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Activity and Safety of Vinorelbine Combined with Doxorubicin or Fluorouracil as First-Line Therapy in Advanced Breast Cancer: A Stratified Phase II Study

^a New York University Medical Center, New York, New York, USA; ^b Comprehensive Cancer Research Group Inc., Miami, Florida, USA; ^c Glaxo Wellcome Inc., Research Triangle Park, North Carolina, USA

Correspondence: Howard S. Hochster, M.D., New York University Medical Center, 160 East 32nd Street, 2nd Floor, New York, NY 10016-6004, USA. Telephone: 212-652-1912, Fax: 212-652-1901; e-mail: howard.hochster{at}med.nyu.edu

	ABSTRACT

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Purpose. To evaluate the efficacy and safety of vinorelbine combined with doxorubicin or continuous infusion of fluorouracil as initial therapy for advanced breast cancer.

Subjects and Methods. A total of 118 women who had not received chemotherapy for advanced breast cancer were enrolled and included in the intent-to-treat analysis. Subjects were stratified into two treatment groups. If subjects were candidates for anthracycline therapy, they received doxorubicin 50 mg/m² on day 1 and vinorelbine 25 mg/m² on days 1 and 8 (n = 62). If subjects had received adjuvant anthracycline therapy or had cardiac disease, they received fluorouracil 750 mg/m²/day by continuous infusion on days 1 through 5 and vinorelbine 30 mg/m² on days 1 and 5 (n = 56). The regimens were repeated every 21 days until evidence of progression of disease or severe toxicity.

Results. For doxorubicin and vinorelbine, the objective response rate was 55% (95% confidence interval [CI]: 42% to 68%), median time to disease progression was 34 weeks, median time to treatment failure was 32 weeks, and median survival was 92 weeks (95% CI: 72 to 128 weeks). For fluorouracil and vinorelbine, the objective response rate was 45% (95% CI: 31% to 59%), median time to disease progression was 32 weeks, median time to treatment failure was 30 weeks, and median survival was 53 weeks (95% CI: 47 to 64 weeks). The most common adverse event was grade 3 or 4 granulocytopenia, which occurred in 95% of subjects in the doxorubicin-vinorelbine group and in 88% of those in the fluorouracil-vinorelbine group. The most common nonhematologic adverse event was grade 3 or 4 stomatitis, which occurred in 9% and 32% of subjects in the two groups, respectively.

Conclusion. Both vinorelbine-containing regimens appear to offer useful options as initial therapy for advanced breast cancer. Both regimens were active, and any efficacy differences between the two may have been related to differences in prognosis for the anthracycline-pretreated group (i.e., selection for prior aggressive adjuvant therapy) and or comorbid cardiac conditions. Both regimens were associated with predictable but manageable toxicity, but a lower dose of fluorouracil (e.g., 600 mg/m²/day) should be used to reduce the risk of stomatitis.

Key Words. Vinorelbine • Doxorubicin • Fluorouracil • Advanced breast cancer • Combination chemotherapy

	INTRODUCTION

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The development of new treatment options has generated considerable optimism regarding the outlook for women with advanced breast cancer, but there is still room for improvement. Breast cancer remains a common diagnosis; the American Cancer Society predicted that 182,800 cases would occur in women in the U.S. during 2000 [1]. Breast cancer remains the second most common cause of cancer deaths in women, with an estimated 41,200 deaths in 2000. The 5-year survival rate for women with distant metastases is 21% [1]. Because of this high prevalence and associated mortality, many women continue to require active and safe treatment options for advanced breast cancer.

In the early 1990s, doxorubicin was considered to be the single most important chemotherapeutic agent for women with advanced breast cancer. This led to evaluations of agents that could be added to doxorubicin to improve its activity, or reduce its toxicity while maintaining its activity. At the same time, doxorubicin was being increasingly used in the adjuvant setting [2]. More recently, taxanes were shown to improve the response rate when substituted for an alkylating agent combined with an anthracycline as first-line therapy for women with metastatic breast cancer [3, 4], and taxanes are being evaluated as adjuvant therapy [5, 6]. This progression of active agents to the adjuvant setting creates a need to identify active alternate regimens with acceptable toxicity for use in the recurrent disease setting.

