CANCER BIOTHERAPYVolume 10, Number 1, 1995Mary Ann Liebert, Inc., Publishers

Interferon-or/5-Fluorouracil: A Novel OutpatientChemo/immunotherapy for Progressive MetastaticRenal Cell Carcinoma

Enrique Lopez Hanninen, Hubert Poliwoda, and Jens AtzpodienDivision of Hematology & Oncology, MHH Univ Medical Center, D-30623 Hannover, Germany

In metastatic renal cell carcinoma, most conventional antineoplastic drugs have yielded no or littleefficacy. To evaluate the tolerance and therapeutic efficacy of second line chemo/immunothérapies, wetreated patients with advanced metastatic renal cell carcinoma upon progression after previousantineoplastic therapy employing an outpatient combination ofsubcutaneous (SC) recombinant interferon-a (rIFN-a) and intravenous (TV) 5-fluorouracil(5-FU).

Thirty-three patients with metastatic renal cell carcinoma received SC doses thrice weekly of rIFN-aat 10 million U/m2 over 8 consecutive weeks. Additionally, patients received TV 5-FU at 750 mg/m2 inweeks 1-3 and 5-7; treatment cycles were repeated until disease progression.

Of 33 patients, one achieved a complete remission (response duration, 24 months) and two patientspresented with partial remissions (median response duration, 7 months) ofpulmonary métastases uponrIFN-a/5-FU after failing SC recombinant interleukin-2 (rIL-2) and rIFN-a. The presentchemo/immunotherapy regimen was overall well tolerated with low to moderate systemic toxicity andpredominantly constitutional symptoms i.e., fever, chills, and malaise.

In summary, the second line outpatient chemo/immunotherapy regimen of SC rlFN-a/TV 5-FUdemonstrated a limited albeit significant efficacy in pretreated patients with progressive metastatic renalcell cancer.

Key words: interferon-a, 5-fluorouracil, renal cell carcinoma

INTRODUCTION malignancy remains a therapeutic challenge.Previous strategies included the use of hormonal

Since metastatic renal cell carcinoma is resistant and cytostatic drugs, whereby overall responseto most antineoplastic agents, treatment of this rates were poor at below 10% for single agent

regimens1"5.More recently, recombinant interferon-a2

(rIFN-a) and interleukin-2 combinations with orAddress reprint requests to Dr. Jens Atzpodien, Abt. without conventional therapy demonstratediamatologie und Onkologie (6860), Medizinische promising efficacy in the treatment of metastaticHochschule Hannover, D-30623 Hannover, Germany r ¡=> j

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Table 1. Interferon-oc/5-FU in Metastatic Renal Cell Cancer:Patient Characteristics

Evaluable patients

SexMaleFemale

AgeMedianRange

PretreatmentTumor nephrectomyChemotherapyRadiotherapyHormonal therapyImmunotherapy

33

267

5943-72

3239524

renal cell carcinoma; among chemotherapeuticagents, vinblastine in combination with rIFN-ahas shown response rates up to 40% inmetastatic renal cell carcinoma patients. Inpreclinical studies, however, also thecombination of 5-FU and rIFN-a yielded an

enhanced antineoplastic activity12,13.In this study, we report the results of SC

rIFN-a in combination with IV 5-FU in a totalof thirty-three patients with advanced metastaticrenal cell carcinoma receiving second linechemo/immunotherapy upon progression afterprevious antineoplastic therapy.

PATIENTS AND METHODS

Thirty-three outpatients with metastatic renal cellcarcinoma (26 male; 7 female; median age of 59years; range, 43-72 years) were treated with a

combination of SC rIFN-a2 and IV bolus 5-FUupon progression after previous antineoplastictherapy. Pretreatment included chemotherapy(n=3), hormonal therapy (n=5) andimmunotherapy (rIL-2/rIFN-a, n=24). Table 1gives the patient characteristics for this study.

Treatment courses consisted of subcutaneous

doses thrice weekly of recombinant IFN-a2 at 10million U/m2 over 8 consecutive weeks.Additionally, patients received IV 5-FU at 750mg/m2 in weeks 1-3 and 5-7. For statisticalanalysis, Wilcoxon tests and paired t- tests were

used wherever applicable.

RESULTS

Table 2 gives the sites of disease and response totreatment in this study. Of 33 patients receivingSC rIFN-a and IV bolus 5-FU, one patientachieved a complete response for 24 months andtwo patients had a partial response in their lungs(median response duration, 7 months) with an

overall response rate of 9% (95% confidenceinterval, 2%-24%). In addition, twenty-twopatients (70%) achieved disease stabilization(median duration, 7 months).

The combination chemo/immunotherapy usedin this study was overall well tolerated with lowto moderate systemic toxicity (Table 3). Themost frequent side effects were World HealthOrganization (WHO) grade 1 or 2 flu-likesymptoms (96%), nausea/vomiting (64%), anddiarrhea (38%). WHO grade 3 fever/chills and

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Table 2. Interferon-a/5-FU in Metastatic Renal Cell Cancer: Results

Tumor site3 CR PR SD PD Total

LungLiver

Lymph nodes

Bone

Local relapseOther

Total(3%)

2(6%)

19

5

13

4

4

5b

23(70%)

6

2

3

1

2

7(21%)

28

7

16

5

6

5

33

Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.a Patients may have had more than one site.b Adrenal gland (n=3), thyroid gland (n=l), heart (n=l).

Table 3. Interferon-a/5-FU in Metastatic Renal Cell Cancer: Systemic toxictiy a

Side Effecta

WHO

Percent of Treatment Cycles

Grade 1 Grade 2 Grade 3 Grade 4

Fever

ChillsMalaise

Anorexia

Nausea/VomitingDiarrheaStomatitis

Hypotension

4

36

44

30

37

30

32

20

68

16

18

22

26

8

16

2

Toxicity grades based on World Health Organization (WHO) criteria.

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malaise occurred in 2% and 4% of treatmentcycles, respectively, and led to a 50% dosereduction; grade 3 diarrhea occurred in 2% oftreatment cycles and resolved spontaneously.Stomatitis was found in 48% of treatment cyclesand was always limited to WHO grade 1 and 2.In all patients, treatment induced systemictoxicity resolved within two weeks aftercessation of therapy. None of the patientsrequired inpatient care for treatment-relatedadverse effects, and no toxic deaths occurred.

DISCUSSION

In advanced metastatic renal cell carcinoma, as

yet, no standard conventional therapy isavailable. While recombinant IFN- has an

overall response rate of approximately 16%,chemotherapy regimens employing concomitantvinblastine yielded significantly higher responserates8"11. Additionally, in preclinical models an

enhanced antineoplastic activity has beendemonstrated for the combination of 5-FU andrecombinant cytokines12,13.

To evaluate the role of a second lineoutpatient chemo/immunotherapy with 5-FU andrIFN-a in advanced metastatic renal cellcarcinoma, we treated a total of 33 patients whohad progressed upon previous antineoplastictherapy. Objective response rate was 9%, withremissions occurring in pulmonary métastases,only.

Overall treatment related systemic toxicitywas low to moderate and toxicity profiles did notvary significantly from rIFN-a/chemotherapytreated patients reported elsewhere8"11. Notably,IV 5-FU at the doses employed here did notproduce severe diarrhea or stomatitis.

In summary, a second linechemo/immunotherapy regimen employingsubcutaneous recombinant interferon-a incombination with intravenous 5-FU demonstratedlimited albeit significant therapeutic efficacy inprogressive metastatic renal cell cancer patientswho had failed previous SC rIFN-a/rIL-2outpatient therapy.

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