The Oncologist, Vol. 7, No. 3, 205-209,
June 2002
© 2002 AlphaMed Press
A Phase II Study of Intravenous Navelbine and Doxorubicin Combination in Previously Untreated Advanced Breast Carcinoma
M. Pawlickia,
J. Rolskib,
J. Zaluskic,
P. Siedleckid,
C. Ramlaue,
P. Tomzakf
a Cancer Institute, Krakow, Poland;
b Oncology Centre, Krakow, Poland;
c Oncology Centre, Poznan, Poland;
d Oncology Centre, Warsaw, Poland;
e Chorob Pluc i Gruzlicy, Poznan, Poland;
f Medical Academy, Poznan, Poland
Correspondence:
M. Pawlicki, M.D., Medical Oncology Department, Cancer Institute, Garncarska 11, 31-115 Krakow, Poland. Telephone: 48-12-423-10-34; Fax: 48-12-423-15-89.
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ABSTRACT
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Purpose. The combination of vinorelbine and doxorubicin, two very active drugs in metastatic breast cancer, has demonstrated impressive results in terms of efficacy, at the price of cardiac toxicity (10% grades 2-4) due to the cumulative dose of doxorubicin delivered. This study was designed to divide the dose of doxorubicin into two administrations (day 1 and 8) in order to reduce the toxicity profile, while keeping the same level of efficacy.
Patients and Methods. Thirty-eight chemotherapy-naïve metastatic breast cancer patients entered into the study and were treated with vinorelbine, 25 mg/m2, and doxorubicin, 25 mg/m2, both on days 1 and 8, every 3 weeks. Thirty-seven patients were evaluable for efficacy and 38 for tolerance; 71% of the patients presented with visceral metastases.
Results. Patients received a median of seven cycles and 94.9% of the intended dose intensity of both drugs. Grade 3-4 neutropenia was reported in 10% of cycles. Alopecia was reported in 89.5% of the patients, and grade 2 nausea/vomiting in 9.3% of the cycles. Grade 1-2 cardiac toxicity was noted in 23.7% of the patients. The objective response rate of the patients was 78.4% (nearly 81% for patients with visceral metastases); the median duration of response was 11.6 months, the median survival 21.6 months, and the 1-year survival 75.2%.
Conclusion. This schedule of vinorelbine/doxorubicin represents an active and well-tolerated combination.
Key Words. Vinorelbine • Fractionated doxorubicin • First-line • Advanced breast cancer
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INTRODUCTION
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Breast cancer still represents the leading cause of cancer death among the female population in western countries. Most efforts to improve treatment are concentrated on optimizing disease control and preserving quality of life. Although several new agents have been introduced over the last few years, the treatment of metastatic breast cancer remains palliative.
Among all treatment approaches, anthracycline-based chemotherapy combinations [1–4] represent the most active forms of therapy and are able to generate objective response rates (ORR) of between 40% and 70%. This was demonstrated in a large meta-analysis done by Fossati et al. [5]. The dose-limiting toxicities of anthracyclines are neutropenia and cardiac impairment [6]. Several studies [7] have been performed in order to reduce the cardiac toxicity profile of anthracyclines, and it would appear that weekly schedules of doxorubicin decrease the risk of toxicities (notably cardiac), allowing for the possibility of administering a higher cumulative dose of doxorubicin [8, 9] with improvement in the therapeutic potential.
In first-line metastatic breast cancer treatment, single-agent therapy with vinorelbine (Navelbine®; Pierre Fabre Medicament; Boulogne, France) has shown overall response rates varying from 40%-60% with good clinical tolerance [10–13], and so it was logical to combine vinorelbine and doxorubicin to evaluate their activity in advanced breast cancer. Impressive results have been obtained through an every-3-week schedule of vinorelbine 25 mg/m2, days 1 and 8, and doxorubicin, 50 mg/m2 day 1 [14], which produced an ORR of 74% (with 21% complete responses [CRs]), with 50% response on liver metastases and 68% on lung metastases. Moreover, this combination led to a median duration of response of 12 months and a median survival of 27.5 months. These results were recently confirmed [15] by a phase III study comparing vinorelbine/doxorubicin with CAF (cyclophosphamide/adriamycin/5-fluorouracil) that showed a significant survival advantage for patients with liver metastases on vinorelbine/doxorubicin treatment. This current phase II study, combining vinorelbine with doxorubicin, both administered on days 1 and 8 every 3 weeks, was designed to test the hypothesis that a weekly fractionated dose of doxorubicin could reduce the toxicity without impairing the efficacy.
