II study

ARTICLE IN PRESS The Breast (2006) 15, 601–609

THE BREAST www.elsevier.com/locate/breast

ORGINAL ARTICLE

Gemcitabine and epirubicin in patients with metastatic breast cancer: A phase I/II study Mario Camponea, Pierre Fumoleaua,,1, Patrice Viensb, Ve ´ronique Die ´rasc, ´g, Eric Pujade-Laurained, Daniel Serine, Thierry Petitf, Marc Espie Louis Kayitalireh, Laurence Bozech, Pierre Pouillartc a

Centre Rene´ Gauducheau, 44805 Nantes-St. Herblain, France Institut Paoli Calmettes, 27 boulevard Lei Roure, 13009 Marseille, France c Institut Curie, Paris, 26, rue d’Ulm, 75248 Paris Cedex 05, France d Ho ˆtel Dieu, Paris, 1, place du Parvis Notre-Dame Paris, 75004 Paris, France e Clinique Sainte Catherine, Avignon BP 846, 84082 Avignon, France f Centre Paul Strauss, Strasbourg BP 42, 3 Rue de la Porte de l’Ho ˆpital, 67065 Strasbourg Cedex, France g Hospital Saint Louis, Paris, 1, avenue C. Vellefaux, 751010 Paris, France h Eli Lilly France, 13 rue Page `s, 92158 Suresnes Cedex, France b

Received 20 April 2005; received in revised form 7 November 2005; accepted 15 November 2005

KEYWORDS Epirubicin; Gemcitabine; Metastatic breast cancer; Phase I/II study

Summary Gemcitabine and epirubicin were evaluated in metastatic breast cancer (MBC) patients to determine the maximum tolerated dose (MTD), efficacy, and toxicity of the combination. Patients initially received 800 mg/m2 of gemcitabine (days 1 and 8) and 50 mg/m2 of epirubicin (day 1) every 21 days. Each dose level had three to eight patients. Phase II used the dose level preceding the MTD. Forty-eight patients enrolled without reaching MTD; therefore, phase II used the highest dose level (1500 mg/m2 of gemcitabine, 90 mg/m2 of epirubicin). After 23 patients (group A) experienced hematologic toxicities and frequent dose reductions, 15 received 1250 mg/m2 gemcitabine (days 1 and 4) and 90 mg/m2 epirubicin (day 1) every 21 days (group B). Out of 38 patients, 46% responded (group A 32%, group B 67%). Median response duration was 8.5 months; median time to progression 8.4 months; and median time to treatment failure 4.8 months. Gemcitabine and epirubicin are well tolerated and active in MBC patients, and the group B regimen warrants further investigation. & 2005 Elsevier Ltd. All rights reserved.

Corresponding author. Centre G.F. Leclerc, 1 rue du Professeur Marion, 21079 Dijon, France. Tel.: +33 3 80 73 75 00;

fax: +33 3 80 73 77 16. E-mail address: [email protected] (P. Fumoleau). 1 Prof. Fumoleau was affiliated with Centre Rene´ Gauducheau during this study. His new affiliation is listed as his corresponding author address. 0960-9776/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2005.11.010

ARTICLE IN PRESS 602

Introduction Chemotherapy used in the first-line treatment of metastatic breast cancer (MBC) commonly includes an anthracycline such as doxorubicin or epirubicin. Epirubicin, an antineoplastic anthracycline derived from doxorubicin, is less myelotoxic and less cardiotoxic than equimolar doses of doxorubicin.1 Single-agent epirubicin has achieved response rates of 16–85% in patients with MBC.2–5 Combination regimens containing an anthracycline have yielded response rates to the order of 40–70% in the first-line setting; however, these patients are prone to relapse, and second-line anthracycline therapy has yielded much lower overall response rates (ORRs) of 10–35%.6–11 Thus, it is a challenge to find agents that offer new possibilities for developing chemotherapeutic strategies in MBC, especially in instances of relapse after first- or second-line chemotherapy. Gemcitabine, a nucleoside antimetabolite, is one such agent that has shown antitumor activity in a variety of human cancers.12–16 Gemcitabine is also well tolerated and its novel mechanism of action minimizes the likelihood of prior drug-associated resistance.17,18 In an early phase II study of gemcitabine in MBC, a dose of 800 mg/m2 given over 4-week cycles produced an ORR of 25% in a mixed population of chemonaive and pre-treated patients.13 More recently published trials in MBC patients have produced ORRs of 14–42% in variously pre-treated patients.19–25 As gemcitabine and epirubicin have shown promising single-agent activity and good tolerability in the treatment of MBC, as well as different toxicity profiles by virtue of their distinct drug classes, we conducted a phase I/II study in patients with MBC to determine the maximum tolerated dose (MTD) of gemcitabine plus epirubicin in phase I evaluation, and the efficacy and safety of the combination in the subsequent phase II evaluation. Preliminary results from this study have been previously reported.26,27

