Infusional 5-FU, Folinic Acid, Paclitaxel, and Cisplatin for Metastatic

April 1, 1997

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose, 24-hour infusional 5-fluorouracil(5-FU)/folinic acid (HD5-FU/FA) in intensively pretreated patients with metastatic

ABSTRACT: Our phase II study results demonstratinghigh efficacy and low toxicity for a weekly schedule of high-dose, 24-hourinfusional 5-fluorouracil(5-FU)/folinic acid (HD5-FU/FA) in intensivelypretreated patients with metastatic breast cancer prompted addition ofpaclitaxel (Taxol) to the regimen, for a phase I/II study of outpatientsecond-line treatment of metastatic breast cancer. That study further promptedthe addition of cisplatin (Platinol) to the regimen for first-line treatment.So far, 28 patients with metastatic breast cancer have been evaluated.Pretreatment comprised adjuvant chemotherapy in 24 of 28 patients, butno prior chemotherapy for metastatic disease. Patients were treated withHD5-FU 2 g/m² (24-hour infusion) plus FA 500 mg/m² (2-hour infusionprior to FU) weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36); in addition,paclitaxel 175 mg/m² (3-hour infusion) was administered on days 0and 21 and cisplatin 50 mg/m² (1-hour infusion) on days 1 and 22 priorto HD5-FU/FA, repeated every 50 days. Patients were treated as outpatientsusing Port-a-Cath systems and portable pumps. Neutropenia was common (67%World Health Organization grade 3) but mild to moderate in most patientsand was of short duration. No hospitalizations were required because offebrile neutropenia, and no granulocyte colony-stimulating factor supportwas used. Aside from common total alopecia, nonhematologic toxicities consistedmainly of moderate myalgia, diarrhea, mucositis, and nausea and vomiting.Hand-foot syndrome and peripheral neuropathy were cumulative and occurredmost commonly during the third treatment cycle, with mild-to-moderate expression.In 28 patients with bidimensionally measurable disease, 25% (7/28)attained a complete response, 57% (16/28) achieved partial response, 11%(3/28) had stable disease, and 7% (2/28) had disease progression. Overallresponse was 82% (95% confidence interval, 66% to 100%). Eight of 28 patientsare still receiving treatment. It is concluded that the combination ofpaclitaxel/cisplatin with weekly HD5-FU/FA appears to be effective in thefirst-line treatment of metastatic breast cancer. Preliminary results mustbe confirmed by the final analysis of response duration, time to progression,and survival. [ONCOLOGY 11(Suppl):38-40, 1997]


A phase I/II study of high-dose 5-fluorouracil/folinic acid (5-FU/FA),given weekly for six weeks by 24-hour infusion, demonstrated high efficacy,with a response rate of 41% (13 of 32 patients), and low toxicity in intensivelypretreated patients with metastatic breast cancer.[1] Based on these results,we added paclitaxel (Taxol) to the regimen in a second phase I/II study,also in pretreated patients with metastatic breast cancer.[2] The combinationof paclitaxel with weekly high-dose infusional 5-FU/FA was well toleratedand highly effective (response rate, 59%; 32 of 54 patients) in these patients,including those with anthracycline-refractory disease. In an ongoing phaseII study, we intend to estimate the value of adding cisplatin to this regimenas first-line treatment of metastatic breast cancer to create an effectivetreatment for patients who have received anthracyclines in the adjuvantsetting.


In June 1995, we initiated this phase II study of first-line treatmentin patients with metastatic breast cancer and no prior chemotherapy formetastatic disease.

Eligibility Criteria

All patients had histologically proven breast cancer; were pretreatedwith chemotherapy only in the adjuvant setting; had not had any chemotherapyfor metastatic disease; had bidimensionally measurable disease with orwithout evaluable disease (ie, bone metastases); and had adequate hematologic,renal, and hepatic function, as well as no severe, uncontrolled comorbidities.Additional eligibility criteria included an Eastern Cooperative OncologyGroup performance status of 0, 1, or 2; life expectancy of at least 3 months;and age 18 or more years. Pregnancy was excluded prior to study entry.All patients gave informed consent before participating in this study,which was approved by the institutional review board. A quality-of-lifeanalysis was performed throughout the study and during follow-up.