Vinorelbine (Navelbine^® [vinorelbine tartrate] Injection) was selected for clinical development because of its improved therapeutic index compared with other vinca alkaloids. Vinorelbine therapy was associated with reproducible response rates as a first-line, single agent in phase II studies of women with advanced breast cancer [7-12]. Furthermore, vinorelbine is suitable for use in combination with other agents because it lacks the subjective toxicities associated with many agents, cardiotoxicity associated with anthracyclines, and mucosal effects associated with continuous infusion of fluorouracil. Like other vinca alkaloids, vinorelbine is associated with some neurotoxicity, but this is seldom dose-limiting. The dose-limiting effect of vinorelbine is granulocytopenia, but it is rapidly reversible and does not usually cause neutropenic fever requiring hospitalization [13].

We conducted a phase II study (P70-07) to evaluate the efficacy and safety of vinorelbine combined with doxorubicin or, if subjects were not candidates for anthracycline therapy, continuous infusion of fluorouracil as initial therapy for advanced breast cancer. The dosages were based on those used in earlier phase II studies [14, 15], which produced encouraging results in subjects who had not received chemotherapy for advanced breast cancer. This report describes the mature data presented earlier in preliminary form [16, 17].

	SUBJECTS AND METHODS

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Subjects
Women, 18 years of age or older, were eligible for the study if they had microscopically confirmed, bidimensionally measurable, advanced breast cancer. Subjects were excluded if they had received cytotoxic chemotherapy for advanced breast cancer, surgery within 2 weeks, or radiotherapy within 3 weeks. Patients could have received adjuvant chemotherapy if the disease-free interval was at least 12 months after completion of adjuvant chemotherapy. Subjects were also excluded if they had metastatic disease in the central nervous system; malignancy within 5 years; clinically significant peripheral neuropathy; unstable medical condition; uncontrolled cardiac disease or history of congestive heart failure; inability to comply with study protocol and weekly follow-up visits; Karnofsky performance status <70; life expectancy 16 weeks; or granulocytes <2,000/mm³, platelets <100,000/mm³, hemoglobin <9g/dL, creatinine >2.5 mg/dL, total bilirubin 1.3 mg/dL, or serum glutamic oxaloacetic transaminase >3.0 times upper limits of normal. Finally, pregnant or nursing subjects were excluded. Informed consent was obtained before study entry. This study was performed after approval by local human investigations committees at each institution.

Stratification and Interventions
Subjects were stratified by cardiac risk factors. If subjects were candidates for anthracycline therapy, they received doxorubicin 50 mg/m² on day 1 and vinorelbine 25 mg/m² on days 1 and 8. If subjects had received adjuvant anthracycline therapy, had active cardiac disease and were not considered to be good candidates for doxorubicin, or had a baseline left ventricular ejection fraction (LVEF) <50%, they received fluorouracil 750 mg/m²/day on days 1 through 5 and vinorelbine 30 mg/m² on days 1 and 5. Doxorubicin and vinorelbine were administered by i.v. bolus; fluorouracil was administered by continuous i.v. infusion. Each cycle was repeated every 21 days until progression of disease or severity of toxicity warranted discontinuation. Commercial supplies of doxorubicin and fluorouracil were used; vinorelbine was supplied by Glaxo Wellcome Inc. (Research Triangle Park, North Carolina).

Dose modifications for hematologic toxicities were based on assessments made before each treatment (Table 1). Dose modifications were also specified for nonhematologic toxicities, but no dose modifications were required for renal insufficiency. For both groups, treatment was delayed 1 week for neurotoxicity grade 2; the subject was removed from the study for neurotoxicity grade 2 that persisted for >4 weeks. Fluorouracil was delayed 1 week for mucositis or diarrhea grade 1, and reduced to a dose of 500 mg/m² for mucositis or diarrhea grade 3. Subjects were removed from the study for treatment delayed for >4 weeks.

