Interferon-α, 5-FU and prednisone in metastatic renal cell carcinoma: A phase II study

Annals of Oncology 5: 245-248, 1994. © 1994 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Interferon-a, 5-FU and prednisone in metastatic renal cell carcinoma: A phase II study

'Department of Oncology, Regional Hospital Trondheim; 2 Department of Medical Oncology and Radiotherapy, The Norwegian Radium Hospital; 3 Department of Internal Medicine, Central Hospital Lillehammer; 4 Department of Oncology, Regional Hospital Tromse, Norway Summary

Background: Due to the possibility of a synergistic effect between Interferon (IFN-a) and 5-Fluorouracil (5-FU), a phase II trial was conducted in metastatic renal cell carcinoma (MRCC) combining recombinant IFN-a, 5-FU and prednisone. Prednisone has been shown to decrease IFN-arelated toxicity without reducing the response rate. Patients and methods: Thirty-one patients with measurable MRCC were entered into the trial; 16 of them had lung metastases only. In 26 patients (nos. 6-31) the following dose schedule was applied during an 8-week treatment cycle: IFN-a (Roferon*, Roche, Basel, Switzerland): 12 x 106U s.c. 3 times weekly; Days 1-5: 5-FU: 600 mg/mVday continuous i.v. infusion; Weeks 3-8: 5-FU 600 mg/m2 x 1 weekly (bolus i.v.); prednisone: 10 mg x 2 per os daily for 2 weeks, and thereafter 5 mg x 2. In the first 5 patients higher doses of 5-FU led to unacceptable toxicity and subsequent dose alteration of the trial schedule. All 31 patients were

evaluable for response. Seventy treatment cycles were given. Results: One complete and 6 partial responses were observed (response rate: 23%, 95% CI: 10%-41%), with a median response duration of 11 months. Except in one patient, hematologjcal toxicity was confined to grades I and II. Eight patients developed grade III oral mucositis. Adverse cardiac events were observed in 3 patients. Dose modifications of 5-FU were necessary in 16 cycles. The IFN-a doses were transiently reduced during 8 cycles. Conclusion: The assessed combination of IFN-a, 5-FU and prednisone is moderately active in MRCC, with response rates similar to those seen in patients on IFN-a monotherapy. The latter treatment approach seems preferable, as 5-FU-related toxicity (mucositis, cardiac toxicity) is averted. Key words: interferon-a, 5-FU, prednisone, renal cell carcinoma, response rate, adverse effects

Introduction

Patients and methods

Immunotherapy with Interferon-a (IFN-a) and/or Interleukin-2 (IL-2), possibly combined with cytostatic drugs, represents one of the few therapies in metastatic renal cell carcinoma (MRCC) with reproducible response rates of >10% [1-6]. Based on promising results with respect to synergistic effect of the combination of IFN-a + 5-Fluorouracil (5-FU) [8, 9], this combination was also introduced into the treatment of MRCC. This combination seemed of particular interest as floxuridine (FUDR), another pyrimidine analogue in recent phase II studies [10,11], has been shown to have moderate tumour activity in MRCC. Based on this background and our group's previous experience with IFN-a in MRCC with or without lowdose oral prednisone [12, 13], a multicenter phase II study was performed in patients with MRCC, investigating the combination of IFN-a and 5-FU.

Patients From March 1991 to March 1993 31 patients with bidimensionally measurable MRCC were included in a multicenter phase II study which evaluated the response rate and toxicity of the combination of IFN-a (Roferon8, Roche, Basel, Switzerland), 5-FU and prednisone (Table 1). The majority of patients had lung metastases, and 16 had only lung metastases. Thirty patients had not been treated with cytotoxic or hormone agents at trial entry. One patient had received IFN-a + prednisone 3 years before trial inclusion. This treatment had been discontinued after one year when he had achieved a complete response (CR) of lung metastases. One and a half years later he developed recurrent lung metastases and was than included in the present study. Treatment and dose modifications Doses 5-FU 750 mg/mVday was applied as a 5-day continuous intra-

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H. Haarstad,1 A.-B. Jacobsen,2 S. A. Schjolseth,3 T. Risberg4 & S. D. Fossa2

246 Table 1. Patient characteristics. 56" (17-71)" 17/14 26 9(1-118) 30 1 27 1 2 1 21 9 6 4 1 30 (4-140) 12.4 (8.4-15.5) 22 (5-84) 219(125-2181) 106(67-152) 51(15-221)

" Median. b Range. c With measurable soft tissue extension. Table 2. Treatment and dose levels.

