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Phase II Study of Vinorelbine With Protracted Fluorouracil Infusion as a Second- or Third-Line Approach for Advanced Breast Cancer Patients Previously Treated With Anthracyclines

From the Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, and Oncologia Medica, Azienda Ospedaliera San Giovanni, Molinette, Torino; Oncologia Medica Azienda Ospedaliera San Luigi, Orbassano; Centro di Senologia Azienda Ospedaliera Istituti Ospitalieri, Cremona; Oncologia Medica Istituto Oncologico, Bari; and Oncologia Medica Ospedale Santo Spirito, Casale Monferrato, Italy.

Address reprint requests to Luigi Dogliotti, PhD, Oncologia Medica, Azienda Ospedaliera San Luigi, Regione Gonzole 10, 10043 Orbassano, Italy; email luigi.dogliotti{at}unito.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate the feasibility and activity of vinorelbine in association with protracted infusional fluorouracil in patients with advanced breast cancer who were previously treated with anthracycline-containing regimens.

PATIENTS AND METHODS: Eighty-three consecutive patients were entered onto the study. Forty-three patients experienced treatment failure or relapse after anthracycline-based, first-line chemotherapy for advanced disease and 29 experienced treatment failure or relapse after first- and second-line approaches; 11 patients experienced progressive disease within 6 months of completion of adjuvant anthracycline therapy. Sites of involvement were as follows: liver involvement, 42 patients (50.6%); lung 24 (28.9%); bone, 49 (59.0%); and skin/lymph nodes, 21 (25.3%). Treatment consisted of vinorelbine 30 mg/m² administered on days 1 and 15 every 28 days and fluorouracil 200 mg/m²/d given continuously over a 24-hour period.

RESULTS: Toxicity was recorded for 441 cycles. The scheme was well tolerated: grade 1/2 nausea/vomiting occurred in 13 patients (15.6%), grade 1/2 diarrhea in nine (10.8%), and grade 2/3 stomatitis in six (7.2%). Three patients (3.6%) experienced grade 3/4 leukopenia and four (4.8%) experienced grade 2/3 anemia. Grade 2/3 neurologic toxicity was observed in three cases (3.6%), and grade 2/3 hand-foot syndrome was observed in three (3.6%). The median relative dose-intensity was 92% and 100% for vinorelbine and fluorouracil, respectively. Six patients (7.2%) attained a complete clinical response and 45 (54.2%) attained a partial response, for an overall response rate of 61.4% (95% confidence interval, 50.9% to 71.9%). Twenty-one patients (25.3%) obtained disease stabilization, and 11 (13.3%) experienced disease progression. Median time to progression in responding patients was 15 months; median overall survival of the entire population was 22 months.

CONCLUSION: Vinorelbine associated with protracted infusional fluorouracil is an active and manageable scheme in advanced breast cancer patients previously treated with anthracyclines. The response obtained is durable.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
BREAST CANCER IS the most common malignancy affecting women in Italy and in Western countries.¹ Despite adequate therapy, 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.² For metastatic breast cancer, there is no known treatment that seems to substantially prolong disease-free or overall survival,³ and the main goal of therapy for the patients is the palliation of symptoms.

Although many cytotoxic drugs have proven activity in breast cancer, anthracyclines alone or in combination are the most extensively used for first-line treatment of advanced breast cancer,^3-6 yielding 40% to 75% response rates that usually last 8 to 10 months.^4-6 Results of second-line chemotherapy after an initial treatment with anthracyclines are disappointing. Complete remissions are rare, and overall response rates for most of the regimens range from 10% to 35%.^7,8

The increased use of anthracyclines in the adjuvant setting limits their use in relapsed patients, thus demanding the testing of new effective regimens with a favorable therapeutic index. Patients who have progressive disease during or immediately after adjuvant anthracycline treatment have a poor prognosis and a small chance of achieving an objective response when treated with other cytotoxic agents.^7,8

Vinca alkaloids, a cytotoxic drug class acting as mitotic spindle poisons, have been largely used in breast cancer patients, alone or included in combination regimens.⁹ Among them, vinorelbine is substituted on the catharantine moiety, and the structural modification results in higher and more selective affinity for mitotic tubulin than with the classical vinca alkaloids.¹⁰ Used as a single agent, the drug yields response rates of 40% to 60%^11-13 in previously untreated advanced breast cancer patients. Neurotoxicity and bone marrow depression are the most frequently documented side effects.¹⁴

