FA) in intensively pretreated patients with metastatic breast cancer

Annals ofOncology 7: 55-58, 1996. © 1996 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Phase I/II study with a weekly 24-hour infusion of 5-fluorouracil plus high-dose folinic acid (HD-FU/FA) in intensively pretreated patients with metastatic breast cancer H. Wilke, U. Klaassen, W. Achterrath, M. Losch, U. Vanhoefer, J. Hayungs, A. Harstrick, M. Stahl, W. Eberhardt, R. Becher & S. Seeber Department of Internal Medicine (Cancer Research), Essen University Medical School, West German Cancer Center, Essen, Germany

Results: FID-FU/FA was well tolerated. No dose-limiting toxicity occurred at dl 1 or 2. Only 3/32 (9%) patients Background: In metastatic breast cancer patients who have had WHO grade 3/4 toxicities (gastrointestinal toxicities, had prior exposure to anthracyclines, single agents induce hand-foot-syndrome) at dl 3. The response rate for all 32 of less than 15% and combination chemotherapy less than the patients treated at dl 3 was 41% (13/32). In the 24 20%-30% of objective responses. Therefore more active and patients with anthracycline-refractory disease, a response rate of 41% (10/24) was achieved. The median remission tolerable salvage regimens are needed. Patients and methods: Forty-three patients with advanced duration was 11 months and the median survival time 19 breast cancer pretreated with 1-5 (median 2) different months. chemotherapy regimens were entered into this phase I/H Conclusions: This schedule of FU/FA is a safe outpatient trial. Treatment consisted of folinic acid (FA) (500 mg/m2, treatment with substantial activity in intensively pretreated i.v., 2-hour infusion) followed by a 24-hour infusion of breast cancer patients. 5-fluorouracil (FU) which was escalated from 1.5 g/m2 (dose level (dl 1)), to 1.8 g/m2 (dl 2) to 2.1 g/m2 (dl 3). Therapy was given as outpatient treament once weekly times 6 followed by Key words: phase I/n trial, folinic acid/5-fluorouracil, prea 2-week rest. treated breast cancer Summary

Introduction

Anthracycline and alkylating agent-based regimens are routinely used as first- and second-line treatment for metastasized breast cancer. These combinations induce approximately 50%-70% of major responses with a median response duration of 8-16 months [1]. However, disease progression usually occurs during or after initial treatment. Therefore, the development of active and well-tolerated salvage regimens is one goal of the palliative treatment of metastasized breast cancer. In anthracycline-pretreated patients less than 15% of objective responses were induced by either cisplatin, mitomycin, mitoxantrone, etoposide, teniposide, and vinca-alcaloids [1]. Higher response rates (approx. 20%-30%) were reported only for the new drugs, taxol, taxotere and gemcytabine [2]. Even with combination chemotherapy overall response rates are usually less than 25% [1]. The results of several recent phase II trials indicated activity of FU/FA in breast cancer patients pretreated with doxorubicin-containing regimens. With various dose and time schedules of FU/FA ± other drugs an overall remission rate of approximately 25%-30% and

a median remission duration of 5-9 months were reported [3-7]. In these trials, FA and FU were usually administered as bolus injection. However, experimental and clinical data indicate higher activity of this combination with protracted infusions of FA/FU and if FU is administered with a high dose intensity [8-13]. Based on these results and on the experience with weekly HD-FU/FA in colorectal cancer [14-18], we tested this combination in heavily pretreated breast cancer patients. The dose of 500 mg/m2 of folinic acid was chosen on the basis of results of weekly schedules of FU/FA in colorectal cancer showing that significantly higher response rates were induced by high-dose FA than by low-dose FA [14]. This, of course, does not imply that we know how much FA is really needed for biomodulation if FU is administered as protracted infusion. However, answering this question was not an objective of this trial. In view of the fact that all patients were pretreated with various myelosuppressive cytostatic agents, we first conducted a dose finding pilot study with a fixed dose of FA and escalating doses of FU. After establishing the dose of HD-FU in combination with FA recommended for further clinical investigation, additional patients were entered at this dose level.

