A multi-institutional phase II trial of a novel inpatient schedule of continuous interleukin-2 with interferon {alpha}-2b in advanced renal cell carcinoma: major durable responses in a less highly selected patient population

J. I. Clark1,2,+, T. M. Kuzel3, T. M. Lestingi4, S. G. Fisher2, P. Sorokin5, B. Martone3, M. Viola4 and J. A. Sosman5

1Edward Hines Jr VA Hospital, Hines, IL; 2Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL; 3Northwestern University Medical School, Chicago, IL; 4Lutheran General Hospital, Park Ridge, IL; 5University of Illinois at Chicago, IL, USA

Received 27 June 2001; revised 19 September 2001; accepted 23 October 2001.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background

A prospective multi-institutional phase II trial was undertaken to define the activity and toxicity of a unique decrescendo infusion of interleukin-2 (IL-2) in combination with interferon (IFN) in patients with metastatic renal cell carcinoma. The identical regimen has shown promise in advanced melanoma.

Patients and methods

Between February 1997 and March 1999, 47 patients with metastatic renal cell carcinoma, from five institutions, were treated with outpatient s.c. IFN (10 mU/m2/day) on days 1–5, followed by inpatient IL-2 via continuous i.v. decrescendo infusion [18 million International Units (MIU) (1 mg)/m2/6 h, followed by 18 MIU/m2/12 h, then 18 MIU/m2/24 h and 4.5 MIU/m2/24 h for the following 3 days] on days 8–12, in a hospital ward without intensive care unit (ICU)-type monitoring. Treatment was repeated every 4 weeks. In contrast to high dose IL-2 protocols, patient eligibility did not require pulmonary function tests and allowed serum creatinine up to 2 mg/dl.

Results

Among 44 eligible patients, 57% (25) had their primary in place, 57% (25) had bone or visceral involvement, and only 4% (2) had lung as their only site of disease. The overall response rate in 43 response-evaluable patients was 16.3% [95% confidence interval (CI) 5.3 to 27.3], with three complete responses and four partial responses observed. The median survival was 13 months; nine patients remain alive at >23 months. The median duration of response is 36 months (range 11.5 to 48+ months). Toxicity was modest, consisting of typical cytokine-induced systemic symptoms and rare organ dysfunction. Severe grade 4 toxicity occurred in only 13% of the 130 cycles.

Conclusions

This unique, reasonably well tolerated IL-2/IFN combination induced a modest response rate with a number of durable remissions. While the optimal IL-2-based regimen for the treatment of advanced renal cell carcinoma remains elusive, the present regimen should attract considerable interest. This is based on tumor activity very similar to high dose IL-2 in a patient population not as carefully selected for optimal organ function.

Key words: decrescendo IL-2, interferon, kidney cancer, phase II


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
As the tenth leading cause of cancer death in the United States, renal cell carcinoma (RCC) was responsible for ~12 000 deaths in the year 2000 [1]. Surgery remains the most definitive curative treatment for this disease. The median survival in patients with disseminated or unresectable disease can be measured in months, and may not have improved over a number of years for the majority of patients. The only FDA-approved systemic treatment for advanced RCC is high-dose bolus IL-2.

High-dose bolus IL-2 has been shown to produce partial and complete responses in a minority of excellent-performance status metastatic RCC patients with pristine organ function [27]. As a single agent, doses of IL-2, as originally described by Rosenberg et al., ranging from 600 000 to 720 000 IU/kg every 8 h given as i.v. bolus therapy have consistently yielded overall response rates of 17–27% [25]. A substantial number of these responses are complete, and durable remissions lasting beyond 5 years are well documented [2, 5, 8]. Unfortunately, high-dose IL-2 is associated with significant toxicity and, generally, only patients with an excellent performance status who lack cardiac or pulmonary disease can tolerate such therapy [9, 10]. The search for more tolerable regimens of IL-2 alone or in combination with other agents has therefore been undertaken.

Various treatment schedules of lower dose IL-2 have been, or are being tested [1113]. Although generally better tolerated, it remains to be proven whether comparable response rates using these lower dose schedules will produce durable remissions as described with high-dose bolus IL-2. On the basis of evidence of synergistic antitumor activity in pre-clinical models [1418], a number of clinical studies have been conducted combining a variety of doses and schedules of IL-2 with interferon-{alpha}, the two most active cytokines in advanced RCC [1924]. Additional phase II and a phase III study of this combination with prolonged follow-up have yielded response rates similar to those observed with high-dose IL-2 [2528].

