (or last follow-up evaluation), respectively. Toxicity was assessed in each treatment cycle of therapy using the National Cancer Institute common toxicity criteria.

Statistical Considerations
The primary objective of this study was to estimate the overall response rate of the regimen. The Simon two-stage phase II design was used to determine the sample size. The regimen would be considered worthy of further testing if at least 21 out of 34 eligible patients had an objective response (62%), with a significance level of 5% and a power of 90%. In the second stage, 61 additional patients would be needed, with an overall sample size of 95 patients. Duration of response, time to progression, and overall survival were assessed using the Kaplan-Meier method; for descriptive data, comparison were made using the {chi}2 test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
From November 1997 to July 1999, 97 patients with metastatic breast cancer entered this multicenter trial. Five patients were not considered assessable for response. One patient with massive liver involvement had severe hepatotoxicity (reversible grade 4 AST/ALT elevation) and entailed prompt withdrawal from the study. Another patient developed herpes zoster requiring discontinuation of treatment, and the remaining three patients refused further treatment after the first cycle. All patients were assessable for toxicity.

Patient characteristics are listed in Table 1. None of the patients included in the study had previously received chemotherapy for advanced disease; 43 patients had received adjuvant cyclophosphamide, methotrexate, and fluorouracil, and 13 patients had prior hormonal therapy for advanced disease. Among 92 assessable patients, we observed 15 (16.3%) complete responses and 50 (54.3%) partial responses, for an overall response rate of 70.6% (95% CI, 62% to 80%). Disease remained stable in 17 patients (18.5%), with a median duration of 8 months. Responses according to disease site were as follows: soft tissue, 94%; bone, 60%; and viscera, 66%. Response rate according to number of metastatic sites was as follows: one site, 64.3% (27 of 42 patients); two sites, 79% (34 of 43 patients); and three sites, 57.1% (four of seven patients). No significant differences were seen in response rate according to estrogen receptor status, previous adjuvant chemotherapy, and disease-free interval. The median number of cycles administered was six (range, one to eight cycles). Median time to response was 2 months (range, 1 to 5 months); median duration of response was 9 months (range, 3 to 27+ months), without differences between complete response and partial response; median time to progression was 10 months (range, 3 to 27+ months) (Fig 1); and median survival was 26 months (range, 5 to 30+ months) (Fig 2).


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  		Table 1.  Patient Characteristics
 


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  		Fig 1. Time to progression.

 


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  		Fig 2. Patient overall survival.

 
Toxicity data are listed in Table 2. The dose-limiting toxicity was myelosuppression, including grade 4 neutropenia in 36% of the patients, with a median duration of 3 days. Neutropenic fever occurred in 26% of the patients, with two patients requiring hospital admission. A 25% epirubicin and vinorelbine dose-reduction was required in 20 patients because of grade 4 neutropenia with fever, whereas treatment was postponed in 10 patients because of delay in bone marrow recovery. Mean epirubicin and vinorelbine dose-intensities were 29.9 and 14.8 mg/m2/wk, respectively, which are equivalent to 89.8% and 89.2% of the planned dose-intensities. Mild thrombocytopenia was observed in 19% of the patients, whereas it was grade 4 in one patient; grade 3 to 4 anemia was observed in 8% of the patients. Alopecia was universal. Mild nausea and vomiting was encountered in 50% of the patients; it was severe in one patient. Mucositis was of grade 3 in 27% and of grade 4 in 1% of the patients. Hepatotoxicity (reversible AST/ALT elevation) was recorded in 10% of the patients (mild in 9% and severe in 1% of the patients). Mild and transient peripheral neurotoxicity was recorded in 5% of the patients. Mild local pain in the site of venous injection and grade 1 myalgias and/or arthralgias were observed in 10% of the patients.


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  		Table 2.  Main Toxicities in 97 Assessable Patients
 
The median cumulative epirubicin dose was 600 mg/m2 (range, 100 to 800 mg/m2). There were no instances of congestive heart failure or grade 1 to 3 cardiotoxicity.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Anthracycline-containing regimens induce in advanced breast cancer objective response rates in the range of 50% to 80%, with median duration of response between 10 and 18 months and median survival between 18 and 24 months.12 Responding patients usually experience substantial palliation, but remissions are short-lasting, highlighting the need for new chemotherapy strategies such as the use of new agents, among which vinorelbine seems to be particularly promising.