Materials and methods Patient eligibility Women with histologically confirmed, stage IV MBC (as per the American Joint Committee on Cancer Staging) with lesions not amenable to surgery or radiation of curative intent, and who met the following criteria, were eligible for the study: age 18–70 years, World Health Organization (WHO) performance status 0–2, an estimated life expec-

M. Campone et al. tancy of at least 12 weeks, and adequate bone marrow reserve and cardiac function. Prior cancerrelated hormonal treatments were permitted, but concurrent hormonal treatment was not allowed. Patients in phase I study could have had measurable or evaluable lesions, while patients in phase II study had to have at least one bidimensionally measurable lesion. Radiation treatment within 1 week of study entry was permitted if the irradiated site was not the only site of measurable disease. Phase I patients may have received up to one prior chemotherapy regimen (adjuvant, neoadjuvant, or in the metastatic setting) if completed at least 1 month before study entry. Phase II patients may have received previous chemotherapy (adjuvant only) if completed at least 1 year before study entry. Patients were excluded for: 1. Prior gemcitabine therapy. 2. Cumulative epirubicin doses of 450 mg/m2 or doxorubicin doses of 300 mg/m2 during a previous regimen. 3. Abnormal bilirubin, liver transaminase, creatinine, and calcium levels. 4. Congestive heart failure (gradeX3). 5. Acute myocardial infarction and previous myocardial infarction that led to New York Heart Association grade 3 or 4 congestive heart failure. 6. Acute inflammatory cardiac disease or cardiac arrhythmias with severe impairment of hemodynamics. 7. Pregnancy or breast-feeding. 8. Active infection or serious systemic disorder considered incompatible with the study. 9. Any central nervous system metastases. 10. Previous cancer within 5 years of enrollment. 11. Secondary primary malignancy excluding cervical carcinoma in situ or basal cell carcinoma. 12. Previous high-dose chemotherapy with autologous stem cell rescue. 13. Bone metastases as the only site of disease. This study was conducted according to the guidelines of good clinical practice and the tenets of the Declaration of Helsinki, and was approved by the local ethics committees of the participating centers. Patients were required to give written informed consent before enrollment.

Study design and treatment This was a multicenter, open-label, nonrandomized phase I/II study of gemcitabine and epirubicin

ARTICLE IN PRESS Gemcitabine and epirubicin in patients with metastatic breast cancer: A phase I/II study administration in patients with MBC. Gemcitabine was administered intravenously over 30 min on days 1 and 8, and epirubicin was given intravenously after gemcitabine infusion over 10–30 min on day 1 of 21-day cycles. Each patient received full supportive care during the study. No hematopoietic growth factors were allowed except for patients experiencing febrile neutropenia. After a minimum of two cycles, patients received up to six additional cycles after a complete response (CR), and up to four additional cycles after a partial response (PR) or stable disease (SD). Patients were discontinued from the study due to progressive disease (PD), unacceptable toxicity (including congestive heart failure, left ventricular ejection fraction (LVEF) o45%, or decreases in LVEF of 15%), or after reaching a cumulative epirubicin dose of 1000 mg/m2 (including prior epirubicin or equivalent doses of doxorubicin). In phase I, patients in cohorts of three were initially treated at dose level 1 (800 mg/m2 of gemcitabine, 50 mg/m2 of epirubicin). Three additional patients were accrued at any given dose level if only one of the three patients exhibited a dose-limiting toxicity (DLT). The MTD was defined as the dose level that produced any of the following DLTs (as per the WHO scale) in three out of six patients during the first treatment cycle: 1. Grade 4 neutropenia lasting 41 week. 2. Grade 4 neutropenia associated with fever X38.5 1C requiring 448 h of intravenous antibiotic treatment. 3. Grade 4 thrombocytopenia associated with hemorrhage. 4. Persistence of a nonhematologic toxicity Xgrade 2 (excluding alopecia) at scheduled retreatment. 5. Grade 3 or 4 gastrointestinal distress (diarrhea or constipation) or flu-like symptoms (fever, myalgia/arthralgia, and fatigue). 6. Other grade 3 or 4 toxicities with the exception of grade 3 vomiting, grade 3 peripheral neuropathy, or any grade alopecia. Phase II portion of the study had a two-stage design. Initially, a total of nine patients were treated and evaluated. If no response was observed in these patients, the study was terminated. If at least one response was observed, an additional 26 patients were planned. A total of 14 responders out of 35 patients allowed an estimated response rate of 40% with a 95% confidence interval (CI) of 24–58%. Phase II dose level was prospectively defined as that dose level immediately preceding the MTD, or in the absence of an MTD, as dose level