It is well known that multidrug resistance gene expression is a mechanism of tumor resistance to anthracyclines and vinca alkaloids. However, a lack of cross-resistance of vinorelbine with doxorubicin, vinblastine, and etoposide has been found in vitro in an multidrug resistance gene–expressing murine cancer cell line.¹⁵ The data are consistent with clinical results showing a 30% response rate with single-agent vinorelbine in anthracycline-pretreated breast cancer patients.^14,16

The taxoid plant alkaloids, such as paclitaxel and docetaxel, are new drugs that have been approved for the treatment of anthracycline-resistant breast cancer.^17,18 Docetaxel in particular seems to be associated with a higher response rate (close to 50% as second-line approach)¹⁹ than vinorelbine, but this increased activity is balanced with a higher level of toxicity. A recent nonrandomized comparison of docetaxel, paclitaxel, and vinorelbine showed that each of these drugs led to a similar duration of quality-adjusted progression-free survival, but vinorelbine was less costly.²⁰

Fluorouracil administered as bolus injection does not stand among the most active single agents in advanced breast cancer.^21,22 Myelosuppression and mucositis are the main dose-limiting side effects. Fluorouracil is an S-phase–specific agent with a short serum half-life of 10 to 20 minutes, making it active only against a small proportion of tumor cells in the S phase at any one time.

A greater number of actively dividing cells exposed to the drug, when it is given over an extended period of time, supports the use of fluorouracil as a continuous infusion. Studies of single-agent infusional fluorouracil at doses of up to 300 mg/m²/d led to a response rate up to 53% in nonpretreated breast cancer^23-26 and in 30% of patients with disease refractory to conventional therapy.²⁷ In addition, as a consequence of the altered plasma concentration profile, larger cumulative fluorouracil doses administered after continuous infusion are better tolerated than bolus injection, particularly in terms of myelosuppression, even though an increased incidence of hand-foot syndrome was observed. ^28,29

The moderate myelotoxicity of infusional fluorouracil allows combination with other myelotoxic agents. A very high response rate was observed when continuous infusion fluorouracil was combined with epirubicin and cisplatin³⁰ or cyclophosphamide,³¹ or with methotrexate and cyclophosphamide.³² Theoretical advantages for the association of vinorelbine with infusional fluorouracil include the following: (1) each drug has its own unique mechanism of cytotoxicity, (2) their proposed mechanisms of resistance are different, and (3) they possess relatively nonoverlapping toxicities.

The therapeutic activity of the combination of fluorouracil with vinorelbine in metastatic patients has already been tested by other investigators in six phase II studies. In two studies, fluorouracil was administered in bolus,^33,34 whereas in the other four studies, it was administered as a continuous infusion over 3 to 5 days.^35-38 Overall, the combination was able to achieve high response rates (up to 70% as first-line approach), but tolerance was not satisfactory (grade 3/4 leukopenia was observed in a high percentage [20% to 90%] of cases).

In view of the encouraging results reported with the combination of vinorelbine plus fluorouracil in breast cancer and considering the good results in terms of activity and compliance obtained in gastrointestinal tumors with protracted fluorouracil infusion,³⁹ we tested the combination of vinorelbine plus protracted fluorouracil in a prospective phase II study in a group of advanced breast cancer patients pretreated and/or resistant to anthracycline-containing schemes. The primary aim of the study was to evaluate the activity of the combination regimen, and the secondary aim was to assess toxicity, time to progression, and overall survival.

	PATIENTS AND METHODS

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Eligibility Criteria
To be eligible for the study, patients had to meet the following criteria: age greater than 18 years and less than 75 years; histologically proven breast cancer with progressive metastatic disease; previous treatment with anthracyclines in an adjuvant setting or for advanced disease; previous one or two lines of chemotherapy for advanced disease or progressive disease less than 6 months after adjuvant anthracycline-containing schemes; at least one measurable tumor site (target lesion) with index lesions on physical examination, x-ray, ultrasound, or computed tomography scan; Eastern Cooperative Oncology Group performance status of 0 to 3; estimated life expectancy 3 months; reasonable bone marrow function (leucocyte count 3,500/µL, platelet count 100,000/µL, and hemoglobin levels 11 g/dL); adequate hepatic and renal function, including AST, ALT, bilirubin, alkaline phosphatase, and serum creatinine values 1.25 times the upper limit of normal; no severe uncontrolled comorbidities; no second malignancies; no simultaneous or previous radiotherapy on the assessable tumor target; and no prior exposure to vinorelbine or infusional fluorouracil.

Hormone therapy, in the adjuvant setting or for advanced disease, was permitted. Concomitant hormone therapy was not allowed. Brain or leptomeningeal involvement was not considered to be exclusionary criteria if the patient presented with another metastatic target lesion. Written informed consent was obtained before registration. All data were managed in a central data registry located at the Division of Oncologia Medica at the Azienda Ospedaliera San Luigi, Orbassano, Italy.

