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Treatment of Advanced Breast Cancer with Vinorelbine and Docetaxel With or Without Human Granulocyte Colony-Stimulating Factor

From the Department of Internal Medicine I, Division of Oncology, Vienna University Medical School, Vienna; Department of Surgery, Wr Neustadt General Hospital, Neustadt; Department of Surgery, Baden General Hospital, Baden; Department of Surgery, Neunkirchen General Hospital, Neunkirchen; and Department Internal Medicine, Kirchdorf General Hospital, Kirchdorf/Krems, Austria.

Address reprint requests to Univ Prof Dr Gabriela V. Kornek, Department of Internal Medicine I, Division of Oncology, Vienna University Medical School, Waehringer Guertel 18-20, A-1090 Vienna; email: werner.scheithauer{at}akh-wien.ac.at

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: A multicenter phase II trial was performed to investigate the efficacy and tolerance of docetaxel, vinorelbine with or without recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer.

PATIENTS AND METHODS: Between February 1998 and March 1999, 57 patients participated in this trial. Forty-two patients received this combination as first-line and 15 patients as second-line chemotherapy, including 10 patients who had failed anthracyclines. Therapy consisted of vinorelbine 30 mg/m² on days 1 and 15 and docetaxel 30 mg/m² on days 1, 8, and 15 every 4 weeks. Depending on the absolute neutrophil counts on the day of scheduled chemotherapeutic drug administration, a 5-day course of G-CSF 5 µg/kg/d was given.

RESULTS: The overall response rate was 64.3% (95% confidence interval, 48.1% to 78.4%) in patients receiving docetaxel plus vinorelbine as first-line chemotherapy, including eight complete (19%) and 19 partial remissions (45.3%); 11 patients (26.2%) had disease stabilization, and only four (9.5%) progressed. Second-line treatment with this regimen resulted in eight (53.3%) of 15 objective responses, four had stable disease, and three had progressive disease. The median time to progression was 12 months in the first-line and 9.8 months in the second-line setting, respectively. After a median follow-up time of 18 months, 38 patients (65%) were still alive with metastatic disease. Myelosuppression was commonly observed; World Health Organization grade 3 or 4 neutropenia both occurred in 18 patients (32%) and was complicated by septicemia in four cases; grade 3 or 4 thrombocytopenia was seen in two patients (4%), and grade 3 anemia was seen in only one patient (2%). Severe (grade 3) nonhematologic toxicity, except for alopecia, was rarely observed and included nausea/vomiting in two patients (4%), and stomatitis, peripheral neuropathy, and skin toxicity each in one patient.

CONCLUSION: Our data suggest that docetaxel and vinorelbine with or without G-CSF is an effective and fairly well tolerated regimen for the treatment of advanced breast cancer. It might be particularly useful in patients previously exposed to adjuvant or palliative anthracyclines and/or alkylating agents.

	INTRODUCTION

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WORLDWIDE, BREAST cancer represents a major health problem, being responsible for 20% of cancer deaths in the Western world. Despite progress achieved in screening and management of early breast cancer, including adjuvant treatment, 25% to 30% of patients with negative axillary lymph nodes, and more than two thirds of those with axillary node involvement at the time of diagnosis will have recurrent and/or metastatic disease within a decade after surgery and will subsequently die.^1,2

Conventional combination chemotherapy has not been able to change the natural history of advanced breast cancer, and current treatment approaches seem to have reached their maximum efficacy. Therefore, the identification of new agents and/or drug combinations with a superior therapeutic index remains a principal goal of investigational efforts. Among several different such promising new cytotoxic agents currently undergoing clinical evaluation in advanced breast cancer (ABC) are drugs that poison the mitotic spindle, such as taxanes and vinca-alkaloids.^3-6 Both drugs result in an arrest of metaphase in dividing cells by different mechanisms. Docetaxel promotes tubulin assembly into microtubules, stabilizes microtubules, and inhibits depolymerization to free tubulin.⁷ Conversely, vinorelbine induces a disruption of microtubules by their reversible binding to tubulin, resulting in mitotic spindle dissolution.⁸ This combination would create a total microtubule poison and could offer theoretical advantages based on potential synergy when the drugs are given together. Preclinical data have shown that the combination was synergistic in vitro when both drugs were given simultaneously or vinorelbine preceded docetaxel; in contrast, antagonism was observed when docetaxel was administered before vinorelbine.^9-11 Another interesting observation concerning this combination is that docetaxel could overcome resistance to vinorelbine resulting from mutations in tubulin, and vice versa.¹¹ Favourable results were obtained when the two drugs were combined in a phase I trial of patients with ABC, and in several phase I/II studies investigating this combination in patients with advanced non–small-cell lung cancer.^12-16