603

9 (1500 mg/m2 of gemcitabine and 90 mg/m2 of epirubicin). Initially, 23 patients received dose level 9 (1500 mg/m2 of gemcitabine on days 1 and 8 and 90 mg/m2 of epirubicin on day 1), the highest dose level tested in phase I. This schedule produced cumulative hematologic toxicities (leukopenia and neutropenia) resulting in frequent dose reductions, mostly occurring on day 8. On the basis of the favorable toxicity findings by Conte et al. reported at that time,28,29 phase II regimen in the protocol was amended to 1250 mg/m2 of gemcitabine on days 1 and 4 and 90 mg/m2 of epirubicin on day 1 of a 21-day cycle. A total of 15 patients received the revised dose and are hereafter referred to as group B. The 23 patients who received the initial protocol regimen are hereafter referred to as group A.

Dose adjustments Neutropenia with an absolute neutrophil count (ANC) of 0.5–1.49
109/l or thrombocytopenia with a platelet count of 50–99
109/l after the first dose in a cycle resulted in a 50% reduction of day 8 gemcitabine. Gemcitabine was not administered on day 8 in patients with an ANC of o0.5
109/l, a platelet count of o50
109/l, or any WHO nonhematologic grade 4 toxicities after the first dose within a cycle. Grade 3 nonhematologic toxicities, with the exception of nausea, vomiting, or alopecia, resulted in a 50% dose reduction or omission of the day 8 gemcitabine dose. Subsequent cycles in phase I were delayed if ANC was o1.5
109/l or platelet count was o1
109/l. If 414 days had elapsed between the last dose and the start of a new cycle, treatment was paused until blood counts recovered, and the next cycle began at a 50% dose reduction of both drugs. Febrile neutropenia or thrombocytopenia with bleeding also resulted in a 50% dose reduction of both drugs. If the doses were tolerated, reescalation in subsequent cycles to 75% or 100% of the original doses was allowed. Any patient who could not receive drugs for 6 weeks after the time of the last treatment was suspended from the study. Dose adjustments in phase II were the same as those in phase I with the following exceptions: within a cycle, the second gemcitabine dose was reduced by 25% for grade 3 toxicities except for nausea, vomiting, and alopecia; both drugs were reduced by 25% for an ANC of 1.0–1.5
109/l or a platelet count of 75–100
109/l, and by 50% for febrile neutropenia, grade 4 thrombocytopenia, or

ARTICLE IN PRESS 604 thrombocytopenia with bleeding; subsequent cycles were delayed if ANC was o1.0
109/l or platelet count was o75
109/l.

Treatment assessments Tumor measurements of lesions that were measurable by physical examination were performed before every cycle. Radiologic imaging studies using computed tomography (CT) scans, magnetic resonance imaging (MRI), or bone scans were conducted before the third cycle and every two cycles thereafter, and were repeated 4 weeks after the initial response using the same diagnostic technique that was used at baseline. Tumor response was assessed using standard WHO criteria. All patients in phase II who received at least two cycles of study therapy were considered evaluable for efficacy (they were also included if they had discontinued prior to this point due to unacceptable toxicity). Estimates of time to progressive disease (TTP), time to treatment failure (TTF), and duration of response were calculated according to the Kaplan–Meier method using PROC LIFETEST in Statistical Application Software (SAS). Toxicity was evaluated at the end of each treatment cycle according to the WHO toxicity scale. All patients who received at least one dose of gemcitabine or epirubicin were considered evaluable for safety.