Dose level I 4-week cycle 3 patients

Dose level II 4-week cycle 2 patients

Dose level III 8-week cycle 26 patients

IFN-a 1

5-FU'

9 x 10 6 Us.c. x 3 weekly

Day 1-5: 750 mg/m2/day continuous I.V. infusion Week 3 + 4 750 mg/mVday x 1 /weekly i.v. bolus

9 x 106 Us.c. x 3 weekly

6

12 x 10 U s.c. x 3 weekly

Day 1-5: 600 mg/m2/day continuous i.v. infusion Week 3 + 4: 600 mg/mVday x 1 weekly i.v. bolus Day 1-5: 600 mg/mVday continuous i.v. infusion Week 3-8: 600 mg/mVday x 1 weekly i.v. bolus

Dose modifications In instances of grade II leukopenia or grade II thrombocytopenia [14] in the 26 patients receiving dose level III, 5-FU was withheld until complete recovery, whereas the IFN-a injections were continued. After recovery, the daily 5-FU dose was reduced to 400 mg/ m2. In patients with repeated grade II hematological toxicity at this dose, further 5-FU reduction (to 300 mg/m2) was recommended. If more than grade I hematological toxicity occurred in spite of this dose, the patients went off-study. In instances of grade III hematological toxicity 5-FU was to be discontinued until complete recovery, whereas IFN-a injections were to be continued. If no recovery had taken place within 2 weeks after discontinuation of 5-FU, IFN-a was also discontinued. After recovery from grade III hematological toxicity, 5-FU was continued at the daily doses of 400 mg/m2. Diarrhoea and oral mucositis were expected to be the most frequent non-hematological side effects. In patients with grade II or III diarrhoea or mucositis, 5-FU injections were withheld until all symptoms had resolved. Further 5-FU injections were given at a dose of 400 mg/m2. Patients were to receive the above treatment for at least 8 weeks. Responding patients were to be treated for one year or until progression or intolerable toxicity. In patients with progression (PD) after 8 weeks, treatment was discontinued, whereas patients with 'no change' continued treatment for a further 2 months. In these patients treatment was discontinued if no tumour size reduction was observed after a total of 4 months of treatment.

Response Response was evaluated according to the WHO criteria [14] after at least 8 weeks of treatment. In responding patients the maximal response category was recorded.

Toxicily

Toxicity was scored by the WHO recommendations [14] except for flu-like symptoms which were assessed clinically and categorized as follows: 0: none; 1: slight, no dose reduction of IFN-a necessary; 2: moderate, dose reductions of IFN-a necessary; 3: severe, transient LFN-a discontinuation; 4: life-threatening, permanent IFN-a discontinuation.

• In addition all patients received prednisone per os (Week 1 + 2 , 20 mg/day; thereafter 10 mg/day).

Results venous infusion on days 1-5 of a 4-week cycle (dose level I, Table 2), and then as a single weekly intravenous bolus infusion on days 15 and 22. A new 5-day continuous 5-FU injection was started on Day 29. Due to cardiac infarction in the third patient with dose level I, which in the investigators' opinion was related to the 5-FU applications, the daily 5-FU dose was reduced to 600 mg/m2 in patients 4 and 5 (dose level II). The timing of the 5-FU application was the same as described for dose level I. Patient no. 4 developed a lifethreatening enteritis during cycle 2 which led to further reduction of the 5-FU dose in subsequent patients. One cycle of dose level III lasted for 8 weeks, starting with a 5-day 5-FU continuous infusion (600 mg/m2 daily, days 1-5). Single bolus injections of 5-FU (600 mg/m2) were given once per week in weeks 3-8. All patients received IFN-a subcutaneously every Monday, Wednesday and Friday. The single IFN-a doses consisted of 9 x

A total of 70 cycles were given to the 31 patients. Thirteen of the patients received one cycle only, 9 patients had 2 cycles and 4 had 3 cycles. Four cycles or more were given to 5 patients. Six partial responses (PR) and one CR were observed among the 31 evaluable patients, yielding a 23% response rate (95% confidence interval [CI]: 10%41%). The patient who had previously been treated with EFN-a had an ongoing (8+ months) CR. Partial responses were seen in lymph node metastases (1) and lung metastases (5) and lasted for 4, 10, 11, 11+, 12+ and 13 months, respectively. In 11 patients the best

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Age (years) Males/females Nephrectomy Interval from diagnosis to treatment start (months) Performance status (WHO) 0/1 2 Weight loss 0 <5% 5-10% >10% Site of indicator metastases Lung Lymph nodes Liver Locoregional Bonec Sedimentation rate (1 hour, mm) Hemoglobin (g%) ALAT (U/l) Alkaline phosphatase (U/l) Creatinine (umol/1) GT(U/1)

106U for dose levels I and II and 12 x 106 for dose level III (Table 2). During the first 2 weeks the patients were treated with oral prednisone 10 mg x 2 daily. Thereafter, the daily dose was reduced to 5 mg twice daily. This dose was continued during the entire treatment period.