Assessments
Tumor status was assessed before treatment, every 3 weeks by physical examination or every 9 weeks by computerized tomography or magnetic resonance imaging, and upon discontinuation of treatment. Complete and partial responses and stable disease were confirmed 4 weeks after the initial response determination. Complete response was defined as the disappearance of all cancerous lesions and evaluable clinical evidence of cancer, improvement in cancer-related symptoms, and stable or improved performance status. Partial response was defined by a 50% decrease in the size of all measurable lesions (i.e., sum of the products of the perpendicular diameters), and stable or improved symptoms and performance status. Stable disease was defined as failure to meet the criteria for response or progressive disease, and stable or improved symptoms and performance status. Progressive disease was defined as a 50% increase in the size of all measurable tumor areas, appearance of a new lesion, or significant worsening of symptoms or performance status.

Time to disease progression was defined as the time from the first day of treatment to disease progression or relapse. Time to treatment failure was defined as the time from the first day of treatment to disease progression, treatment-related toxicity resulting in discontinuation of therapy, or death from any cause. Survival was defined as the time from the first day of treatment to death and was censored at the date of last contact for subjects who were alive.

A complete physical examination, clinical assessment, analysis of vital signs, chest x-rays, and laboratory tests were performed at predetermined intervals and study termination. All symptoms, toxicities, and adverse experiences were documented weekly and graded for intensity by modified National Cancer Institute Adverse Events Criteria.

Statistical Analysis
The planned sample size was approximately 50 subjects in each treatment group, with stratification based on prior exposure to anthracyclines and active cardiac disease. The final analyses used data collected through approximately 25 months after the last subject was enrolled. Demographic and baseline characteristics were summarized by descriptive statistics.

Efficacy and safety parameters were evaluated in all enrolled subjects (intent-to-treat analysis). Confidence intervals on response rates were computed using the binomial distribution. Survival was evaluated by Kaplan-Meier methodology. Adverse events and laboratory abnormalities were summarized by descriptive statistics.

	RESULTS

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Subjects
Investigators from 13 centers in the U.S. enrolled 118 subjects between July 1991 and August 1994. One subject remained on study as of the data cutoff date of December 1996. The primary reasons for discontinuation in the remaining 117 subjects were disease progression (n = 57 [49%]); symptoms/toxicities/adverse experiences (n = 27 [23%]); failure to return or refused treatment (n = 10 [9%]); death (n = 8 [7%]), and other (n = 15 [13%]). Seventeen subjects (14%) were enrolled as exceptions to the entry criteria, such as completion of prior therapy within 2 weeks of enrollment (n = 8 [7%]), hematologic or laboratory abnormality (n = 8 [7%]), history of other malignancy (n = 2 [2%]), or a combination thereof. Reasons for discontinuation and exceptions to the entry criteria were evenly distributed between the two treatment groups.

Subjects in the two treatment groups had similar demographic features and characteristics at study entry (Table 2), with one important exception: subjects who received fluorouracil and vinorelbine were more likely to have received prior therapy, especially adjuvant chemotherapy (71% versus 40%), compared with those who received doxorubicin and vinorelbine. In the fluorouracil-vinorelbine group, adjuvant therapy usually consisted of an anthracycline-containing regimen (54%); whereas, in the doxorubicin-vinorelbine group, the most common adjuvant regimen was cyclophosphamide, methotrexate, and fluorouracil (39%).

Efficacy
Treatment with doxorubicin and vinorelbine was associated with seven complete and 27 partial responses for an objective response rate of 55% (95% CI: 42% to 68%) (Table 3). The median time to disease progression was 34 weeks. The median time to treatment failure was 32 weeks. Thirty-four subjects were censored because they were still alive at the time of analysis. The median duration of survival was 92 weeks (95% CI: 72 to 128 weeks) (Fig. 1). The 1-year survival rate was 75.5%.

View larger version (16K): [in this window] [in a new window]   Figure 1. Kaplan-Meier estimate of the duration of survival in all enrolled subjects who received doxorubicin and vinorelbine (n = 62) or fluorouracil and vinorelbine (n = 56).