Results Patient characteristics The present study was conducted between March 1997 and December 2000. A total of 43 women with MBC were enrolled and received treatment in phase I. Thirty-eight of the 39 patients enrolled in phase II received treatment; one patient did not return for the scheduled treatments after the initial visit. Baseline patient characteristics are summarized in Table 1.

Phase I Forty-three patients were consecutively enrolled in phase I evaluation and received a total of 227 cycles; the median number of cycles completed per patient was 6 (range, 1–10). Dose-limiting toxicities noted at dose levels 5–9 were grade 4 febrile neutropenia and prolonged grade 4 neutropenia (Table 2). One patient died at dose level 6 from cachexia, which was considered unrelated to the therapy. The MTD was not reached since fewer than

M. Campone et al. Table 1

Patient characteristics. Phase I

Phase II

Number of patients Median age, years (range)

43 56 (29–70)

38 57 (36–69)

Menopausal status Pre-menopausal Menopausal Post-menopausal Unspecified

14 9 19 1

(33.3%) (21.4%) (45.2%) (2.3%)

7 (18.4%) 9 (23.7%) 22 (57.9%) 0

WHO performance status 0 1 2

24 (55.8%) 18 (41.9%) 1 (2.3%)

23 (60.5%) 12 (31.6%) 3 (7.9%)

Major tumor metastatic sites Bone Liver Breast Lung

28 20 14 9

(65.1%) (46.5%) (32.6%) (20.9%)

21 25 6 12

(55.3%) (65.8%) (15.8%) (31.6%)

Number of metastatic sites 1 2 3 X4

12 14 9 8

(27.9%) (32.6%) (20.9%) (18.6%)

6 18 8 6

(15.8%) (47.4%) (21.1%) (15.8%)

Estrogen receptor status Positive Negative Unknown

20 (46.5%) 10 (23.3%) 13 (30.2%)

25 (65.8%) 10 (26.3%) 3 (7.9%)

36 35 23 28 15 20

(83.7%) (81.4%) (53.5%) (65.1%) (34.9%) (46.5%)

33 30 19 19 19 19

6 (14.0%) 2 (4.7%)

0 0

Prior therapy Surgery Radiotherapy Hormonal therapy Chemotherapy Chemonaive Adjuvant and/or neoadjuvant only Metastatic only Adjuvant and/or neoadjuvant plus metastatic Anthracyclines

22 (51.2%)

(86.8%) (78.9%) (50.0%) (50.0%) (50.0%) (50.0%)

17 (44.7%)

WHO ¼ World Health Organization.  Some patients are counted in more than one category.

three patients at any dose level exhibited DLTs. Therefore, the recommended dose used for the subsequent phase II evaluation was dose level 9 (1500 mg/m2 of gemcitabine and 90 mg/m2 of epirubicin).

Phase II The median number of cycles completed per patient was the same for each group (six cycles); however, the rate of dose reduction was considerably higher for group A compared with that of the modified schedule in group B, particularly for

ARTICLE IN PRESS Gemcitabine and epirubicin in patients with metastatic breast cancer: A phase I/II study Table 2

605

Phase I dose-limiting toxicities (DLTs).

Dose level

Gemcitabine/ epirubicin (mg/m2)

DLT/total patients

DLT

1 2 3 4 5

800/50 1000/50 1200/50 1200/60 1200/75

0/3 0/3 0/3 0/3 2/6

6

1300/75

2/7

7 8 9

1400/75 1500/75 1500/90

0/3 2/8 1/7

0 0 0 0 Grade 4 neutropenia with fever, prolonged grade 4 neutropenia Grade 4 neutropenia with fever, prolonged grade 4 neutropenia 0 Prolonged grade 4 neutropenia Grade 4 neutropenia with fever

 One patient received 50% of the dose on day 8 due to neutropenia, so a seventh patient was added to ensure that six patients were treated with full doses at this dose level.