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PATIENTS AND METHODS
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Before entering the study, patients must have had histologically confirmed advanced breast carcinoma, with at least one bidimensionally measurable lesion. They must not have been previously treated for metastatic disease, and in the case of prior adjuvant therapy without anthracyclines, an interval of 6 months must have elapsed. Patients had to be 2 weeks from prior surgery, 3 weeks from radiation therapy to the pelvis (or spine or long bones), and at least 2 weeks from prior hormonotherapy.
Other eligibility criteria were as follows: age between 18 and 75 years; World Health Organization (WHO) performance status 
2; life expectancy >12 months; no clinical signs of peripheral neuropathy; adequate bone marrow reserve (absolute granulocyte count 
2,000/mm3, platelet count 100,000/mm3, hemoglobin level 10 g/dl), and adequate hepatic and renal function including aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase, and serum creatinine values 1.25 times the upper normal limit. All patients who entered the study had given written informed consent following the recommendations of the Helsinki Declaration. Noninclusion criteria were as follows: left ventricular ejection fraction (LVEF) <45%-50% or any electrocardiogram (ECG) abnormality; primary or secondary ischemic myocardial disease or history of congestive heart failure; carcinomatous lymphangitis or bone metastasis or ascites as only lesions to assess efficacy; clinical symptoms or computerized tomography (CT) scan evidence of brain metastases; hypercalcemia; or other concomitant malignancies.
The protocol was approved by the Ethics Committee of each participating center. Treatment consisted of doxorubicin, at a dose of 25 mg/m2 administered i.v. into a running infusion of normal saline, or 5% dextrose on days 1 and 8 of a 21-day course. Vinorelbine, at a dose of 25 mg/m2, was diluted in 50 ml of normal saline and administered by i.v. infusion over 6 to 10 minutes, followed by flushing the vein with 250 ml normal saline solution. Doses were given every 3 weeks. Courses were postponed until recovery of a neutrophil count that was <1,500/mm3 and/or a platelet count <100,000/mm3 on day 1 of any cycle.
Patients who showed evidence of CR or partial response (PR) remained on therapy until they had completed eight cycles. In cases where there was no change (NC), the patients received a maximum of six cycles. Tumor response was reassessed every two courses. Treatment was discontinued earlier if there was progressive disease (PD) or unacceptable toxicity. Toxicity was evaluated according to WHO criteria, by clinical and laboratory evaluations at day 21 of each cycle, and a complete blood count was performed weekly during the treatment period. All patients underwent 12-lead ECG before study entry, and ECGs were repeated before each course and at the end of treatment. LVEF was determined before the start of treatment and after, in cases of clinical cardiac abnormalities.
Response assessment was performed according to WHO criteria, after every two cycles of treatment. CR was defined as the complete disappearance of all known lesions, on two separate measurements performed at least 4 weeks apart. PR was defined as a decrease of at least 50% of bidimensional measurable disease lasting more than 4 weeks, or as a decrease of at least 30% for unidimensional measurable lesions. Stable disease was defined as a decrease of less than 50% (for bidimensional measurable lesions) or 30% (for unidimensional measurable lesions), or an increase of less than 25% with no new lesions. Progressive disease was defined as an increase of more than 25%, or the appearance of new lesions.
All patients who received at least two courses of treatment were considered assessable for response. Duration of response for CR was measured from registration until relapse, and from registration until the date of progression for PR. Survival was measured from registration until death or last follow-up. Survival, time to progression, and duration of response were calculated using the Kaplan-Meier method.
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RESULTS
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Patient Characteristics
Between February 1995 and April 1996, 38 patients (37 female and 1 male) were entered into the study. Among them, 37 were eligible and evaluable for efficacy, and all 38 were evaluable for tolerance. Patients' clinical characteristics are shown in Table 1
. Ninety-seven percent of the population had a performance status of 0-1 and 38% were premenopausal. More than half of the patients had undergone surgery as their primary treatment; 29% had received adjuvant chemotherapy and one-third hormonal therapy. All other patients were chemotherapy naïve and received CT for metastatic disease. Most patients were stage IV at study entry, with 71% of them having visceral metastases, and 71% having two or more organs involved (Table 2).
Treatment and Tolerance
The mean number of administered cycles was 6.6 (range 2-8) with a total of 251 courses given to 38 patients. The theoretical dose intensity of both vinorelbine and doxorubicin was 16.66 mg/m2/wk for this schedule (25 mg/m2 on days 1 and 8 for both drugs); the actual median doses administered were 15.8 mg/m2/wk for both vinorelbine and doxorubicin (range 10-18 mg/m2/wk), representing a median value of 94.9% of the intended dose of each drug.