Safety
The most common adverse event was granulocytopenia in both treatment groups (Table 4). At least one episode of grade 3 or 4 granulocytopenia occurred in 95% of subjects who received doxorubicin and vinorelbine and in 88% of those who received fluorouracil and vinorelbine. Two subjects died because of neutropenic sepsis, one in each treatment group. Other hematologic abnormalities were less common. For example, grade 3 or 4 thrombocytopenia was reported in only 6% of subjects who received vinorelbine and doxorubicin and 5% of subjects who received vinorelbine and fluorouracil. Hepatic enzymes, especially alkaline phosphatase, were frequently elevated, but the elevations were usually grade 1 or 2 and were probably attributable to underlying disease [13].

View this table: [in this window] [in a new window]   Table 4. Hematologic toxicity and chemistry abnormalities observed in 10% of subjects

View this table: [in this window] [in a new window]   Table 5. Adverse events observed in 10% of subjects, which were reasonably or possibly attributed to study medication

	DISCUSSION

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It is not surprising that fluorouracil and vinorelbine appeared to be associated with a shorter duration of survival (12 versus 21 months) than was doxorubicin and vinorelbine in the current study, given the fact that there were two distinct patient populations treated in this trial. The fluorouracil-vinorelbine group was a preselected, poorer prognosis group as evidenced by the fact that patients were more likely to have received prior surgery and radiation in addition to anthracycline-based adjuvant chemotherapy (Table 2). Despite the differences in survival data, the response rate (45% versus 55%), and median times to disease progression (32 versus 34 weeks) and treatment failure (30 versus 32 weeks) were similar for the fluorouracil-vinorelbine and doxorubicin-vinorelbine groups. The poorer prognosis would also account for the failure to reproduce the response rate (62%) or median survival (23 months) reported by Dieras et al. [15] in their intent-to-treat analysis of the same dosages of fluorouracil and vinorelbine as first-line therapy. Nolè et al. [22] reported the same response rate (62%) as Dieras et al. [15] and a high 1-year survival rate (78%) in assessable subjects enrolled in another phase II study, but their regimen differed because it included folinic acid and lower doses of fluorouracil. Although exposure to adjuvant chemotherapy appeared to be similar in all three studies, subjects who developed recurrent disease within 12 months after completion of adjuvant chemotherapy were probably enrolled in the current study. The clinical significance of this patient population was not fully recognized when this study was designed, so a new eligibility criterion was added within months after opening the study. Unfortunately, some subjects were enrolled before the amendment could be activated at all study sites, but the exact number of subjects whose disease-free interval was <12 months is unknown. Collectively, these findings underscore the limitations of comparing findings from phase II studies because they have inherent differences in study design and, more importantly, study populations.

The most common toxicity was hematologic in the current study, and there was one death due to neutropenic sepsis in each treatment group. The high incidence of grade 3 or 4 neutropenia on day 15 was probably attributable to the administration of a second dose of vinorelbine on day 5 or 8 if the granulocyte count was 500 to 1,000 cells/mm³, but this was not usually associated with complications. Nearly universal grade 3 or 4 granulocytopenia has also been reported in other studies involving vinorelbine plus either doxorubicin [19] or fluorouracil [15, 22, 23], which was sometimes associated with neutropenic fever but rarely with the need for hospitalization. The risk of granulocytopenia associated with these combination regimens can be minimized by coadministration of antibiotics or hematopoietic growth factors [20, 24], which were not used prophylactically in the current study. The incidence of grade 3 or 4 granulocytopenia was probably underestimated in another study in which blood counts were only performed every 3 weeks [18]. The incidence of granulocytopenia was only 41% in a study involving identical dosages of doxorubicin and vinorelbine, possibly because of a slightly lower dose intensity and more delays between cycles [14].