Patient Characteristics

At this time, 28 patients have entered this ongoing phase II study.Patients had progressive disease and/or tumor-related symptoms prior tostudy treatment. All patients had at least one bidimensionally measurabletumor site. The characteristics of the patients treated are outlined inTable 1.

Study Design

Patients were treated with high-dose 5-FU 2.0 g/m² (by 24-hourinfusion) plus FA 500 mg/m² (by 2-hour infusion prior to 5-FU) weeklyfor 6 weeks (days 1, 8, 15, 22, 29, and 36). Cisplatin 50 mg/m² (by1-hour infusion) was administered on days 1 and 22, and paclitaxel 175mg/m² (by 3-hour infusion) was given on days 0 and 21 after standardpremedication with corticosteroids and H1- and H2-receptorantagonists. Each cycle comprised 6 weeks, followed by 2 weeks of rest,with a total of three cycles planned. All patients were treated under outpatientconditions using intravenous port systems and portable pumps (Figure1).

Mode of Administration/ Drug Therapy

All patients had intravenous port systems. Folinic acid 500 mg/m²was dissolved in 500 mL of a 0.9% saline solution and given over 2 hoursas a continuous infusion, prior to a 24-hour continuous infusion of 5-FU(2 g/m²), given by portable pump. This application was performed weeklyfor 6 weeks. Cisplatin 50 mg/m² was given on days 1 and 22, and paclitaxelat a dose of 175 mg/m² was given on days 0 and 21. We used standardpremedication with corticosteroids and H1- and H2-receptorantagonists, as well as polyvinyl chloride-free infusion material and filtersystems for paclitaxel administration. Cisplatin and paclitaxel, dissolvedin 1,000 mL of 0.9% saline solution, were given prior to the FA/5-FU. Whilethe number of applied cycles depended on response and toxicity, three fullcycles were planned for patients without tumor progression and withoutworsening of performance status or tumor-related symptoms during chemotherapy.Cytokines were not administered.

The 5-FU dosage was reduced by 20% in cases of mucositis or stomatitisor of diarrhea greater than World Health Organization (WHO) stage 2. Ifmucositis, stomatitis, or diarrhea greater than WHO stage 2 were presenton the day of planned treatment, chemotherapy was delayed until full recoveryfrom side effects and the dose of 5-FU was reduced by 20% for the remainingtreatment period.

Patient Evaluation

Prior to treatment, all patients underwent physical examination, chestx-ray, abdominal ultrasound, thoracic and/or abdominal computed tomographyscan if indicated, bone scan, blood cell counts, routine biochemical tests,and tumor-marker screening. Tumor response was evaluated after each treatmentcycle, using those techniques required to assess tumor locations presentat study entry. Full restaging was done following induction of an objectiveresponse, upon progressive disease assumed due to contradictory resultsbetween imaging techniques and biochemical tests, upon worsening of performancestatus or clinical symptoms despite tumor regression or stable disease,and at the end of treatment.

Blood cell counts and assessment of toxicities were done weekly duringtreatment, prior to each treatment period, and after the last chemotherapycycle. Biochemical parameters and tumor markers were measured after eachtreatment cycle. Quality-of-life assessment was performed thoughout thetreatment period and during follow-up, using the European Organizationfor Research and Treatment of Cancer quality-of-life scale. Toxicity wasgraded according to the WHO scale.