Table 3

Summary of dose administration—phase II. Group A

Group B

Number of patients Median number of cycles completed (range)

23 6.0 (1–9)

15 6.0 (1–8)

Gemcitabine Median dose delivered (mg/m2) Range (mg/m2) Relative dose intensity Doses reduced Doses omitted Doses delayed

1146 598–1506 78.7% 45.7% 1.3% 13.1%

1198 823–1250 91.4% 23.8% 0.6% 12.2%

Epirubicin Median dose delivered (mg/m2) Range Relative dose intensity Doses reduced Doses omitted Doses delayed

86.0 45–92 87.1% 33.3% 0% 25.4%

85.0 60–91 91.7% 28.0% 0% 24.4%

gemcitabine (45.7% versus 23.8%; Table 3). This is largely the result of the lower percentage of gemcitabine dose reductions found on day 4 in group B patients (23.2%) compared with that on day 8 in group A patients (55.6%). Accordingly, the relative dose intensity for group A was lower than that for group B, particularly for gemcitabine (78.7% versus 91.4%). The primary reason for dose adjustments was leukopenia. Of the 38 patients who received treatment in phase II, one patient (group A) was not considered evaluable for tumor response since her bidimensionally measurable lesion had been previously irradiated. Seventeen out of 37 patients had a CR (one patient) or PR, for an ORR of 45.9% (95% CI,

29.9–62.0%; Table 4). Overall response rates were 31.8% and 66.7% for groups A and B, respectively. The median duration of PR was 8.5 months (95% CI, 7.7–11.4 months). For all patients in phase II, the median TTF was 4.8 months (95% CI, 3.9–8.1 months), and median TTP was 8.4 months (95% CI, 7.4–9.4 months). Kaplan–Meier curves for TTP and TTF are presented in Figs. 1 and 2, respectively. Toxicity was evaluated in all 38 patients treated in phase II; WHO grades 3 and 4 toxicities are summarized in Table 5. Grade 4 hematologic toxicities (anemia, leukopenia, neutropenia, and thrombocytopenia) were considerably lower in group B than in group A. Fever (grade 2) associated with grade 4 neutropenia was also higher in group A

ARTICLE IN PRESS 606 Table 4

M. Campone et al. Tumor response—phase II.

Response

All patients ðn ¼ 37Þ number (%)

Group A ðn ¼ 22Þ number (%)

Group B ðn ¼ 15Þ number (%)

Complete response (CR) Partial response (PR) Stable disease Progressive disease Not evaluated Overall response (CR+PR) 95% confidence interval

1 (2.7) 16 (43.2) 15 (40.5) 2 (5.4) 3 (8.1) 17 (45.9) 29.9–62.0

1 (4.6) 6 (27.3) 12 (54.6) 1 (4.6) 2 (9.1) 7 (31.8) 12.4–51.3

0 10 (66.7) 3 (20.0) 1 (6.7) 1 (6.7) 10 (66.7) 42.8–90.5

(56%, 9 out of 16) versus group B (40%, 4 out of 10); however, there was no hemorrhaging or the need for platelet transfusion in either group. The only grade 4 nonhematologic toxicity was grade 4 infection reported during cycle one in group A. This patient died of bronchopneumonia (considered probably related to therapy) and septic shock in cycle one (3 days after day 8 gemcitabine dose). Another patient in group A died from generalized edema and heart failure (considered unrelated to therapy) in cycle one. This patient had been pretreated with 5-fluorouracil/epirubicin/cyclophosphamide (FEC) for five cycles, making a cumulative epirubicin dose (pre-treatment plus study epirubicin) of 375 mg/m2. Four patients in group A and one patient in group B were suspended from the study due to adverse events considered related to the study therapy. These events were asthenia and a rash in one patient each (group A), LVEF decreases of X15% in two patients (group A), and leukopenia in one patient (group B).

Figure 1 Kaplan–Meier curve of time to progressive disease for groups A and B ðn ¼ 37Þ.