247

with Mitomycin and 5-FU (35%, 95% CI: 22%-49%), or that recorded by Atzpodien et al. [16] using 5-FU, WHO grade IFN-a and IL-2 (response rate: 46%, 95% CI: 29%63%). II 0 I ni rv As described for other types of immunotherapy [5], a) Maximal hematological toxicity per cycle responses were predominantly seen in patients who (69 evaluable cycles) presented with lung and lymph node metastases. This Number of cycles accords with the suggestion put forward by Dillmann et al [17], that selection of patients entered into clinical _ 6 16 Leukopenia 47 studies is probably more important for the final reThrombocytopenia 59 6 2 1 1 sponse rate to different immunotherapeutic regimens b) Maximal non-hematological toxicity per cycle than alteration of dose, time schedules, etc. (69 evaluable cycles) Except in 3 patients our treatment schedule with Number of cycles IFN-a, 5-FU and prednisone was generally tolerable, 6 22 2 Flu-like symptoms 39 and dose modifications were necessary in only 20% of Nausea/vomiting 62 4 1 2 the cycles. The 5-FU related oral mucositis, however, Alopecia 64 3 2 (even though most often not life-threatening) repreDiarrhoea 62 6 1 sented a major concern for the patients. Peripheral neurotoxicity 68 1 Oral mucositis 54 6 — 8 1 Adverse cardiac events were observed in 3 patients with pretrial histories of cardiac disorder. IFN-a theraOther Mental depression (1); Lnfarcrus cordis (1): Dermatitis, py and, in particular, high-dose 5-FU treatment may hands/feet syndrome (1) Thrombosis (1); Psoriasis (1); Angina pecyield cardiotoxicity [18]. At the present time we would toris (2); Weight loss > 10%/3 months (1): Metallic taste (1). recommend particular awareness of the risk of cardiotoxicity in patients with a slight degree of coronary response was 'no change' and 13 patients progressed artery disease for whom IFN-a therapy or high-dose during the study. 5-FU treatment is considered. Immunotherapy of MRCC is palliative in the majoriToxicity ty of patients. Though long-lasting complete responses have been obtained with IFN-a, IL-2 and the combinaSixty-nine cycles in 30 patients were evaluable for tox- tion of these drugs, this approach's role as life-prolongicity (Table 3). On dose level II patient no. 4 developed ing treatment has not been determined in phase HI multiple life-threatening side effects (grade IV diar- trials. Based on Dillman et al's report [17] and a recent rhoea, mucositis, thrombocytopenia). Grade HI throm- European overview [19] it might also appear that the bocytopenia was observed in one patient on dose level efficacy of IFN-a or IFN-a combinations is similar to HI during the 1st cycle. Patient no. 4 (dose level II) that of IL-2 or IL-2 combinations. However, there are as developed grade IV thrombocytopenia during the 2nd yet no results from major randomized trials comparing cycle. Grade HI mucositis was encountered during 8 the efficacy of IFN-a with IL-2 or their combination. cycles of dose level ETI. Severe mental depression in one In particular, there might exist subgroups of MRCC patient and more than 10% weight loss in another patients in whom higher response rates to one of the caused premature treatment discontinuation in these 2 drugs (or drug combinations) translates into improved partially responding patients. Two patients experienced survival. When comparing the present combination an increased frequency of attacks of retrosternal pain with our overall experience of IFN-a therapy [12] and during the end of their first 5-FU infusions (dose level the published observations [17, 19, 20], we currently HI). A third patient developed a cardiac infarction 2 feel that IFN-a immunotherapy is a reasonable theraweeks after her second 5-FU infusion (dose level I). peutic option for the routine treatment of MRCC if sysDose modifications of 5-FU were necessary in 16 temic therapy is to be given in an individual patients. cycles. The EFN-a dose was transiently reduced during We recommend that patients with MRCC be entered 8 cycles. No clear tendency towards LFN tachyphylaxis into clinical trials evaluating new immunotherapeutic was observed. approaches with, for instance, different types of Interleukins. If this is not possible, IFN-a monotherapy may be regarded as one of several 'standard treatments' in selected patients in whom systemic therapy has to be Discussion started outside a clinical trial. Our response rate of 23% is comparable to response rates obtained with IFN-a monotherapy [1, 12, 13] (with or without prednisone), IL-2 regimens and with References combination immunotherapy [1-3]. The response rate 1. StahJ M, Wilke H-J, Seeber S et al. Cytokines and cytotoxic achieved in the present study is, however, lower than agents in renal cell carcinoma: A review. Semin Oncol 1992; the one reported by Sella et al. [15] combining IFN-a 19:70-9. Table 3. Toxicity.

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