Alternative approaches to dose and schedule of these agents aimed toward reduction of toxicity of high-dose IL-2 may be important in improving the durability of responses and allow for less acute toxicity, which requires extensive expertise to manage. One such regimen developed by Keilholz and co-workers has been reported in the treatment of metastatic malignant melanoma [29]. Keilholz et al. reported an overall response rate of 41%, with three of 27 patients achieving a complete response, using a novel decrescendo schedule of continuous infusion i.v. IL-2 in combination with a standard s.c. IFN dose. A key finding in this report was that toxicity was significantly reduced when compared with a sequential phase II trial at their institution using the same IFN dose and schedule combined with continuous infusion high-dose IL-2 [29]. The schedule and doses have also become the basis for nu-merous trials conducted by the European Organization for Research and Treatment of Cancer (EORTC) and others in combination with chemotherapy for advanced melanoma. Given these promising data, we felt that this novel combination and schedule deserved investigation in the treatment of advanced RCC. The objectives of this study were to better characterize the antitumor efficacy of this regimen/schedule in terms of overall response rate and durability of these responses, and to further define toxicity.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient selection
Between February 1997 and March 1999 47 patients were enrolled onto this phase II multi-institutional trial. All patients gave informed consent. Eligibility requirements included the following: histological confirmation of metastatic or advanced-unresectable RCC, bidimensionally measurable or evaluable disease, Southwest Oncology Group (SWOG) performance status (PS) of 0 or 1, age of 18 years or older, no evidence of active brain metastases, adequate organ function including an absolute neutrophil count of >=1500/µl, platelet count >=100 000/µl and hemoglobin >=8.0 g/dl, serum creatinine level <2.0 mg/dl or calculated creatinine clearance of >=50 ml/min, serum bilirubin <2.0 mg/dl and AST/ALT less than four times the institutional upper limit of normal. Patients were excluded if they had received prior immunotherapy with IL-2 or IFN for their kidney cancer, if they had active cardiac disease, significant dyspnea at rest, or an active infection requiring i.v. antibiotics. Women who were pregnant or lactating were also ineligible.

Each patient was evaluated before initiation of treatment. A history and physical examination were obtained, as were appropriate laboratories and radiographic imaging of measurable or evaluable disease. Patients with a prior history suggestive of heart disease were required to undergo cardiac evaluation with an exercise treadmill stress test. This stress test was required to be negative for ischemia in order for patients to be eligible. Patients with a prior myocardial infarction were ineligible. Pulmonary function testing was not required.

Treatment plan
Recombinant human IFN{alpha}-2b (intron-A) was reconstituted with saline immediately prior to s.c. injection. Recombinant human IL-2 (proleukin) was reconstituted in sterile water prior in preparation for i.v. infusion.

All patients were instructed on self-administration of IFN with the initial injection. IFN{alpha}-2b was given as a single daily s.c. injection, usually in the afternoon or evening, at a dose of 10 000 000 U/m2 body surface area on days 1–5 of each 28-day cycle (Table 1). After 2 days off therapy, patients were admitted to the oncology inpatient floor to receive IL-2 by continuous decrescendo i.v. infusion. The IL-2 infusion began on day 8 of each cycle at a dose of 18 MIU (1 mg)/m2/6 h; the rate was then reduced in a stepwise fashion to 18 MIU/m2/12 h, then 18 MIU/m2/24 h, then 4.5 MIU/m2/24 h for three consecutive days. The total IL-2 dose to be administered was therefore 67.5 MIU/m2. Patients received appropriate supportive medications during IL-2 infusion in order to abrogate IL-2 toxicity. Corticosteroids were not to be administered during protocol treatment, unless life-threatening symptoms developed.