Discussion In a previous dose-escalating study of gemcitabine and epirubicin both given once weekly over 28-day cycles in patients with MBC and treated with prior adjuvant chemotherapy, the MTD was 1000 mg/m2 for gemcitabine and 20 mg/m2 for epirubicin; the DLT was hematologic, specifically myelosuppression.30 In our phase I study of the combination, administering a 21-day schedule in variously pretreated patients, hematologic DLTs were observed at four of the nine dose levels tested, but the MTD was not reached, and the highest dose level (1500 mg/m2 of gemcitabine on days 1 and 8 and 90 mg/m2 of epirubicin on day 1) was carried forward into phase II evaluation. Cumulative hematologic toxicities encountered at the highest dose level in phase II study caused 47% of the gemcitabine doses to be reduced or

Figure 2 Kaplan–Meier curve of time to treatment failure for groups A and B ðn ¼ 37Þ.

omitted. This prompted the consideration of a dose and schedule modification. At that time, preliminary data of single-institution phase II studies in

ARTICLE IN PRESS Gemcitabine and epirubicin in patients with metastatic breast cancer: A phase I/II study Table 5

607

Maximum WHO* toxicity grades 3 and 4—phase II. Group A ðn ¼ 23Þ, number (%)

Group B ðn ¼ 15Þ, number (%)

Grade 3

Grade 4

Grade 3

Grade 4

Hematologic Anemia Leukopenia Neutropenia Thrombocytopenia

8 (34.8) 10 (43.5) 5 (21.7) 2 (8.7)

2 (8.7) 12 (52.2) 16 (69.6) 4 (17.4)

4 (26.7) 13 (86.7) 5 (33.3) 6 (40.0)

0 2 (13.3) 10 (66.7) 1 (6.7)

Nonhematologic Constipation Rash Alopecia Infection Nausea/vomiting Mucositis

1 (4.3) 2 (8.7) 16 (72.7) 0 4 (17.4) 6 (26.1)

0 0 0 1 (4.3) 0 0

0 0 8 1 4 7

0 0 0 0 0 0

(53.3) (6.7) (26.7) (46.7)

WHO ¼ World Health Organization.

patients with MBC were available in which gemcitabine was administered on days 1 and 4 in combination with epirubicin and paclitaxel (both given on day 1) of a 21-day cycle (the GET regimen).28,29 Gemcitabine was administered in this fashion in an attempt to avoid the possible onset of neutropenia and thrombocytopenia, which tend to manifest a week later or around the time of day 8 dose of a typical 3-week schedule. When gemcitabine was administered using this schedule, dose reductions were only necessary in 14% of the treatment cycles.29 Furthermore, no clinically significant toxicities were observed, leading to the conclusion that administering nearly full doses of these three agents over a 21-day cycle, with gemcitabine given on days 1 and 4, was safe and reproducible. On the basis of these data and the findings of unacceptable toxicity at the highest dose level tested, the gemcitabine schedule was changed from days 1 and 8 to days 1 and 4, and the dose was reduced from 1500 to 1250 mg/m2, while the epirubicin regimen was kept the same. The modified group B regimen produced considerably lower rates of hematologic toxicity and therefore required fewer dose reductions among group B patients compared with those of group A patients; this was particularly evident for gemcitabine given on day 4 (23% of the doses reduced) versus day 8 (56% of the doses reduced). Accordingly, the relative dose intensity of group B was considerably higher than that of group A, most notably for gemcitabine (91% in group B versus 79% in group A). The ORR in group B was almost two-fold higher (67%) than that in group A (32%). The ORR for groups A and B combined was 46% with one CR.

Recently published studies of the combination of gemcitabine and anthracyclines (doxorubicin or epirubicin) in MBC have produced promising activity. Using a 4-week schedule of 800 mg/m2 of gemcitabine and 25 mg/m2 of doxorubicin in chemonaive or previously treated (adjuvant chemotherapy only) patients with MBC, an ORR of 55% and a median response duration of 12 months were reported.31 Neoadjuvant treatment with 1200 mg/m2 of gemcitabine (days 1 and 8) and 60 mg/m2 of doxorubicin (day 1) in patients with locally advanced breast cancer produced an ORR of 95% and a CR rate of 18%.32 Another neoadjuvant study in patients with locally advanced breast cancer treated with 1200 mg/m2 of gemcitabine (days 1 and 8) and 75 mg/m2 of epirubicin (day 1) obtained a clinical ORR of 91% and a CR rate of 21%.33 A recent phase II study of the combination administered in 4-week cycles (1000 mg/m2 of gemcitabine and 15 mg/m2 of epirubicin on days 1, 8, and 15), produced an ORR of 28.6%, a median TTP of 5.8 months, and a median survival of 17.1 months in 35 evaluable patients.34