The combination of epirubicin and vinorelbine plus G-CSF evaluated in this study seems to be very active in terms of response rates, because 70.6% (95% CI, 62% to 80%) of the patients achieved a response, which was complete in 16.3% of the cases. Responses were observed in all disease sites, being 60% in bone, 66% in visceral, and 94% in soft tissue disease. Median time to progression was 10 months. The most important side effect was neutropenia, which was severe in 36% of the patients. Nevertheless, it generally lasted only a few days and was febrile in 26% of the cases, with only two episodes of serious infections. Mucositis was frequent and significant but usually manageable. Other toxicities were negligible. Thus, the overall tolerability of treatment was good, and there were no treatment-related deaths.

Although vinorelbine as single agent in metastatic breast cancer has been reported as active as other new effective agents, such as taxanes, only in a few studies has it been combined with anthracyclines in comparison to the latter. The combination of epirubicin and vinorelbine has been evaluated in six phase II trials13-18 (Table 3), with response rates up to 76%, but the relative small number of patients enrolled in each of these studies would have precluded any firm conclusion about the merits of this regimen. In this regard, the present study, in which 97 patients were treated, seems to more reliably confirm the high activity of the epirubicin-vinorelbine combination.


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  		Table 3.  Epirubicin and Vinorelbine Phase II Trials
 
In at least four studies,9,19-21 vinorelbine was combined with doxorubicin. In one of these studies,9 the size of the trial and the results were remarkably similar to those of the present trial. Responses were observed in 74% of 89 assessable patients, with a median duration of responses of 12 months and a median survival of 27.5 months. However, cardiotoxicity was encountered in a considerable number of patients in this study, and cardiac-related deaths were registered in three patients. Cardiac events also occurred in the other three studies.19-21 In contrast, a striking evidence of the epirubicin-vinorelbine regimen was the apparent lack of cumulative cardiotoxicity. Although epirubicin is reported to be less cardiotoxic than doxorubicin,22 this may be in part because of the fact that maximum cumulative drug dose was 800 mg/m2 because the protocol included a maximum of eight cycles of treatment. This seems a wise and safe approach, considering that data have been accumulated demonstrating no significant survival advantage when metastatic first-line chemotherapy was prolonged more than six to eight cycles.9,23

Perhaps the combination of anthracyclines and taxanes has been the most widely explored in recent years. In general, when doxorubicin has been combined with paclitaxel, very high response rates (up to 90%) have been reported,24 but the incidence of congestive heart failure (approximately 20%) was almost prohibitive. In fact, paclitaxel has been shown to change the pharmacokinetic profile of doxorubicin and doxorubicinol, resulting in approximately a 30% increase in exposure to doxorubicin and its active metabolite.25 When doxorubicin has been substituted with epirubicin, a level of activity similar to that reported with the doxorubicin-paclitaxel combination has been obtained,26 with no signs of cumulative cardiotoxicity.27 Nevertheless, paclitaxel has been reported to increase significantly the plasma concentration time curves for the 7d-Aone and glucuronidated metabolites of epirubicin.28

The combination of epirubicin and docetaxel seems to be particularly attractive because it is apparently devoid of those pharmacokinetic interactions that may enhance the toxicity of regimens including paclitaxel and an anthracycline.29 The epirubicin-docetaxel regimen has been so far evaluated in several trials,29-37 with response rates ranging from 54% to 87.5%.

Among the nontaxane combinations, the epirubicin-vinorelbine regimen tested in the present study showed an overall objective response rate of 70.6%, suggesting a marked antitumor activity in patients with metastatic breast cancer. Clinical responses achieved were long lasting, and patient survival is noteworthy, with a median of 26 months.

An overview38 of randomized chemotherapy trials in advanced breast cancer showed that the inclusion of doxorubicin in Cooper-type regimens produces a median survival of 18 months. A median survival of 17 months was also achieved with vinorelbine alone given as first-line treatment in metastatic breast cancer.39 Thus, although a survival advantage can be demonstrated only in randomized trials, the survival in our patient population seems encouraging.

In conclusion, the combination of epirubicin and vinorelbine has been shown in this study to be highly active and manageable in patients with advanced breast cancer because results are similar to, and perhaps better than, those reported with other effective but more toxic regimens, including those combining anthracyclines and taxanes26,33,40,41; although in these studies, some patients had received prior adjuvant anthracyclines. In addition, it has the advantages of a more practical drug administration. Although this epirubicin-vinorelbine combination constitutes a valid therapeutic option for patients with metastatic breast cancer, its high efficacy in terms of tumor shrinkage may be of great value in the neoadjuvant setting, where a high response rate is particularly useful. It is also conceivable that this effective regimen could be suitable for comparison with standard combinations in early-stage breast cancer.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Ahmann DL, Schaid DJ, Bisel HP, et al: The effect on survival of initial chemotherapy in advanced breast cancer: Polychemotherapy versus single drug. J Clin Oncol 15: 1928-1932, 1987