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Table 1. Treatment schedule
 
Treatment was continued until progression of disease, complete response or development of significant toxicity occurred. Dose modifications during therapy were determined based on toxicities experienced. IFN treatment was held for grade 3 toxicities or a decline in performance status to 3 or greater. Treatment was resumed at full dose after toxicity improved to grade 1 or better and performance status improved to baseline or within one level of baseline if the performance status was initially 0. If doses of IFN were held for 1 week or more in order for toxicities to resolve, the 5-day course was then completed at that time at 75% dose. Subsequent courses were initiated with the reduced IFN dose. Further toxicities required a 50% dose (from the initial dose). A third toxicity to IFN or any grade 4 toxicity associated with IFN required removal from study treatment. The IL-2 infusion was discontinued and resumed at the pre-vious rate but at 75% dose when the following toxicities developed and subsequently resolved: (i) refractory hypotension unresponsive to bolus i.v. fluid and low dose dopamine; (ii) oliguria, defined as <200 cc/24 h, unresponsive to fluid replacement and diuretics; (iii) respiratory distress when further diuretics and vasopressor could not be tolerated, or when blood pressure maintenance depended on the continued administration of fluids; and (iv) confusion. For other grade 3 toxicities, therapy with IL-2 was discontinued and resumed at the previous dose and rate upon improvement of toxicity to a level of <2. The decrescendo infusion of IL-2 may have been held for up to 48 h. If toxicities were still unresolved after 48 h, the course was terminated. Future courses may still have been administered but at lower initial doses.

Patients were monitored daily during IL-2 infusion, and weekly during non-IL-2 treatment weeks with laboratory work including complete blood cell count with differential and serum chemistry analysis. Patients underwent history and physical examination every 4 weeks during therapy. All patients had reassessment of measurable/evaluable disease performed every 8 weeks until maximum response, and every 2 months thereafter until disease progression. All patients were to be followed until death.

Response assessment
Standard response criteria were used. Complete response (CR) was defined as the complete absence of all clinical evidence of malignant disease for at least two determinations, 4 weeks apart. Partial response (PR) required >50% decrease in the sum of the products of the perpendicular diameters of all measurable lesions for at least two measurements, at least 4 weeks apart. Minor response (MR) was <50% but >25% reduction but was in fact considered stable disease. Stable disease was defined as including MR, no change, or <25% increase in disease and no new disease. Progressive disease was defined as >25% increase in the sum of the products of perpendicular diameters of all lesions, or the appearance of any new lesion. Response duration was measured from the date of PR or CR, and survival was measured from the date of entry into the study.

Statistical considerations
The primary objective of this multi-institutional Phase II study was to evaluate the antitumor efficacy of this unique IFN and IL-2 regimen/schedule in terms of response rate and durability of response. We also set out to characterize the clinical toxicity of this regimen and its feasibility in an inpatient non-intensive care setting. A two-stage design based on tumor response was used for patient accrual [30]. Given a minimum acceptable response rate of 15%, at least one response was required among the initial 19 evaluable patients (based on binomial distribution, P = 0.954). Assuming a minimum of one documented response, recruitment would continue to include a total of 45–50 patients. If there were no responses among the first-stage sample, the study would be discontinued. Interim monitoring of the toxicity profile was also conducted. If >7 of the first 25 patients [28%; 95% confidence interval (CI) 10 to 46] enrolled experienced dose limiting toxicity, required transfer to the intensive care unit (ICU) setting or had IL-2 stopped, the protocol was to be terminated permanently. It was felt then, that this regimen would be considered too toxic and not of significant benefit for standard therapy. The survival curve was estimated using the Kaplan–Meier method [31].


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
From February 1997 to March 1999, 47 patients with advanced RCC were enrolled at five institutions onto this multi-institutional phase II trial. Three patients were ineligible due to an increased performance status in two and an elevated serum bilirubin in one. Of the eligible patients (Table 2) 32 males and 12 females were enrolled (median age 56 years, range 28–78 years). Performance status (PS) included more patients with a PS of 1 with 23 patients than with a PS of 0 with 21 patients. Nineteen of the 44 patients (43%) had undergone a prior nephrectomy. The median time from prior nephrectomy was 6 months (range 1 month to 14 years). The median number of sites involved with disease was three (range 1–6). Twenty-five patients had bone and/or visceral metastases that did not include the lungs, while only two had disease confined to the lungs. Seven patients had had prior treatment for their metastatic disease: five had prior palliative external beam radiation therapy to symptomatic bony lesions and two had prior systemic treatment (TNP-470 antiangiogenesis agent in one and platinum-based chemotherapy in the other).