Assessment of Response and Toxicity
The pretreatment evaluation included medical history and physical examination, complete blood cell count, serum chemistries, liver function tests, ECG, echocardiography, tumor marker evaluation (CA 15-3), and staging studies appropriate to define the extent of metastatic disease, which included chest x-ray, abdominal ultrasound, thoracic and/or abdominal computed tomography scan, and bone scan. Clinical monitoring was performed once weekly, and a complete blood cell count, serum electrolytes, and liver function tests were performed every 2 weeks. Toxicity was evaluated according the World Health Organization (WHO) criteria.⁴⁰

Antitumor activity was evaluated every 3 months on all measurable lesions, and all patients were scheduled for at least a 2-month treatment to be eligible for assessment of tumor response. In patients with tumor response or stable disease, the treatment was planned to be continued for up to 6 months; thereafter, maintenance or no therapy was based on the clinician’s choice. After the completion of the treatment plan, the patients were monitored every 3 months.

Tumor response was classified according to WHO criteria⁴⁰ and documented by two investigations at least 6 weeks apart. A complete response was defined as complete disappearance of all clinical, radiographic, and biochemical evidence of disease for a minimum of 1 month. A partial response required a 50% or greater reduction in the sum of the products of the longest diameter and its perpendicular. Stable disease indicated a decrease of less than 50% or an increase of less than 25% in the product of the longest perpendicular diameters of measurable lesions lasting 3 months. Progressive disease was defined as the appearance of new lesions or an increase of 25% in the sum of the products of the longest diameter and its perpendicular, as compared with the lowest value recorded. All deaths and treatment discontinuations (for toxicity or patient refusal) were considered as treatment failures. Time to progression was calculated from the beginning of cytotoxic chemotherapy until the date of objective evidence of progressive disease. Survival was dated from the first day of treatment until death or was censored on the date of the last follow-up appointment.

Treatment Plan
Treatment consisted of vinorelbine (Navelbine; Pierre Fabre Pharma, Milano, Italy) 30 mg/m² on days 1 and 15 every 28 days given as a 10-minute infusion in a 100-mL saline solution and fluorouracil given at a dose of 200 mg/m²/d as a protracted continuous infusion using an elastomeric pump. Both drugs were administered on an outpatient basis. All patients had a central venous access. Dose modifications were performed as follows: in case of myelosuppression, if the WBC count was 2,500/µL and/or the platelet count was less than 100,000/µL, then fluorouracil was continued, but vinorelbine, at day 1 or at day 15, was delayed for 1 week. If the blood count had recovered, vinorelbine was then administered at full dose. If the blood count had not recovered, then vinorelbine was delayed for a further week, and subsequently its dose was reduced by 25%. Regarding the hand-foot syndrome, for mild to moderate plantar-palmar erythema (dryness and erythema with pain), patients continued fluorouracil; for severe plantar-palmar erythema with blistering and desquamation, fluorouracil was interrupted until healing had occurred. For WHO grade 1 or 2 diarrhea, antidiarrheal agents were prescribed, but for persistent diarrhea, fluorouracil, but not vinorelbine, was discontinued for 1 week. In patients with grade 2 mucositis, infusional fluorouracil was stopped for 1 week; for grade 3/4 mucositis, fluorouracil was withdrawn until recovery and restarted at a 25% dose reduction. Vinorelbine dose was delayed for 1 week in case of grade 2 neurotoxicity, but it was reduced by 50% in subsequent cycles in the event of grade 3 neurotoxicity.

Relative dose-intensity was defined as the actual weekly doses of vinorelbine and fluorouracil at the end of treatment, divided by the planned weekly dose. Mild antiemetic drugs, such as metoclopramide and dexamethasone, were administered. The use of hematopoietic growth factors was not routinely planned. No specific treatment for patients who experienced treatment failure with the cytotoxic regimen was recommended in the treatment plan.

Statistical Analysis
The primary end point of the study was the assessment of the response rate (intent-to-treat analysis). According to the optimal two-stage phase II study design by Simon,⁴¹ the treatment program was designed to refuse response rates 20% (p0) and to provide a statistical power of 90% in assessing the activity of the regimen as a 35% response rate. The upper limit for first-stage drug rejection was eight responses of the first consecutive 37 patients; the upper limit of second-stage rejection was 22 responses of 83 cases consecutively enrolled. Secondary end points were the determination of time to progression and overall survival. All survival functions were computed using the Kaplan-Meier method. All analyses were performed using the SPSS/PC software program (SPSS, Inc, Chicago, IL).

