564

Alpha-2B-Interferon Plus Floxuridine in Metastatic Renal Cell Carcinoma

A Phase 1-11 Study

Alfredo Falcone, M.D., Claudia Cianci, M.D., Sergio Ricci, M.D., lsa Brunetti, M.D., Maurizio Bertuccelli, M.D., and Pier Franco Conte, M.D.

Background. Both alpha-interferon and floxuridine are active in metastatic renal cell carcinoma (MRCC); the two agents have demonstrated antitumor synergism and different clinical toxicities. The purpose of this study was to determine the maximum tolerable dose (MTD) of floxuridine (FUDR), administered as a constant continu- ous infusion for 14 days every 28 days, in combination with fixed doses of alpha-2B-interferon and to prelimi- narily evaluate the antitumor activity of this combina- tion.

Methods. Sixteen patients entered the study; six had previously received alpha-interferon. Alpha-2B-inter- feron was administered at the dose of 10 x 10' IU intra- muscularly 3 times/week and floxuridine at the starting daily dose of 0.075 mg/kg. This dose was escalated at each subsequent cycle up to dose-limiting toxicity.

Results. Most common toxicities included fever and flue-like symptoms, fatigue, anorexia, diarrhea, mucosi- tis, and nausea, and 55% of patients experienced greater than or equal to Grade 2 toxicity, mostly diarrhea, for floxuridine doses greater than 0.125 mg/kg/d. Among 15 evaluable patients, 1 achieved a complete response and 4 achieved a partial one (33%; 95% confidence interval, 12- 62%). Three partial responses were obtained in patients pretreated with alpha-interferon plus vinblastine.

Conclusions. The combination of alpha-2B-inter- feron and floxuridine is feasible, and in our regimen the recommended daily dose of floxuridine for Phase I1 stud- ies was 0.125 mg/kg. This combination is active in meta- static renal carcinoma, but further studies are needed to determine whether alpha-2B-interferon has added any- thing to the FUDR infusion or vice versa. Cancer 1993; 72~564-8.

From the Division of Medical Oncology, S. Chiara Hospital,

The authors thank Dr. Jeffrey W. Clark, Brown University, Pro-

Address for reprints: Alfredo Falcone, M.D., U.O. Oncologia

Accepted for publication March 5, 1993.

Pisa, Italy.

vidence, Rhode Island, for helpful suggestions.

Medica, Ospedale, S. Chiara, via Roma 67, 56100 Pisa, Italy.

Key words: renal cancer, alpha-interferon, FUDR, combi- nation therapy.

Renal cell carcinoma is a relatively common cancer, and there is no satisfactory therapy for patients who have metastatic disease. Conventional chemotherapy and hormone therapy have little benefit.' Several immuno- logic approaches have been tested including interferons (IFN), interleukin-2 (IL-2) with or without lymphokine- activated killer (LAK) cells, autolymphocyte therapy (ALT) coumarin plus cimetidine, Bacillus-Calmette Guhrin (BCG), and others, but the best results have been obtained with alpha-IFN, IL-2, and ALT.'j3 In par- ticular, ALT has been shown to prolong survival with mild adverse reaction^.^ Many combinations have been also evaluated, but so far standard therapy is repre- sented by alpha-IFN alone at "intermediate" doses that achieve a 15-20% response rate.4-7 Some interest has been recently raised by the use of 5-fluoro-2-deoxyuri- dine (FUDR) administered as continuous or circadian shaped infusion.'-'' In particular, chronopharmaco- logic infusion of FUDR has allowed to rise significantly maximum tolerable dose (MTD) from 0.125-0.150 to 0.225-250 rng/kg/d,'z9 and if dose-intensity is at all important this strategy may improve outcome. Re- sponse rates with FUDR infusion have ranged from 15- 50%, and activity has been reported also in patients pretreated with IFN.8-'o Furthermore, experimental and more recent clinical studies have shown synergism be- tween fluoropyrimidines and IFN."-18 Because of these findings and the different clinical dose-limiting toxici- ties between FUDR and IFN, we have conducted a Phase 1-11 study in patients with metastatic renal cell carcinoma (MRCC) to determine the MTD of FUDR, which can be administered as a 14-days continuous in- fusion every 28 in combination with fixed therapeutic doses of alpha-2B-IFN and to preliminarily evaluate the

Interferon Plus Floxuridine/Falcone et al . 565

antitumor activity of this combination. An initial report of these results has been previously published.’’

tinued for a maximum of 12 months or until progressive disease.