56 Patients and methods

Patient characteristics

Eligibility criteria

Between 2/1992 and 12/1993, 43 patients were entered into the trial. Seven patients were treated at dose level 1, 4 patients at dose level 2 and 32 patients at dose level 3. All patients had previously failed standard chemotherapy regimens and had had progressive disease and/or tumor-related symptoms prior to study treatment Seventy percent of them were pretreated with 2 or more different combinations. All patients had at least one measurable tumor site. The characteristics of the patients treated at dose levels 1-3 are outlined in Table 1.

Patients with histologically-proven measurable or evaluable metastatic breast cancer failing to respond to or relapsing after previous chemotherapy were eligible. Other eligibility criteria included a WHO performance status 0-2, life expectancy of at least 3 months, normal liver and kidney functions, no severe uncontrolled co-morbidities, no second malignancies, and informed consent. Evaluation at study entry, during and after chemotherapy Prior to treatment, all patients underwent a physical examination, chest X-ray, abdominal ultrasound, thoracic and/or abdominal CT scan if indicated, bone scan, blood cell counts, routine biochemical tests and tumor marker screening. Tumor response was evaluated after each treatment cycle using those techniques required to assess rumor locations present at study entry. A full restaging was done after induction of an objective response, if progressive disease was assumed to be due to contradictory results between imaging techniques and biochemical tests, if the performance status or clinical symptoms worsened despite tumor regression or stable disease of known tumor sites, and at end of treatment. Blood counts and assessment of toxicities were done weekly during treatment, prior to each and after the last chemotherapy cycle. Biochemical parameters and tumor markers were measured after each treatment cycle. To get some information about the palliative potential of this treatment we documented weekly the course of tumor-related symptoms (pain, weight loss, dyspnea, appetite, etc.) during treatment using a simple scale (complete relief, better, unchanged, worse). Symptoms were judged by the patients themselves. Toxicity was graded according to the WHO scale.

Table 1. Patient characteristics [dose levels 1-3 (n - 43)]. Age (years) WHO performance status I/n Premenopausal/peri-postmenopausal Number of tumour sites 1 2 >2 Metastatic disease sites Lung Liver Bone Node/soft tissue Other Pretreated with anthracyclines Refractory to anthracyclines No. of prior chemotherapy regimens 1 2 3 4 5

56 (37-73) 34/9 13/30 7 19 17 25 22 29 16 14 41 35 11 18 9 3 2

Response criteria/statistical analysis Tumor response was classified according to WHO criteria and documented by two investigations at least 6 weeks apart. Remission duration and duration of stable disease was calculated from the first day of treatment until time of relapse or progression and survival from start of treatment (Kaplan-Meier method) [19].

Results Dose levels 1/2

No dose-limiting toxicities and no objective tumor responses were observed in 7 patients (18 cycles) treated at dose level 1 and in 4 patients (14 cycles) treated at Drug therapy dose level 2. No dose reduction or treatment delay Folinic acid was given in a fixed dose of 500 mg/m2 as a 2-hour infu- were necessary at both dose levels. Three of 7 patients sion followed by a 24-hour infusion of FU (1.5 g/m2 at dl 1; 1.8 at dose level 1 had stable disease and 4 had progressive g/m2 at dl 2; 2.1 g/m2 at dl 3) on days 1, 8, 15, 22, 29, 36 followed disease. The 4 patients treated at dose level 2 had by a 2-week rest (— 1 cycle). Three full cycles were planned for pastable disease as their best response. tients without tumor progression and without worsening of performance status or tumor-related symptoms during chemotherapy. Treatment was administered on an outpatient basis using i.v. port systems and portable pumps. FU doses were escalated if no dose limiting toxicities (WHO grade) occurred in 1 out of 4 patients or 2 out of 8 patients per dose level, respectively. Dose-limiting toxicities were defined as neutrocytopenia 4* or neutrocytopenia 3* associated with infection >2", thrombocytopenia > 2*, and mucositis or stomatitis or diarrhea > 2*. If any nonhematological toxicity or neutrocytopenia 2" or thrombocytopenia 2* were present on the day of planned treatment, chemotherapy was delayed until full recovery from all side effects. If a patient had any of the dose-limiting toxic effects specified above, the dose of FU was reduced by 20% for the remaining treatment period.