Conclusions In conclusion, the combination of gemcitabine and epirubicin is active and well tolerated in variously pre-treated patients with MBC. In the initial phase I evaluation, the MTD was not reached at the highest dose level tested (1500 mg/m2 of gemcitabine on days 1 and 8, and 90 mg/m2 of epirubicin on day 1). The application of this dose level in the subsequent phase II study produced cumulative hematologic

ARTICLE IN PRESS 608 toxicity (group A), which led to a regimen change for gemcitabine (1250 mg/m2 of gemcitabine on days 1 and 4). The modified regimen (group B) appears less toxic and may be more effective than group A regimen and as such, merits further investigation in a larger study. Further development of this regimen toward improving efficacy, in addition to the current triple investigations of GET and GAT,35,36 includes a sequential approach with different agents such as taxanes, which have different mechanisms of action and noncrossresistance.

M. Campone et al.

12.

13.

14.

15.

16.

Acknowledgments The authors wish to thank Ms. Caroline Robert and Mr. Peter Fairfield for their technical assistance. This study was sponsored by Eli Lilly and Company.

17. 18.

19.

References 1. Cersosimo RJ, Hong WK. Epirubicin: a review on the pharmacology, clinical activity, and adverse effects of an adriamycin analogue. J Clin Oncol 1986;4:425–39. 2. Campora E, Nobile MT, Sertoli MR, et al. Phase II study of 40 epi-doxorubicin in advanced breast cancer. Cancer Treat Rep 1984;68:1285–6 (abstract). 3. Perez DJ, Harvey VJ, Robinson BA, 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. 4. Eksborg S, Hardell L, Bengtsson NO, et al. Epirubicin as single agent therapy for the treatment of breast cancer—a pharmacokinetic and clinical study. Med Oncol Tumor Pharmacother 1992;9:75–80. 5. Sledge G, Roth B, Munshi N, et al. High-dose epirubicin (EPI) as initial therapy for advanced breast cancer. Proc Am Soc Clin Oncol 1992;11:85 (abstract). 6. Habeshaw T, Paul J, James R, et al. Epirubicin at two dose levels with prednisolone as treatment for advanced breast cancer: the results of a randomized trial. J Clin Oncol 1991;9:295–304. 7. Dogliotti L, Berruti A, Buniva T, et al. Lonidamine significantly increases the activity of epirubicin in patients with advanced breast cancer: results from a multicenter prospective randomized trial. J Clin Oncol 1996;14:1165–72. 8. French Epirubicin Study Group. A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 1988;6:679–88. 9. Buzdar AU, Asmar L, Hortobagyi GN. Impact of patient characteristics on treatment outcome: anthracycline resistance. Eur J Cancer 1997;33(Suppl 7):S3–6. 10. Porkka K, Blomqvist C, Rissamen P, et al. Salvage therapies in women who fail to respond to first-line treatment with fluorouracil, epirubicin and cyclophosphamide for advanced breast cancer. J Clin Oncol 1994;12:1639–47. 11. Rahman ZU, Frye DK, Smith TL, et al. Results and longterm follow-up for 1581 patients with metastatic breast