Patients and Methods

Patients

Sixteen patients entered the study. Eligibility criteria in- cluded histologically confirmed diagnosis of renal cell carcinoma with recurrent or metastatic disease, Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2, life expectancy greater than 3 months, measurable or evaluable disease, ade- quate renal (serum creatinine less than or equal to 3.0 mg/dl), hepatic (serum bilirubin less than 1.5 mg/dl and transaminase less than 2.5 times normal values), and bone marrow (leukocyte count greater than 3500 mm3 and platelets greater than or equal to 100,000 mm3) functions. Patients with a history of other malig- nant tumors except for in situ carcinoma of the cervix or nonmelanoma skin cancer, symptomatic cardiac dis- ease, major surgery or infections within 4 weeks of study entry, and cerebral metastases were excluded. All patients gave an informed oral consent.

Treatment

Recombinant alpha-2B-IFN (Intron-A, Schering- Plough) was administered intramuscularly 10 X lo6 IU 3 times a week. Treatment was temporarily interrupted and doses were subsequently reduced to 5 X lo6 IU (and if not tolerated to 3 X lo6 IU) if intolerable IFN-re- lated toxicity had occurred. To improve IFN tolerability, most patients received concomitant therapy with acet- aminophen and prednisolone (8 mg/d), which has been shown to improve subjective tolerability of IFN without decreasing effi~acy.’~*’~ FUDR was adminis- tered through an implantable central venous catheter and external volumetric pump (CADP-1; Pharmacia) as a continuous 14-day constant infusion starting from day 1 of IFN therapy and repeated every 28 days. Start- ing FUDR dose was 0.075 mg/kg/d. Dose was esca- lated at each subsequent cycle of 0.025 mg/kg/d up to FUDR-related World Health Organization (WHO) toxic- ity greater than or equal to Grade 2 had occurred. After recovery from toxicity, FUDR therapy was resumed and continued at the dose immediately before the one that had caused the greater than or equal to Grade 2 toxicity. This was considered the MTD for the patient. The rec- ommended starting FUDR dose for Phase I1 studies was defined the maximum administerable dose of FUDR that did not cause greater than or equal to Grade 2 toxic- ity in more than 30% of patients. Treatment was con-

Assessability, Toxicity and Response Criteria

Pretreatment evaluation included history and physical examination, performance status assessment, complete blood cell (CBC) with differential and platelets count, complete blood profile, urine analysis, electrocardio- gram, chest radiograph, abdominal sonogram, or CT scan and any other appropriate examination to evaluate metastatic sites. A physical examination with CBC, blood profile, and urine analysis were performed every 2 weeks, and sites of metastatic disease were evaluated every 8 weeks. A chest radiograph and/or an abdomi- nal sonogram were repeated every 6 months if there was no evidence of pulmonary or abdominal disease, respectively. Toxicity and responses were scored ac- cording to standard WHO criteria.” In particular, a complete response was defined as the complete disap- pearance of all known disease for at least 8 weeks; a partial response, a 50% or greater decrease in total tu- mor size for at least 8 weeks; a minor response, a 25- 50% decrease in total tumor size; stable disease, when neither a 25% decrease or a 25% increase in total tumor size had been demonstrated for at least 4 months; and progressive disease, the appearance of any new lesion not previously identified or a 25% or greater increase of one or more existent lesions. Duration of response was calculated as follows: the complete response from the date the complete response was first recorded to the date the progressive disease was first noted, the partial response from the first day of treatment to the date of first observation of progressive disease.