	RESULTS

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Patients
From January 1997 to April 1999, 83 patients were entered onto the study. All were assessable for response and toxicity. No patient was lost to follow-up. The demographic data, sites of metastatic tumor, and prior therapies are listed in Table 1. The median age was 59 years (range, 30 to 75 years), and Eastern Cooperative Oncology Group performance status was good (0 or 1 in 80% of cases). Thirty-two patients (38.6%) had one metastatic site, and 51 patients (61.5%) had multiple metastases involving two or more organ systems. Predominant visceral sites were found in 64 cases (77.1%): 39 hepatic (47.0%), 14 lung (16.9%), seven brain (8.4%), three peritoneum (3.6%), and one pericardium (1.2%). Predominant bone and soft tissue sites were found in 13 (15.7%) and six cases (7.2%), respectively.

On the whole, 28 patients (33.7%) received one chemotherapy line with an anthracycline-containing scheme (11 in an adjuvant setting and 17 as first-line therapy for advanced disease). Thirty-six patients (43.4%) received two chemotherapy lines (26 as adjuvant and for advanced disease, and 10 only for advanced disease). Nineteen patients (22.9%) had been submitted to three chemotherapy lines (one in an adjuvant setting and two for advanced disease). Taxanes (paclitaxel or docetaxel) were administered in 22 patients (26.5%; as first-line therapy in three patients and as second-line therapy in 19 patients).

Treatment Activity
The best responses recorded for each patient are listed in Table 2. An objective regression was recorded in 51 of 83 women (61.4%; 95% confidence interval, 50.9% to 71.9%): six patients (7.2%) achieved a complete response, and 45 (54.2%) achieved a partial response. Stable disease was observed in 21 patients (25.3%), and progressive disease was observed in 11 (13.3%). Among the patients attaining a complete response, two presented with lung involvement, two presented with skin metastases, and one presented with liver metastases; one patient had lung and liver involvement. The distribution of responses according to disease site is listed in Table 3. The highest response rate (76.7%) was found in patients with lung involvement. However, approximately one half of the patients with liver metastases obtained a disease response. A partial response, defined as reduction of more than 50% of the overall carcinomatous infiltration at nuclear magnetic resonance imaging, associated with neurologic improvement, was obtained in the two cases with meningeal involvement, whereas in the subgroup of patients with brain metastases, disease stabilization was observed in three and disease progression was observed in two. Three of four patients with malignant peritoneal effusion and the only patient with pericardial effusion attained a partial response with minimal residual effusion at postchemotherapy ultrasound evaluation. Overall response was higher in patients with only one disease site (75.0%) than in those with two (55.3%) or three sites (46.2%). According to the previous treatment, a disease response was obtained in 19 (67.9%) of 28 cases previously submitted to only one chemotherapy line (with anthracycline-containing regimens), in 20 (55.6%) of 36 cases submitted to two chemotherapy lines, and in 10 (52.6%) of 19 cases who previously received three chemotherapy lines. Eleven (50.0%) of 22 patients with progressive disease after treatment with anthracyclines and taxanes responded to the treatment scheme.

View larger version (10K): [in this window] [in a new window]   Fig 1. Time to progression (- - -) and overall survival (——) of the patients obtaining a disease response to the cytotoxic treatment.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Second- or third-line cytotoxic treatments in advanced breast cancer patients are only palliative; therefore, the search for schemes with an excellent compliance is mandatory. The administration of drugs without overlapping toxicity is along that line. In this regard, the combination of protracted fluorouracil infusion and vinorelbine is appropriate.

The present study comprised a relatively large number of patients with advanced breast cancer whose pretreatment characteristics seemed to be predictive of a less favorable outcome. Among them, previous exposure to two or more chemotherapy lines including anthracyclines and visceral metastases (including brain involvement) have been clearly shown to be related to a poor outcome.⁸ The only favorable prognostic parameter was the relatively good performance status.

In this setting, the combination of vinorelbine 30 mg/m² on days 1 and 15 with protracted fluorouracil infusion 200 mg/m²/d showed considerable activity, with an overall response rate of 61.4% (95% confidence intervals, 47.8% to 75.0%) and a complete response rate of 7.2%. The observed overall response rate is among the highest reported in the literature.⁴² Responses were seen in soft tissue and visceral sites, as well as in patients with one site or multisite involvement.