Response Criteria/Statistical Analysis

Response guidelines were performed according to standard WHO criteria:Tumor response was documented in two evaluations performed at least 6 weeksapart. Complete remission and partial remission response duration werecalculated from the date the response was first documented. Survival andtime to progression were computed actuarially, using the Kaplan-Meier method,beginning with the date the patient was placed on study. Duration of responsealso was calculated according to Kaplan-Meier, from the date of responseto the date of progressive disease.[3]



With a total of 65 treatment cycles and a median of two treatment cyclesper patient (range, one to three cycles), all 28 patients were evaluablefor toxicity. No serious acute hypersensitivity reactions were attributedto paclitaxel. Neutropenia was common but moderate in most patients (WHOgrade 3 in 35% of cycles). No hospitalizations were necessary for febrileneutropenia. The duration of grade 3 and 4 neutropenia was generally brief.No cytokines were used. Aside from common total alopecia, nonhematologictoxicities consisted primarily of moderate (defined as WHO grade 2 in percentof cycles) myalgia (45%), diarrhea (53%), mucositis (39%), nausea and vomiting(52%), and hand-foot syndrome (51%). Peripheral polyneuropathy was cumulativeand occurred most frequently during the third treatment cycle, with mild-to-moderateexpression. World Health Organization grade 3 toxicity occurred in 7% ofcycles as nausea and vomiting and in 11% of cycles as diarrhea.


The following results have been achieved: 25% (7 of 28) of patientshave attained a complete remission and 57% (16 of 28) a partial remission;11% (3 of 28) have stable disease, and 7% (2 of 28) have progressive disease.Overall response rate was 83% (95% confidence interval, 66% to 100%) (Table2). Median time to maximum response was 2 months (range, 1 to 5), medianremission duration was 8 months (range, 4 to 22). Eight of the 28 patientsare still receiving treatment, and the median survival time has not yetbeen reached.


Sledge and coworkers[4] summarized cisplatin as a significant, activesingle agent for the first-line treatment of metastatic breast cancer.Additionally, preclinical data suggest a synergistic interaction for combiningcisplatin with either paclitaxel or 5-FU.[5,6] Further, our own clinicaltoxicity data of combination paclitaxel plus high-dose 5-FU/FA allows theaddition of a third combination partner for use in a less-pretreated patientpopulation.[2]

The preliminary results of this ongoing phase II study of weekly high-dose,24-hour infusional 5-FU/FA with paclitaxel/cisplatin indicate an activeoutpatient combination regimen for
first-line treatment of women with metastatic breast cancer. In this study,we will further estimate the value of this regimen with respect to responseduration, survival, toxicity, and quality of life during and after treatment.This active combination could have an impact on the management of metastaticbreast cancer because of the more frequent use of anthracyclines and high-dosechemotherapy with peripheral stem cell support in the adjuvant setting.


1. Wilke H, Klaassen U, Achterrath W, et al: Phase I/II study with aweekly 24-hour infusion of 5-fluorouracil plus high dose folinic acid (HD5-FU/FA) in intensively pretreated patients with metastatic breast cancer.Ann Oncol 7:55-58, 1996.

2. Klaassen U, Wilke H, Phillippou Pari C, et al: Phase I/II study withpaclitaxel in combination with weekly high dose 5-fluorouracil/folinicacid (HD 5-FU/FA) in the treatment of metastatic breast cancer. SeminOncol 22(suppl 14):7-11, 1995.

3. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations.J Am Stat Assoc 53:457-481, 1958.

4. Sledge J, Loehrer PJ, Roth BJ, et al: Cisplatin as first-line therapyfor metastatic breast cancer. J Clin Oncol 6:1811-1814, 1988.

5. Vanhoefer U, Harstrick A, Wilke H, et al: Schedule-dependent antagonismof paclitaxel and cisplatin in human gastric and ovarian carcinoma celllines in vitro. Eur J Cancer 31A:92-97, 1995.

6. Klaassen U, Harstrick A, Schleucher N, et al: Activity and schedule-dependentinteractions of paclitaxel, etoposide and hydroperoxy-ifosfamide in cisplatin-sensitiveand -refractory human ovarian carcinoma cell lines. Br J Cancer74:22-228, 1996.