2. Mourisden HT: Systemic therapy of advanced breast cancer. Drugs 44: 17-28, 1992 (suppl 4)

3. French Epirubicin Study: A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 6: 679-688, 1988[Abstract]

4. Italian Multicenter Breast Study with Epirubicin: Phase III randomized study of fluorouracil, epirubicin and cyclophosphamide vs fluorouracil, doxorubicin and cyclophosphamide in advanced breast cancer. J Clin Oncol 6: 976-982, 1988[Abstract/Free Full Text]

5. Greenberg PA, Hortobagyi GN, Smith TL, et al: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14: 2197-2205, 1996[Abstract]

6. Smith GA: Current status of vinorelbine for breast cancer. Oncology 9: 767-773, 1995[Medline]

7. Fumoleau P, Delgado FM, Delozier T, et al: Phase II trial of weekly intravenous vinorelbine in first line advanced breast cancer chemotherapy. J Clin Oncol 11: 1245-1252, 1993[Abstract/Free Full Text]

8. Canobbio L, Boccardo F, Pastorino G, et al: Phase II study of navelbine in advanced breast cancer. Semin Oncol 16: 33-36, 1989[Medline]

9. Spielmann M, Dorval T, Turpin F, et al: Phase II trial of vinorelbine/doxorubicin as first-line therapy of advanced breast cancer. J Clin Oncol 12: 1764-1770, 1994[Abstract/Free Full Text]

10. Bastohlt L, Dalmark M, Gjedde SB, et al: Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: A randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol 14: 1146-1155, 1996[Abstract/Free Full Text]

11. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 207-241, 1981[CrossRef][Medline]

12. Ellis MJ, Hayes DF, Lippman ME: Treatment of metastatic breast cancer, in Harris JR (ed): Diseases of the breast ( ed 2 ). Philadelphia, PA, Lippincott Williams & Wilkins, 2000, pp 749-797

13. Chadja M, Izzo J, May-Levin F, et al: Preliminary data on 4'epiadriamycin (EPI)-vinorelbine (VNB): A new active combination in advanced breast cancer (ABC). Proc Am Soc Clin Oncol 12: 88, 1993 (abstr 152)

14. Blomqvist C, Hietanen P, Teerenhovi L, et al: Vinorelbine and epirubicin in metastatic breast cancer: A dose finding study. Bur J Cancer 31a: 2406-2408, 1995

15. Ezzat A, Motawy S, Berry J, et al: Pilot study of navelbine (NVB) and epirubicin (EPR) for the treatment of inoperable locally advanced and metastatic breast cancer. Ann Oncol 7: 31, 1996 (abstr)[Abstract/Free Full Text]

16. Baldini B, Tibaldi C, Chiavacci F, et al: Epirubicin/vinorelbine as first line therapy in metastatic breast cancer. Breast Cancer Res Treat 49: 129-134, 1998[CrossRef][Medline]

17. Pronzato P, Tognoni A, Pensa F, et al: A dose finding study for the combination of epidoxorubicin and vinorelbine, delivered every two weeks with G-CSF support, in advanced breast cancer. J Chemother 10: 326-330, 1998[Medline]

18. Tabiadon D, Zonato C, Frontini L, et al: Multicentric phase II study with vinorelbine (VNB) and epirubicin (EPI) as first line chemotherapy in metastatic breast cancer (MBC): Preliminary data. Proc Am Soc Clin Oncol 17: 176a, 1998 (abstr 679)

19. Hochster HS: Combined doxorubicin/vinorelbine (Navelbine) therapy in the treatment of advanced breast cancer. Semin Oncol 22: 55-60, 1995 (supp 5)[Medline]

20. Blajman C, Balbiani L, Block J, et al: A prospective, randomized phase III trial comparing combination chemotherapy with cyclophosphamide, doxorubicin and 5-fluorouracil with vinorelbine plus doxorubicin in the treatment of advanced breast carcinoma. Cancer 85: 1091-1097, 1999[CrossRef][Medline]

21. Norris B, Pritchard KI, James K, et al: Phase III comparing study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA8. J Clin Oncol 18: 2385-2394, 2000[Abstract/Free Full Text]

22. Torti FM, Bristow MR, Lum BL, et al: Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy. Cancer Res 46: 3722-3727, 1986[Abstract/Free Full Text]