It is well known that the extent of previous therapies will usually influence the results of the protocol treatment. Accordingly, our study yielded a higher overall response rate (67%) in patients previously submitted to only one anthracycline-based chemotherapy line, administered as adjuvant or for advanced disease, than in patients submitted to two or three chemotherapy lines. However, the more than 50% response rate obtained in the latter cases was noteworthy, because it seemed to be higher than expected in a heavily pretreated patient population.^7,42

Interestingly, the salvage treatment with vinorelbine plus infusional fluorouracil was active in 50% of patients who had previously failed anthracycline and taxane combinations. Such results, however, should be interpreted with caution, because our study was not specifically designed to test the cross-resistance between our schedule and taxanes.

The responses achieved were durable, with a median time to progression for responding cases of 15 months and a median survival of 22 months. The latter finding was unexpectedly high, considering the poor prognosis and the chemoresistance of the patients enrolled. The relatively good performance status of the enrolled patients and the long duration of the responses obtained may have been both contributory. The latter suggestion, however, must be confirmed in randomized trials.

The results of the study clearly show that the combination regimen seems to be non–cross-resistant to anthracyclines and represents a valid option to be tested in randomized studies for patients with primary resistance to anthracyclines in an adjuvant setting or in metastatic disease or in patients with progressive disease after discontinuation of anthracycline-based chemotherapy.⁷

The non–cross-resistance of vinorelbine with respect to anthracyclines has repeatedly been reported.^14,15 However, it is unlikely that vinorelbine alone can yield such results, because its reported activity in anthracycline-resistant patients has not exceeded 30%.^14,16 Similarly, the response rate obtained with protracted fluorouracil infusion as a second- or third-line approach in metastatic breast cancer was 20% to 33%.^26,27 Therefore, the high response rate of vinorelbine and fluorouracil in the present study was probably due to in vivo synergism between the two drugs rather than an overlapping effect.

It is noteworthy that a high therapeutic activity of fluorouracil and vinorelbine combination schemes has already been described by other investigators,^33-37 with one exception.³⁸ However, with respect to other trials, our results are clearly better in terms of toxicity. This may be due to the schedule adopted, in terms of the fluorouracil infusion (protracted v infusion over a few days) and the timing of vinorelbine administration. In particular, the combination resulted in minimal hematologic toxicity, because grade 3/4 leukopenia was found in only 3.6% of cases, compared with 20% to 90% reported in the aforementioned studies.

Side effects possibly related to fluorouracil, such as mucositis and hand-foot syndrome, and those related to vinorelbine, such as constipation, were rarely observed. The adverse events related to both drugs, such as asthenia, were found in approximately 20% of cases but were mild in all of them.

The toxicity of this combination, on the whole, seems to be even less than that obtained in published data for the two drugs used as single agents.^11-14,23-27 The low dose-intensity adopted for each drug and the absence of an overlapping toxicity profile could account for the better tolerability of this regimen.

With previously treated metastatic breast cancer patients, concerns are heightened regarding the resiliency of the bone marrow to further myelosuppressive agent exposure. In keeping with our goal of palliation with limited toxicity, we decided to discontinue vinorelbine administration for 1 week even in case of grade 2 myelotoxicity. It is for this reason that, notwithstanding the mild toxicity, 47.0% of cases delayed vinorelbine administration at least once for 1 week. Nonetheless, more than 80% of cycles were administered at full dose of either vinorelbine and fluorouracil, and the weekly dose-intensity of both drugs was elevated.

Another group in Italy conducted a study similar to the present one in which vinorelbine was administered at the dose of 20 mg/m² on days 1 and 8 and fluorouracil at 250 mg/m²/d as a protracted infusion as a second- or third-line approach in advanced breast cancer patients.⁴³ The results were noteworthy (68% response rate), but toxicity in terms of mucositis (grade 3/4, 28%) and hand-foot syndrome (grade 3/4, 21%) was greater than that seen in our study. It may be attributable to the higher fluorouracil dose administered. Our fluorouracil schedule may thus represent the optimal one for heavily pretreated patients.

In conclusion, by incorporating a biweekly short infusion of vinorelbine with protracted infusional fluorouracil, the objectives of an active and low-toxicity chemotherapy regimen for metastatic breast cancer are met. The ease of administration of the schedule makes it acceptable for outpatient use, and it seems efficacious in a pretreated population. Further phase III investigations comparing the regimen with traditional combinations seem warranted. An important future end point for the association of vinorelbine with protracted fluorouracil infusion will be to determine whether patients with responsive or stable disease in conjunction with limited treatment toxicity experience enhanced quality of life.

	NOTES

 
Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, May 15-18, 1999, Atlanta, GA.

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Submitted November 18, 1999; accepted June 6, 2000.

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