The aim of the present study was thus to evaluate the antitumor activity and tolerance of vinorelbine plus docetaxel in previously untreated patients with advanced breast cancer as well as in those who had failed one previous palliative chemotherapy regimen. To minimize acute toxicities and counteract myelosuppression that was likely to constitute the dose-limiting toxicity with this combination, we decided to use a weekly administration schedule of the taxane^17,18; in addition, the hematopoetic growth factor granulocyte colony-stimulating factor (G-CSF) was given depending on absolute neutrophil counts on the day of scheduled chemotherapeutic drug administration.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients Selection
Patients eligible for this study had histologically confirmed metastatic breast cancer with documented progressive, bidimensionally measurable disease. All patients were required to be 75 years old or younger, to have a World Health Organization (WHO) performance status of less than 3, to have an expected survival time of more than 12 weeks, and to have adequate bone marrow (absolute neutrophil count [ANC] 2,000/µL, and platelet count 100,000/µL), adequate renal (serum creatinine concentration < 132 µmol), and adequate hepatic function (serum bilirubin level and serum transaminase level < two times the upper limit of normal). Previous radiation therapy (with at least one target lesion outside the radiation port), previous hormonal therapy for advanced disease, and a maximum of one previous regimen of palliative chemotherapy were allowed. Previous therapy must have been completed at least 4 weeks before study entry with full resolution of toxicities. Adjuvant treatment was acceptable if the time interval between adjuvant therapy and the chemotherapy for metastatic disease was longer than 1 year. All patients gave informed consent according to institutional regulations. Patients with osteoblastic bone lesions as the only site of disease, patients with CNS metastases and those with previous or a second coexisting invasive malignancy were excluded.

Treatment Protocol
Chemotherapy consisted of vinorelbine 30 mg/m² on days 1 and 15, followed by docetaxel 30 mg/m² on days 1, 8, and 15 both diluted in 250 mL of saline and infused over 30 minutes (vinorelbine) or 1 hour (docetaxel). When the ANC was 1,000 to 2,000 on the day of planned chemotherapeutic drug administration, to maintain dose-intensity, a 5-day course of the hematopoetic growth factor G-CSF (5 µg/kg/d given subcutaneously) was to be started on the subsequent day. In patients experiencing neutropenia, G-CSF support was not continued routinely during subsequent courses, the decision was always dependent an actual ANCs. Treatment courses were repeated every 4 weeks, and were to be continued in patients achieving complete response (CR), partial response (PR), or stabilization of disease with a total of six courses. To avoid fluid retention and/or anaphylactic reactions, patients were premedicated with dexamethasone 8 mg orally taken the night before, morning of, and evening after treatment (total dose, 24 mg/wk). In addition, granisetron 3 mg was routinely administered before cytotoxic drug administration.

Toxicity and Dosage Modification Guidelines
Adverse reactions were evaluated according to WHO standard criteria.¹⁹ Treatment could be delayed for up to 2 weeks if the ANC was lower than 1,000/µL and/or the platelet count was lower than 75,000/µL. Prolonged administration of G-CSF was recommended in the former group of patients. Drug doses were reduced by 30% in case of febrile neutropenia grade 4, if the lowest platelet count was less than 25,000/µL, or any severe (> WHO grade 2) nonhematologic toxicity was observed in the previous cycle. Any patient who required more than 2 weeks for recovery of adverse reactions was taken off the study.

Pretreatment and Follow-Up Evaluation
Pretreatment evaluation included a complete medical history and physical examination with measurement of all tumor associated lesions. Laboratory evaluation consisted of a complete blood count with platelet count and leukocyte differential count and an 18-function biochemical profile. Imaging procedures included chest x-ray, bone scan, skeletal bone survey, and computed tomographic scan of the abdomen. Complete blood cell counts and differential counts were performed weekly, and biochemical profiles were assessed before each treatment cycle. Tumor size was measured every 8 weeks by using computed tomographic scan, x-ray, or any other technique that allows retrospective and independent reassessment.

Assessment of Response
The primary efficacy end point was response rate. A CR required the complete disappearance of all objective evidence of disease on two separate measurements at least 4 weeks apart. A PR was defined as a more than 50% reduction in the sum of the products of the perpendicular diameters of measurable bidimensional lesions without CR, no progression of any lesion by more than 25% or the appearance of any new lesion, confirmed on two separate measurements that were 4 weeks apart. In case of bone metastases, CR was attributed only when there was complete disappearance of all lesions on x-ray, and PR was attributed when decrease in size and/or recalcification of lytic lesions occurred. Decreased density of blastic lesions or improvement in bone scan positive, x-ray negative disease were not taken into account. Progressive disease (PD) was defined as the enlargement of any existing measurable lesion by more than 25% or the development of new metastatic lesions. Stable disease was any measurement that did not fulfil the criteria for PR or PD. All tumor measurements in patients who responded were reviewed and confirmed by an independent panel of radiologists and oncologists. Secondary efficacy end points included the duration of response (measured from the onset of the best response to the date of disease progression), time to treatment failure (calculated from the start of treatment to the time of progression or relapse), and overall survival.