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Table 2. Patient characteristics
 
Response and survival
Forty-three patients were evaluable for response (Table 3). Aside from the three ineligible patients, one other patient was removed from study treatment after receiving less than one cycle of therapy at the patient’s request and never underwent subsequent disease evaluation. He received all planned IFN injections but only 2 days of decrescendo IL-2 infusion. This patient died 1 month later, presumably secondary to underlying malignancy, and is included in the survival analysis. Overall, seven of the 43 response evaluable patients experienced a major response for an overall response rate of 16.3% (95% CI 5.3 to 27.3). There were three (7.0%) complete remissions and four (9.3%) partial remissions. Seventeen patients had stable disease (lasting between 2 and 21 months) and 19 developed progressive disease at first evaluation. The median survival for all eligible patients was 13 months. Median time to progression was 60 days. Nine patients remain alive, all of which have survived >=23 months from time of protocol entry (Figure 1). The median response duration is 36 months, with a range of 11.5 to 48+ months. All three of the patients who experienced a complete response remain in remission. Response durations in these three patients are as follows: 37.6+, 38.1+ and 48+ months. Median follow-up for responders has not been reached but exceeds 37.4 months and ranges between 22 and 48+ months.


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Table 3 Response results in 43 evaluable patients
 


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Figure 1. Overall survival for all 44 eligible patients with metastatic renal cell carcinoma treated with interferon-{alpha}2b and decrescendo continuous infusion IL-2. Median survival is 13 months. Nine patients remain alive beyond 23 months. Dotted lines indicate 95% CI.

 
All responses were first observed at the first disease evaluation time point, after two cycles of therapy. The majority of responders, however, continued to show a decrease in their tumor burden beyond these two cycles at subsequent follow-up. Of the responders, most (five of seven) had two, three or four sites of disease; two patients had only one site of disease, including the lung (PR) and renal bed (at the prior nephrectomy site, CR), respectively. All three complete responses were observed in patients who had undergone prior nephrectomy. Two patients in whom a PR was observed went on to undergo nephrectomy, one of whom was consequently rendered disease free. Three of four patients with a PR had a response noted within their primary tumor. Neither of the patients with lung-only disease were among the complete responders; in fact only one responded (PR). No patients with bone metastases developed a response and only two patients with visceral metastases responded (pancreas, testicle). All but one responder had a SWOG PS of zero.

Toxicity
One half of this regimen, IFN, was administered as a s.c. injection on an outpatient basis, followed by IL-2 decrescendo continuous i.v. infusion, which was administered to patients in hospital on a standard medical ward. In general, this treatment was reasonably well tolerated. The total number of cycles received was 130, and the median number of cycles administered per patient was two. Four patients discontinued treatment due to toxicity. There were no treatment-related deaths. Severe grade 4 toxicity was uncommon, occurring in only 13% of cycles administered. Hypotension requiring vasopressor support and ICU monitoring during decrescendo IL-2 infusion was seen in only one patient. Standard cytokine-induced toxicities were observed; however, individually each was relatively infrequent (Table 4). Hematologic toxicity was most common, but overall, grade 3 to 4 toxicity occurred in only 16% of cycles received. Myelotoxicity was confined to neutropenia and anemia, and no grade 3 or 4 thrombocytopenia was observed. Typical constitutional symptoms were observed, but overall were relatively mild. Electrolyte abnormalities were uncommon; however, grade 3 or 4 hyponatremia did occur in 10% of cycles received and always during the decrescendo IL-2 portion of therapy. Seven episodes of grade 3, and one episode of grade 4 hyperglycemia were observed throughout the treatment courses, all of which occurred in patients with a history of diabetes mellitus and all of which responded promptly to oral hypoglycemic agents or insulin as required. Central nervous system, gastrointestinal and renal toxicity was rare.


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Table 4 Common grade 3 or 4 toxicities in 130 cycles
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study intended to evaluate the efficacy and tolerability of a novel sequence of combination outpatient s.c. IFN with a decrescendo continuous infusion inpatient therapy of IL-2 in patients with advanced, unresectable renal cell carcinoma. The overall response rate of 16.3% is comparable to that of high-dose bolus IL-2, the only federally approved therapy for metastatic RCC, and other combinations of IFN and IL-2 with or without cytotoxic chemotherapy [8, 13, 27, 28, 32, 33].