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

carcinoma treated with standard dose doxorubicin-containing chemotherapy: a reference. Cancer 1999;85:104–11. Carmichael J, Possinger K, Phillip P, et al. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol 1995;13:2731–6. Anderson H, Lund B, Bach F, et al. Single-agent activity of weekly gemcitabine in advanced non-small cell lung cancer: a phase II study. J Clin Oncol 1994;12:1821–6. Casper ES, Green MR, Kelsen DP, et al. Phase II trial of gemcitabine (20 20 -difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs 1994;12: 29–34. Lorusso V, Pollera CF, Antimi M, et al. A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Eur J Cancer 1998;34:1208–12. Lund B, Hansen OP, Theilade K, et al. Phase II study of gemcitabine (20 20 -difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 1994;86: 1530–3. Green MR. Gemcitabine safety overview. Sem Oncol 1996; 23(5, Suppl 10):32–5. Plunkett W, Huang P, Searcy CE, et al. Gemcitabine: pharmacology and mechanisms of action. Sem Oncol 1996;23(5, Suppl 10):3–15. Blackstein M, Vogel CL, Ambinder R, et al. Gemcitabine as first-line therapy in patients with metastatic breast cancer: a phase II trial. Oncology 2002;62:2–8. Possinger K, Kaufmann M, Coleman R, et al. Phase II study of gemcitabine as first-line chemotherapy in patients with advanced or metastatic breast cancer. Anticancer Drugs 1999;10:155–62. Brodowicz T, Ko ¨stler W, Mo ¨slinger R, et al. Single-agent gemcitabine or docetaxel as second- and third-line treatment of metastatic breast cancer: results of a retrospective analysis of two phase II trials. Breast 2000;9:338–42. Spielmann M, Llombart-Cussac A, Kalla S, et al. Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology 2001;60:303–7. Valerio MR, Cicero G, Armata MG, et al. Gemcitabine (G) in pretreated breast cancer (BC). Proc Am Soc Clin Oncol 2001;20:51b (abstract 1953). Gerson R, Serrano-O A, Villalobos A, et al. Gemcitabine response in advanced breast cancer in relation to immunohistochemical factors. Proc Am Soc Clin Oncol 2000;19:145a (abstract 572). Schmid P, Akrivakis K, Flath B, et al. Phase II trial of gemcitabine as prolonged infusion in metastatic breast cancer. Anticancer Drugs 1999;10:625–31. Berton-Rigaud D, Viens P, Dieras V, et al. Gemzar (G) and epirubicin (E) in patients with metastatic breast cancer (MBC): final results of a phase I dose finding study. Proc Am Soc Clin Oncol 2000;19:112a (abstract 433). Campone M, Viens P, Dieras V, et al. Gemzar (G) and epirubicin (E) in patients (pts) with metastatic breast cancer (MBC): results of a phase II trial. Proc Am Soc Clin Oncol 2001;20:48b (abstract 1940). Conte PF, Bengala R, Danesi R, et al. Gemcitabine, epirubicin and paclitaxel (GET) in metastatic breast cancer (MBC): preliminary report of a phase I/II study with pharmacokinetic and peripheral blood progenitor cell (PBPC) mobilization assessment. Proc Am Soc Clin Oncol 1998;17:134a (abstract 511). Conte P, Bengala S, Donati S, et al. Gemcitabine, epirubicin and taxol (GET) followed by high-dose chemotherapy (HDCT): high activity with good tolerability in metastatic

ARTICLE IN PRESS Gemcitabine and epirubicin in patients with metastatic breast cancer: A phase I/II study

30.

31.

32.

33.

breast cancer patients. Proc Am Soc Clin Oncol 1999;18: 118a (abstract 449). Luftner D, Flath B, Akrivakis C, et al. Gemcitabine plus doseescalated epirubicin in advanced breast cancer: results of a phase I study. Invest New Drugs 1998;16:141–6. Perez-Manga G, Lluch A, Alba E, et al. Gemcitabine in combination with doxorubicin in advanced breast cancer: final results of a phase II pharmacokinetic trial. J Clin Oncol 2000;18:2545–52. Gomez H, Kahatt C, Falcon S, et al. A phase II study of neoadjuvant gemcitabine plus doxorubicin in stage IIIB breast cancer: a preliminary report. Sem Oncol 2001;28(3, Suppl 10):57–61. Silva A, Gonzalez H, Perez M, et al. Neoadjuvant gemcitabine plus epirubicin in locally advanced breast cancer:

609

evidence of activity in a phase II study. Proc Am Soc Clin Oncol 2002;21:51b (abstract 2015). 34. Hausmaninger H, Morach G, Heinrich B, et al. Gemcitabine combined with epirubicin in the treatment of patients with locally advanced or metastatic breast cancer: a phase II study. Am J Clin Oncol 2004;27:429–35. 35. Mazzoni F, Donati S, Gennari A, et al. A multicentric phase II trial of gemcitabine plus epirubicin plus taxol (GET) as first line chemotherapy for metastatic breast cancer. Breast Cancer Res Treat 2000;64:87 (abstract 347). 36. Sanchez-Rovira P, Jaen A, Gonzalez E, et al. Biweekly gemcitabine, doxorubicin, and paclitaxel as first-line treatment in metastatic breast cancer: final results from a phase II trial. Oncology 2001;15(2, Suppl 3):44–7.