Dose level 3 Two of the initial 4 patients treated at dose level 3 had objective responses. A dose-limiting toxicity occurred in one of them. In the next 4 patients entered at dl 3, no dose-limiting toxicity was observed. Though the predefined criteria for ending the dose escalation were not met, it was felt that there should be no further dose escalation in the palliative treatment where severe side effects should be avoided. Altogether, 32 patients were treated at dose level 3 and were evaluable for toxicity (101 cycles) and response. HD-FU/FA in this dose and schedule was subjec-

57

tively and objectively well tolerated (Table 3). No thrombocytopenia was observed and a neutrocytopenia of 2° was seen in only 3/101 cycles. Five percent of all cycles were associated with nausea/vomiting 3°, 2% with diarrhea 374°, 3% with mucositis 3°, and 2% with hand-foot-syndrome 3°. All instances of grade 3/4 toxicities were seen in only 3 patients. No alopecia occurred. Eighteen of 606 single weekly doses (101 treatment cycles) had to be reduced to 1.8 g/m2 of FU in 3 of 32 patients treated at dose level 3 due to nonhematologic toxicities (Table 3). Treatment delays were necessary in 6 patients (8 single weekly doses). Thirteen objective responses (41%, 95% confidence interval 24%-58%) including 1 clinically complete remission were observed (Table 2). Ten of 24 (41%, 95% confidence interval 20%-61%) patients refractory to anthracyclines defined as having disease progression while receiving anthracyclines, and one refractory to mitoxantrone/prednimustin responded. Two responding patients had failed on cyclophosphamide/methotrexate/FU (CMF) and refused an anthracycline-containing regimen as second-line treatment. Ten of 13 patients with objective responses had failed on prior bolus application of FU or FU/FA. Neither the kind nor the number of prior chemotherapies seemed to influence the response rate. The number of objective responses in patients with 1, 2 or >3 prior regimens was 4/10 (40%), 5/13 (38%), and 4/9 (44%), respectively. There was also no difference in response rates between patients with and those without hormone receptor-positive tumors. Median time to maximum response was 8 (6-12) weeks. Seventeen (53%) patients had stable disease or a tumor regression not fulfilling the criteria of an objective remission. The overall tumor growth control rate Table 2. Response to chemotherapy. CR Dose level i (n - 7) Dose level 2 (n - 4) Dose level 3 All patients (n - 32) Dose level 3 Patients refractory to anthracyclines (n - 24)

PR

SD

PD

34 4 0

CR/PR

0 0

0 0

0 0

1

12

17

2

13(41%)

0

10

12

2

10 (41%)

Table 3. Percentage of cycles ( n - 101) associated with toxicities (dose level 3).