Neutropenia represented the major hematologic toxicity, with grade 3-4 neutropenia in 10% of cycles. Grade 3 anemia was only reported for 0.4% of cycles, and no thrombocytopenia over grade 1 occurred. No grade 3-4 infection or stomatitis occurred. Nausea/vomiting was well controlled, with only 9.3% of the cycles with grade 2 toxicity. Thirty-four patients presented with alopecia (89.5%) and 13.2% of patients reported local phlebitis. Cardiac toxicity was, at maximum, grade 1-2 and affected only 23.7% of the patients (Table 3). Cardiac toxicity was mainly assessed through ECG. The cumulative dose of doxorubicin was between 95 mg/m2 and 426 mg/m2, with a mean of 266 mg/m2.
Efficacy
Only 1 of 38 patients entered in the study was considered as ineligible and not evaluable, as no bidimensionally measurable disease was present at inclusion time. Ten patients achieved a CR (27%) and 19 a PR (51.4%), giving an ORR of 78.4% (range 65.3%-91.5%) for the evaluable patients. Impressive results were obtained in patients with visceral metastases (Table 4) with an ORR of nearly 81%. The most interesting data concerned patients with poor prognosis due to the extent of their disease: an objective response was reported in more than 82% of the patients with liver metastases and nearly 87% of the patients with three or more metastatic sites (Table 5). The median duration of response was 11.6 months (range 2 to >36+), and the median overall survival was 21.6 months (range 2.7 to >47.8+), with a 75.2% 1-year survival rate (Fig. 1).
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DISCUSSION
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The aim of this study was to determine whether fractionating the doxorubicin dose, on days 1 and 8, every 3 weeks, could improve the tolerance without impairing the efficacy. The main tolerance problem encountered with doxorubicin is cardiotoxicity, which is linked to the total administered cumulative dose, leading to congestive heart failure. Therefore, a maximal total administered dose of doxorubicin has been recommended at 550 mg/m2 [16].
Vinorelbine and doxorubicin have demonstrated high efficacy in terms of response rate and survival when the doxorubicin dose was given on the first day [14], but at the price of a high level of cardiac toxicity: out of 89 evaluable patients in that study, three suffered from grade 2 and six from grade 3-4 cardiac toxicities, and three deaths were reported for a cardiac-related problem. Compared with these results, in our study, no grade 3-4 cardiac toxicity was recorded; approximately 80% of the patients did not suffer from any cardiac problem and of the 20% who presented with grade 1 or 2 cardiac toxicity, none had to stop the treatment. This result has been confirmed by two phase II studies performed during the same period in Brazil and Turkey, using the same schedule of vinorelbine and fractionated doxorubicin and with the same selection and evaluation criteria. The three studies demonstrate reproducible results with a median ORR of 74% (range 70%-77%) and a median CR rate of 25% (range 18%-35%) [17]. The tolerance profile, notably cardiac, was good, especially when compared with studies with doxorubicin administered on 1 day only [14].
The fractionated schedule of doxorubicin also seems less hematotoxic, with less grade 3-4 neutropenia and no toxicity-related deaths, in comparison with a classical schedule [14]. It is also very important to note that the dose intensity of both drugs was very close to the theoretical maximum, which means that very few dose reductions or delays were necessary.
Efficacy was obtained in more than 80% of patients with visceral metastases (including liver metastases). Moreover, even in the population with three or more metastatic sites, the ORR was over 86%. Such a high response rate was previously reported by Spielmann [14] and confirmed by Blajman in a phase III trial comparing the classic CAF schedule with vinorelbine/doxorubicin [15], with a 71% ORR in patients with visceral metastases for the two-drug combination versus 62% for CAF. This very high level of activity against visceral metastases has also been confirmed in another two-fractionated doxorubicin phase II study, with an ORR of 56%-86% [17].
More recently [18], these results also were demonstrated with epirubicin, an analogue of doxorubicin characterized by a better cardiac tolerance profile. In that study, vinorelbine and epirubicin were both administered on a weekly schedule with support of growth factors due to the high dose of epirubicin used. The ORR was 77% (with a 19% CR rate) with a very low cardiac toxicity (two patients with grade 2/3). Despite the high dosage of epirubicin administered, this combination was well tolerated.
The combination of vinorelbine and fractionated doxorubicin appears highly active, especially in patients with poor prognoses (visceral metastases, several organs involved) and can be given with an improved tolerability. This regimen is attractive for treating patients on an outpatient basis.
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Received September 28, 2000;
accepted for publication March 13, 2001.
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Abstract
Introduction