Statistical Methods
A response rate of 50% was believed to be of clinical interest, and patients were accrued in a two-stage design.²⁰ If fewer than four responses were noted in the first 17 eligible patients, accrual would be halted. Because responses were observed, additional patients were enrolled to a final accrual of 57 women to better estimate efficacy and characterize the toxicity profile. This sample size was considered sufficient to estimate 95% confidence intervals for the true response rate with a maximum width of 26%. For the response rates, 95% confidence intervals were calculated as previously described.²¹ The distribution of time to death from the date of study entry was estimated by using the Kaplan-Meier product-limit method.²² All patients who were enrolled onto the study were included in the intent-to-treat analysis.

	RESULTS

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Patient Characteristics
Between February 1998 and March 1999, a total of 57 patients took part in this trial, all of whom were assessable for response and toxicity assessment. The demographic data, sites of metastatic tumor, and previous therapies are listed in Table 1. The median age was 59 years (range, 36 to 75 years), and the median WHO performance status was 1 (range, 0 to 2). Except for 20 patients, all had multiple metastases involving two or more organ systems with predominant visceral, bone, and soft tissue sites in 37, 11, and nine patients, respectively. Adjuvant systemic treatment consisted of endocrine therapy in 23 patients, and/or cytotoxic chemotherapy in 27. The median interval from initial diagnosis to relapse was 20 months (range, 0 to 276 months) for the entire study population. Fifteen patients had previous cytotoxic chemotherapy for metastatic disease, and 19 patients had palliative hormonal therapy. Fourteen patients underwent palliative radiation therapy for skeletal manifestations or soft tissue lesions. Previous palliative chemotherapy consisted of cyclophosphamide/methotrexate/fluorouracil (CMF) in five patients, and anthracycline-containing regimens in 10 patients, respectively.

Response to Treatment
The overall response rate was 64.3% for patients who had not received previous chemotherapy for metastatic disease (95% confidence interval, 48.1% to 78.4%), including eight (19%) complete and 19 (45.3%) partial remissions; 11 patients (26.2%) had disease stabilization, and four (9.5%) progressed. Second-line treatment with this regimen resulted in eight (53.3%) of 15 objective responses, four had stable disease, and three had tumor progression. The median time to progression was 12 months (range, 2.5 to 19+ months) in the first-line and 9.8 months (range, 2.0 to 23+ months) in the second-line treatment setting, respectively ( Table 2). After a median follow-up time of 18 months (range, 13 to 26 months), 38 patients (65%) are still alive with metastatic disease.

Toxicity
All 57 patients, who received a total of 285 courses, were assessable for toxicity. Side effects associated with treatment are listed in Tables 3 and 4. Myelosuppression was the most common adverse reaction, although according to the ANC-adapted use of a hematopoetic growth factor, the time to WBC/ANC recovery was generally short: in 96% of the episodes of leukopenia/neutropenia were resolved within 7 days. Administration of G-CSF because of ANCs of 1,000 to 2,000/µL on the day of scheduled chemotherapeutic drug administration, as indicated in the protocol, was effected in 48 patients (84%), most commonly on day 15 of the cycle. A total of 137 5-day courses of G-CSF were delivered, with most of the patients (60.4.%) receiving fewer than four courses. Leukopenia occurred in 50 patients (88%), and was grade 3 or 4 in 30 cases (53%). The median nadir WBC count was 2,800/µL (range, 300/µL to 39,400/µL). The variations in neutrophil counts paralleled those of WBCs; the median nadir count was 1,260/µL (range, 70/µL to 4,860/µL). Thrombocytopenia was rather uncommon (17%) and grade 3 or 4 in only two patients (4%). The median nadir platelet count was 206,000/µL (range, 20,000/µL to 540,000/µL). Only one patient developed severe anemia requiring packed RBC transfusion, whereas mild anemia was recorded in 46 patients (81%). Nineteen patients (33%) developed documented infection, four of whom required hospitalization for intravenous antibiotics.

Dose-intensity was calculated for each patient and for each drug. The mean given dose-intensity of the combination was 95% of the projected dose with no significant difference between first-line (95%) and second-line patients (93.6%). The mean dose of vinorelbine was 12.9 mg/m2/wk (range, 9.6 to 15 mg/m2/wk), and the mean dose of docetaxel was 19.5 mg/m2/wk (range, 14.5 to 22.5 mg/m2/wk).