(CR/PR/SD) was 96% (95% confidence interval 87%100%). Only 2 patients had progressive disease. The median remission duration is 11 (4-21) months,' median duration of stable disease 5 (3-18) months, and median time to progression for all patients 7 (221) months, respectively. The median follow-up is 19 (13-27) months. A median survival time of 19 (4-27+) months was achieved in all 32 patients, with no differences between responding patients and patients with stable disease (19 months for both groups). Discussion Metastatic breast cancer is one of those malignancies in which various chemotherapy approaches are active and may offer good palliation. However, almost all patients will develop progressive disease after first-line chemotherapy. The antitumor activity of subsequent treatment declines with the number of different drugs/combinations previously administered. Prior treatment with anthracyclines, especially if the rumor is refractory to these compounds, is generally accepted as being a poor prognostic factor for response to further chemotherapy [1]. In this clinical situation, most combinations induce less than 30% of objective remissions which are generally of relatively short duration. Furthermore, the value of most of these treatments in terms of palliation remains questionable [1]. Therefore, it is of clinical relevance to develop new regimens which are active and well tolerated for patients failing conventional chemotherapy. In this study HD-FU/FA (dose level 3) demonstrated significant activity in intensively pretreated breast cancer patients. The objective remission rate of 41% in all patients and particularly in patients resistant to anthracyclines (10/24) is noteworthy as well as the remarkable long response duration of 11 months. Well aware of the fact that our estimation of improvement of tumor-related symptoms does not represent a validated quality-of-life analysis, it has to be noted that more than Table 4. Results with 5-FU/FA bolus schedules in metastatic breast cancer. Author

Pretreatment

5-FU-FA*

N

Marini (1987) Fine (1988) Loprinzi (1991)

1 0 1

370/200 370/200 375/500

36 25 21

Swain (1989) Doroshow (1989)

2 2

375/500 370/500

54 60

WHO grade (% of cycles (n-101))

Neutropenia Nausea/vomiting Diarrhea Mucositis Hand-foot syndrome

1

2

3

17 29 19 25 16

3 8 7 4 6

5 1 3 2

4

RR (%)

RD (months)

44 9.6 48 19 RR 29% (95% CI 2O%-35%) 24 17

4

RR 22% (95% CI 15%-29%) • mg/m 2 ,dl-5,qd28.

58 80% of patients who had a tumor response or stable disease reported either complete relief from or reduction of tumor related symptoms present at their study entry. These results compare favourably with bolus schedules of FU/FA and with other salvage regimen (Table 4) [3-7]. The observation that no objective responses were seen at dose levels 1/2 cannot be explained by patient selection. Patients treated at these 2 dose levels had the same characteristics as those of dose level 3. Nevertheless, it cannot be concluded from this trial that the doses of FU used at dose levels 1/2 are ineffective. HD-FU/FA was subjectively well tolerated, and clinically relevant hematological and gastrointestinal toxicities were infrequent. In terms of palliation, HDFU/FA proved to be an effective outpatient treatment. Based on our results, the combination of HD-FU/ FA with other active drugs appears to warrant further clinical investigations. References 1. Henderson IC. Chemotherapy for advanced disease. In Harris JR, Hellman S, Henderson IC. Breast Diseases. Philadelphia PA: Lippincott 1987; 428-79. 2. Rowinsky EK, Onetto N, Canetta RM. Taxol: The first of the taxanes, an important new class of antitumor agents. Semin Oncol 1992; 19: 646-62. 3. Swain SM, Lippman ME, Egan EF et al. Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. J Clin Oncol 1989; 7(7): 890-9. 4. Doroshow JH, Leong L, Margolin K et al. Refractory metastatic breast cancer Salvage therapy with fluorouracil and high-dose continuous-infusion leucovorin calcium. J Clin Oncol 1989; 7:439-44. 5. Marini G, Simonchine E, Zaniboni A et al. 5-Fluorouracil and high-dose folinic acid as salvage treatment of advanced breast cancer: An update. Oncology 1987; 44: 336-40. 6. Fine S, Erlichman C, Kaizer L et al. Phase II trial of 5-FU and folinic acid as first-line treatment for metastatic breast cancer. Proc Am Soc Clin oncol 1988; 7:41. 7. Loprinzi CL. 5-Fluorouracil with leucovorin in breast cancer. Cancer 1989; 63:1045-7. 8. Hansen R, Quebbeman E, Beatty P. Continuous 5-fluorouracil

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Received 16 June 1995; accepted 4 October 1995. Correspondence to: Hansjochen Wilke, M.D. Department of Internal Medicine (Cancer Research) Essen University Medical School HufelandstraBe 55 45122 Essen, Germany