Results

Patients

A total of 16 patients entered the study, and 97 cycles of FUDR were administered (median, 6 cycles per patient). As shown in Table 1, where patients’ characteristics are listed, 11 patients were pretreated and of these, six with IFN.

Toxicity

Fifteen patients were evaluable for toxicity; one patient with an initial performance status (PS) of 2 and diffuse abdominal disease was not evaluable because he died 24 days after starting the treatment for hemorrhage, probably related to disease progression. All evaluable patients experienced flue-like symptoms especially during the initial period of therapy. Others toxicities

566 CANCER July 15, 2993, Volume 72, No. 2

Table 1. Patient Characteristics

Characteristic

No. of patients 16

Median 62 Age (yr)

Range 34-77 Sex

ECOG performance status F/M 5/11

Median 1 Range 0/2

Prior therapy 11 Multiple pretreatment 4 Hormonotherapy 5

Radiation therapy 2

Lung/pleura 11

Prior nephrectomy 15

Alpha-interferon 6

Vinblastine 4 Site of disease

Bone 6 Retroperitoneum 6 Liver 1 Soft tissue 1 Mediastinum 1 Peritoneum 1

Median 8.5 Time from diagnosis to metastases (mo)

Range 0-107

Median 2 Range 1-37

Time from metastases to study entry (mo)

ECOG: Eastern Cooperative Oncology Group.

included fatigue and anorexia, which required IFN dose reductions in seven patients, diarrhea, mucositis, nau- sea and vomiting, leukopenia, and transaminase eleva- tion (Table 2). All patients escalated initial FUDR doses,

Table 2. Overall Toxicity

WHO grade

Adverse event 0 1 2 3 4

Diarrhea Nausea/vomiting Stoma titis Fatigue* Anorexia* Transarninase elevation Leukopenia Thrombocvtouenia

4 5 4 2 0 5 4 4 1 1 7 6 2 0 0 5 4 2 4 0 8 3 1 3 0

14 0 1 0 0 10 4 1 0 0 14 1 0 0 0

WHO: World Health Organization. * Grade 1. mild; made 2. moderate; made 3. severe.

Table 3. Maximum Tolerable Dose of Floxuridine

Dose* patients (mg/kg/day) (n = 9) Vomiting Diarrhea Stomatitis

0.200 1 1 0.175 3 1 2 1 0.150 3 1 2 0 125 2 2 2 1

Toxicity 2 grade 2 No. of

- -

-

~~

* Maximum tolerable dose was defined as the dose 0.025 mg/kg/day lower the dose that caused 2 grade 2 toxicity.

and MTD could be determined in nine. In seven pa- tients, MTD could not be determined because FUDR therapy was interrupted or IFN dose was reduced be- fore they had experienced FUDR-related greater than or equal to Grade 2 toxicity. FUDR MTD ranged from 0.1-0.175 mg/kg/d, and 55% of patients experienced greater than or equal to Grade 2 toxicity, mostly diar- rhea, for doses greater than 0.125 mg/kg/d (Table 3).

Responses

Fifteen patients were evaluable for response (one pa- tient died 24 days after starting therapy and was consid- ered a treatment failure; and one patient was not evalu- able because during the second cycle, she had a trau- matic fracture of her femur, was hospitalized in an orthopedic division, and was lost to follow-up after re- covery). Of the 15 evaluable patients, 1 achieved a complete response and 4 achieved a partial response, for an objective response rate of 33% (95% confidence interval, 12-62%). The complete response was ob- tained in a male with lung and pleural metastases and lasted 9 months. That patient relapsed 3.5 months after the interruption of FUDR therapy (which was adminis- tered for 1 year) while on IFN therapy; FUDR was re- started and he experienced again a partial response. The four partial responses occurred in the lung (two), pleura and mediastinal nodes (one), and retroperitoneal nodes (one) and lasted 5.5, 13.0, 8.5, and 7+ months, respectively. Three of these partial responses occurred in patients pretreated with IFN plus vinblastine. Me- dian time to response was 3 months (range, 1.5-5), and responses were obtained at FUDR doses ranging from 0.075-0.175 mg/kg/d and at IFN doses between 5-10 X lo6 IU. One patient achieved a minor response (retro- peritoneum), six had a stable disease for at least 4 months, and three progressed.