There were no unexpected nonhematologic toxicities in the current study. Alopecia, asthenia, and nausea were common in both treatment groups, but these adverse events were usually grade 1 or 2. The episodes of grade 3 or 4 alopecia appeared to be the result of miscoding because we used a two-point scale for this adverse event in which grade 2 referred to pronounced or complete alopecia. In a review of multicenter studies [13], only 10% of subjects experienced alopecia, which was usually manifested as thinning of hair so that subjects did not require wigs. On the other hand, grade 3 or 4 stomatitis occurred in approximately one-third of subjects who received fluorouracil and vinorelbine, which suggests the need for a lower daily dose of fluorouracil. For example, minimal stomatitis was associated with fluorouracil 350 mg/m²/day and folinic acid 100 mg/m²/day on days 1 through 3 combined with vinorelbine 25 mg/m² on days 1 and 3 in another phase II study [22]. Eighty-two percent of subjects in the doxorubicin-vinorelbine group and 89% in the fluorouracil-vinorelbine group tolerated treatment without evidence of cardiovascular toxicity; grade 3 or 4 cardiovascular toxicity occurred in only 6% and 4% of subjects in the two groups, respectively. The lack of differences between the two groups may be attributable to the assignment of subjects who had comorbid cardiac conditions or previous anthracycline-based adjuvant therapy to the fluorouracil-vinorelbine group.

Our findings may have implications for the direction of future research, such as the use of oral regimens. Continuous oral administration of new fluoropyrimidines was designed to mimic the pharmacokinetic profile of continuous infusion of fluorouracil and provide improved convenience of administration. The combination of capecitabine and intravenous vinorelbine was active and associated with only minimal toxicity in a phase I study of women with advanced breast cancer [25]. The combination produced response rates of more than 50% in a large phase I study [26] and a small phase II study [27]. Preliminary experience with oral vinorelbine suggests that this agent is active and well tolerated in elderly or heavily pretreated women with advanced breast cancer [28]. A newer formulation of oral vinorelbine had similar efficacy and reasonable tolerability compared with the i.v. formulation in patients with lung cancer [29].

In conclusion, this two-stratum, multicenter American study confirms European results and demonstrates the utility of vinorelbine in combination with an anthracycline or a fluoropyrimidine. Both vinorelbine-containing combinations offer useful treatment options for women with advanced breast cancer given their reproducible activity and predictable but manageable toxicity. More studies are needed to identify options that are suitable for the wide variety of women who continue to require treatment for advanced breast cancer.

	Appendix of Principal Investigators

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Roy Ambinder, M.D., Florida Hospital, Orlando, FL; Martin Blumenreich, M.D., Minnesota Oncology/Hematology PA, Waconia, MN; John Costanzi, M.D., Lone Star Oncology Consultants, Austin, TX; Hugh Davis, M.D., Medical College of Wisconsin, Milwaukee, WI; Carol Fabian, M.D., Kansas University Medical Center, Kansas City, KS; Jeffrey Giguere, M.D., Greenville Cancer Treatment Center, Greenville, SC; Anthony Giorgio, M.D., Cancer Care Associates Medical Group, Inc., Torrance, CA; Mark Graham, M.D., University of North Carolina, Cary, NC; Lowell Hart, M.D., Florida Cancer Specialists, Fort Myers, FL; Howard Hochster, M.D., New York University Medical Center, New York, NY; Glen Justice, M.D., Pacific Coast Medical Group, Inc., Fountain Valley, CA; Leslie Laufman, M.D., Hematology/Oncology Consultants, Columbus, OH; Tim Panella, M.D., Thompson Cancer Survival Center, Knoxville, TN; Charles L. Vogel, M.D., Columbia Cancer Research Network of Florida, Plantation, FL.

	ACKNOWLEDGMENTS

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Supported by a grant from Glaxo Wellcome, Research Triangle Park, North Carolina.

We thank all of the principal investigators (see appendix) and Cindy W. Hamilton, Pharm.D., for editorial assistance; Michael Ames, Ph.D., for statistical assistance; and Karen Melich, B.S., for general support.

	REFERENCES

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This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hochster, H. S. Articles by White, R. Search for Related Content PubMed PubMed Citation Articles by Hochster, H. S. Articles by White, R.