Survival
As of April 2000, with a median follow-up duration of 18 months (range, 13 to 26 months), 14 of all 57 patients had died because of PD. Thirty-eight patients (65%) are still alive with metastatic disease, of whom 27 had received other oncologic therapy (chemotherapy with or without hormonotherapy) after subsequent PD. The median survival duration has not been reached yet and was more than 19.5 months (range, 3.0 to 26.0+ months) for patients in the first-line and 15.2 months (range, 2.0 to 23+ months) for those in the second-line chemotherapy setting.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Most patients with metastatic breast cancer will receive systemic chemotherapy at some point during the course of their disease. Because doxorubicin- and epirubicin-based combinations are commonly used in the adjuvant setting, an increasing number of patients presenting with disseminated disease have a history of anthracycline exposure, thus limiting the use of this effective group of anticancer drugs for palliation. There is a need, therefore, for the development of nonanthracycline-based combinations for the treatment of patients with metastatic breast cancer. Two candidate drugs for this purpose are vinorelbine and docetaxel. The rationale for their combined use were (1) the marked antitumor activity and safety of both drugs in ABC when given alone or in combination with other drugs,^3-6 (2) preclinical evidence of a sequence-dependent synergistic interaction,^9-11 and (3) encouraging results of recently conducted phase I/II studies evaluating this combination in non–small-cell lung cancer.^12-16 Apart from few preliminary reports,^12,23-25 to our knowledge, the present study is the first to report mature results on the efficacy of front-line chemotherapy in ABC with a combination of vinorelbine plus docetaxel.

With an overall objective response rate of 64.3%, including 19% complete responses, our data suggest a marked antitumor activity of this drug regimen in patients with metastatic breast cancer. It seems noteworthy that the therapeutic effectiveness was not influenced by adverse prognostic factors such as predominant visceral disease or multiple metastatic sites, both of which were present in about two thirds of our patients. Clinical responses achieved were durable, and after a median follow-up duration of 18 months, 65% of the study population are still alive. A somewhat lower, though still remarkable response activity of 53% was noted in our 15 patients failing previous palliative CMF or anthracycline-based chemotherapy.

As it concerns the tolerance of treatment, neutropenia was the most frequent and dose-limiting side effect associated with this regimen; WHO grade 3 or 4 toxicity occurred in 36 patients (64%) and was complicated by septicemia in four patients. According to the actual ANC-adapted use of G-CSF, however, only 31 (10.9%) of 285 courses had to be delayed for hematologic toxicity reasons. Nonhematologic adverse reactions were generally mild. The most common side effects included nausea/emesis and peripheral neuropathy, although grade 3 symptoms occurred in only two and one patients, respectively. In the latter case and in all other 23 patients with minor neurologic impairments, signs and symptoms reverted after treatment discontinuation. Other nonhematologic side effects were also generally mild and fully reversible, especially no fluid retention or edema occurred. As was noted by other investigators,^26,27 the latter observation is likely to be related to the weekly administration schedule of docetaxel, although the lower cumulative dose of the taxane (according to a limited treatment duration in our study), as well as the rather intense concomitant corticosteroid schedule might have contributed to the absence of this adverse reaction.²⁸

In conclusion, the results of this trial indicate that vinorelbine and docetaxel with or without G-CSF is an effective and tolerable first-line treatment for disseminated breast cancer. It seems to have an excellent and durable antitumor activity with an acceptable level of both hematologic and other organ toxicities. Compared with a recently published phase II investigation of vinorelbine and paclitaxel in 49 patients with untreated ABC,²⁹ which appeared equally effective, the incidence of severe leukopenia (grade 3 or 4 in 93% v 53% in the present trial) and febrile neutropenia (18% v 7%), as well as of certain other adverse reactions, including peripheral neuropathy and total alopecia, seems to be lower. This difference might be explained by the ANC-adapted use of G-CSF, the choice of the taxane, and/or its administration schedule; a valid comparative analysis of two different phase II trials, however, is certainly not possible.

In patients with metastatic breast cancer, an effective combination regimen with a high response activity may not necessarily translate into a survival benefit compared with monotherapy,³⁰ however, because of a significant association between symptom improvement and objective tumor regression and the resultant better chance of palliation,³¹ its use in the front-line setting, in fact, might be preferable. This seems particularly true if the active regimen is associated with an acceptable toxicity profile.

In view of the promising therapeutic index of the described regimen, a comparative trial with standard combinations such as fluorouracil/doxorubicin/cyclophosphamide or CMF, including formal measurements of quality of life, might be considered. Furthermore, in patients previously exposed to anthracyclines and/or alkylating agents, this combination seems to be of particular interest: according to the different mechanism of action and apparent noncross-resistance, further evaluation of its use as second-line therapy, and perhaps as a dose-intense sequential therapy with anthracyclines and alkylating agents in the front-line setting might be considered.

	ACKNOWLEDGMENTS

 
Supported in part by the Austrian Gesellschaft zur Erforschung der Biologie und Behandlung von Tumorkrankheiten.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted June 26, 2000; accepted September 22, 2000.

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