Progression-Free and Overall Survival

Time to progression and survival distributions from the first day of therapy were estimated by the Kaplan-

Interferon Plus FloxuridinelFulcone e t ul. 567

Meier method and are shown in Figures 1 and 2. The median time to progression was 8.5 months, and the median survival time was 16.5 months.

Discussion

Metastatic renal carcinoma is considered a chemoresis- tant tumor. Alpha-IFN represents the most widely used single agent, and response rates of approximately 15- 20% are reported with some long-lasting complete re- sponse. There are some indications for a dose-response relationship, and doses of approximately 10 X lo6 IU given on alternate days are effective and may have the best therapeutic index. Patients in good performance status and limited metastatic disease in the lung have the major benefit from this treatment.'-7 Low-dose corti- costeroids do not seem to affect IFN activity, although they may improve subjective tolerability.21,22 Indeed, 13 of our patients received 8 mg/d of methylprednisolone and only three required IFN dose reductions during the first 2 months of therapy. FUDR has recently also shown activity in MRCC. FUDR has been more fre- quently used according to the principles of chronoinfu- sion developed by Hrushesky to decrease toxicity and to allow dose escalation^^^^^^^; similar activity has been reported also by constant rate FUDR infusion." Several experimental studies have demonstrated synergistic antitumor activity between fluoropyrimidines and al- pha-IFN. Some biochemical effects of IFN could ex- plain the observed synergism like a reduced thymidine kinase (TK) activity, a reduced thymidyne transport into the cell or a decreased thymidilate synthetase (TS) activity."-15 All these effects will lead to a more pro- found depletion of thymidine triphosphate pools in- duced by 5-fluorodeoxyuridine-monophosphate (5- FdUMP), the most important active metabolite of 5-flu- orouracil (5-FU) and FUDR. In particular for FUDR,

100

20 4 o f I 1 I

0 6 1 2 1 8

months Figure 1. Actuarial progression-free survival curve

100

80 - u7 c

60 .- c m Q

Entered Died \ 1 6 6

Entered Died 1 6 6

i 0

0 6 12 18 months

Figure 2. Actuarial overall survival curve.

which is directly activated to 5-FdUMP, these biochemi- cal effects may be particularly important to enhance its antitumor activity. Recent clinical studies in metastatic colorectal cancer have also shown significant antitumor activity with the combination of 5-FU and alpha- IFN.'6-'s Therefore, the rationale for this study was that alpha-IFN and FUDR are active single agents in MRCC and have demonstrated synergism and different dose- limiting clinical toxicities. The results of this study dem- onstrate the following:

1. The combination of alpha-IFN administered at the dose of 10 X lo6 IU intramuscularly 3 times/week with FUDR administered as constant intravenous continuous infusion for 14 days every 28 days is feasible with acceptable toxicities.

2. The recommended initial daily dose of FUDR in this combination for Phase I1 studies is 0.125 mg/ kg. This dosage can be safely administered in most patients for several months, and in some patients dose can be further escalated if toxicity (mostly diar- rhea and mucositis) is not seen.

3. Although the main purpose of this study was not to determine the antitumor activity of FUDR plus al- pha-2B-IFN, this combination has shown activity in MRCC. Whether IFN has added anything to the FUDR infusion or vice versa cannot be determined from this study.

Because of these findings, we are now conducting a larger multicentric Phase I1 study in MRCC with this combination to better evaluate its antitumor activity.

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