23. Sledge GW, Antman KH: Progress in chemotherapy for metastatic breast cancer. Semin Oncol 19: 317-332, 1992[Medline]

24. Gianni L, Munzone B, Capri G: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 13: 2688-2699, 1995[Abstract]

25. Gianni L, Viganò L, Locatelli A, et al: Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol 15: 1906-1915, 1997[Abstract/Free Full Text]

26. Luck HJ, Thomssen C, du Bois A, et al: Preliminary results of a phase II study of epirubicin and paclitaxel as first-line treatment in patients with metastatic breast cancer. Semin Oncol 24: S3-13–S3-16, 1997

27. Conte PF, Baldini E, Gennari A, et al: Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: A regimen with high activity and low cardiotoxicity in advanced breast cancer. J Clin Oncol 15: 2510-2517, 1997[Abstract/Free Full Text]

28. Esposito M, Venturini M, Vannozzi MO, et al: Comparative effects of paclitaxel and docetaxel on the metabolism pharmacokinetics of epirubicin in breast cancer patients. J Clin Oncol 17: 1132-1140, 1999[Abstract/Free Full Text]

29. Kerbrat P, Viens P, Roche H, et al: Docetaxel (D) in combination with epirubicin (E) as first-line chemotherapy (CT) of metastatic breast cancer (MBC): Final results. Proc Am Soc Clin Oncol 17: 151a, 1998 (abstr 579)

30. Raab G, Borquez D, Harstrick A, et al: Phase I study of docetaxel (D) in combination with epirubicin (E) as first-line chemotherapy (CT) in metastatic breast cancer. Proc Am Soc Clin Oncol 17: 168a, 1998 (abstr 644)

31. Trudeau ME, Crump M, Latreille J, et al: Escalating doses of docetaxel and epirubicin as first-line therapy for metastatic breast cancer: A phase I study of the National Cancer Institute of Canada-Clinical Trials Group. Proc Am Soc Clin Oncol 17: 178a, 1998 (abstr 687)

32. Pagani O, Sessa C, Martinelli G, et al: Dose finding study of epodoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer. Ann Oncol 10: 539-545, 1999[Abstract/Free Full Text]

33. Kouroussis C, Kydakis E, Potamianou A, et al: Front-line treatment of metastatic breast cancer with docetaxel and epirubicin: A multicenter dose-escalation study. Ann Oncol 10: 547-552, 1999[Abstract/Free Full Text]

34. Milla-Santos A, Anton Aparicio L, Gonzalez-Baron M, et al: Docetaxel (D) plus high dose epirubicin (E) with lenograstim (L) support as first line therapy in advanced breast cancer (ABC): A phase II study. Proc Am Soc Clin Oncol 19:107a, 2000 (abstr 413)

35. Dominguez S, Morales S, Castellanos J, et al: Combination of two active drugs; epirubicin-docetaxel (Taxotere) (ET) in advanced breast cancer (ABC): Preliminary results. Proc Am Soc Clin Oncol 19: 110a, 2000 (abstr 424)

36. Eidtmann H, Astner A, Ernhardt B, et al: Phase II study of docetaxel and epirubicin as first line chemotherapy in metastatic breast cancer. Proc Am Soc Clin Oncol 19: 114a, 2000 (abstr 442)

37. Estevez L, Domine M, Martin I, et al: Docetaxel (T) in combination with epirubicin (E) as treatment of metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 19: 119a, 2000 (abstr 462)

38. A’Hern RP, Smith IE, Ebbs SR: Chemotherapy and survival in advanced breast cancer: The inclusion of doxorubicin in Cooper type regimens. Br J Cancer 67: 801-805, 1993[Medline]

39. Weber EL, Vogel C, Jones S, et al: Intravenous vinorelbine as first-line and second-line therapy in advanced breast cancer. J Clin Oncol 13: 2722-2730, 1995[Abstract]

40. Sparano JA, Bu P, Rao RM, et al: Phase II trial of doxorubicin and paclitaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 17: 3828-3834, 1999[Abstract/Free Full Text]

41. Sparano JA, O’Neill A, Schaefer PL, et al: Phase II trial of doxorubicin and docetaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: Eastern Cooperative Oncology Group study. J Clin Oncol 18: 2369-2377, 2000[Abstract/Free Full Text]

Submitted June 8, 2001; accepted March 18, 2002.


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R. Tambaro, S. Greggi, R. V. Iaffaioli, A. Rossi, C. Pisano, L. Manzione, E. Ferrari, M. Di Maio, F. Iodice, G. Casella, et al.
An escalating dose finding study of liposomal doxorubicin and vinorelbine for the treatment of refractory or resistant epithelial ovarian cancer
Ann. Onc., September 1, 2003; 14(9): 1406 - 1411.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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