Table 5 summarizes a number of reports using IL-2-based treatment in the therapy of metastatic RCC. In February 2000, Fisher et al. updated long-term results on 255 patients with metastatic RCC who had received high-dose i.v. bolus recombinant IL-2 therapy [8]. Objective responses were observed in 15% of patients with 17 complete responses (7%) and 20 partial responses (8%). The median duration of response was 54 months, ranging from 3 to >131 months. The median survival was 16.3 months, with 10–20% of patients estimated to be alive 5 to 10 years after treatment. It is well known that the IL-2 regimen employed is quite toxic and requires ICU type monitoring to be administered and most importantly requires very careful patient selection for optimal organ function. In an effort to evaluate the importance of IL-2 dose with regard to toxicity and efficacy in patients with metastatic RCC, Yang reported preliminary results of an ongoing prospective randomized phase III trial of three IL-2 regimens in this patient population [13]. Initially, a two-arm study comparing two bolus i.v. IL-2 regimens was undertaken (720 000 IU/kg compared with 72 000 IU/kg every 8 h for 15 consecutive doses). Later, a third arm of outpatient s.c. IL-2 was added (250 000 IU/kg/day for 5 days during week 1, then 125 000 IU/kg/day for 5 days per week over weeks 2–6). Not surprisingly, the lower doses of IL-2 produced significantly less toxicity. Response rates, however, appear to favor the high-dose approach. Survival data were not yet mature to allow for full comparison. Some investigators have suggested that perhaps the combination of IL-2 with IFN may be more efficacious than IL-2 alone. Atkins et al. observed no additional benefit when IFN was added to high-dose bolus IL-2 at 600 000 IU/kg every 8 h, up to 14 doses [4]. However, response rates have been comparable to high-dose bolus i.v. therapy for outpatient combinations of s.c. IL-2 plus IFN as reported by Dutcher for the Cytokine Working Group (CWG) [27] and Vogelzang in another multicenter trial [32]. Response duration, however, for these particular combinations, may be shorter, as reported [27]. We have shown ultra-low doses of combination IL-2 with IFN, on the other hand, to be clinically ineffective despite the advantageous toxicity profile [34]. In a randomized phase III trial, reported by the French, comparing continuous i.v. infusion IL-2 versus s.c. IFN versus both, results favored the combination in terms of response rate and event-free survival [28]. No significant difference in overall survival was observed, however. Lastly, the addition of cytotoxic chemotherapy such as 5-fluorouracil (5-FU) to combination IL-2 plus IFN was thought to be more active than combination immunotherapy alone [3537]. The CWG recently reported the results of a confirmatory phase II evaluation of IL-2, IFN and 5-FU in patients with metastatic RCC, which revealed only significant toxicity without attendant improvement in response rate when compared with other reports of IL-2 + IFN and 5-FU [33]. In a larger randomized trial, the French recently observed no benefit in response or survival when 5-FU was added to an outpatient combination of s.c. IL-2 with IFN; in fact neither regimen was terribly effective [37]. Current efforts within the CWG are therefore directed toward a phase III randomized comparison of high-dose i.v. bolus inpatient IL-2 treatment compared with outpatient s.c. injection of IL-2 + IFN. Preliminary results support a higher response rate for the inpatient high-dose IL-2 regimen [38].


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Table 5. Summary of IL-2-based trials in metastatic renal cell carcinoma
 
The data reported here is provocative based primarily on the durability of the responses extending beyond 3 years with a relatively tolerable regimen in a less carefully selected patient population. Only one patient required ICU-type monitoring for blood pressure management that was transient; all other toxicities were manageable in the outpatient setting during IFN therapy or on a standard hospital ward during IL-2 decrescendo infusion. Severe grade 4 toxicity was uncommon and occurred in only 13% of the 130 cycles of therapy administered. Four of the 44 eligible patients enrolled (9%) discontinued treatment due to toxicity. One possibility as to why this particular schedule of IL-2 induces less toxicity than that of high-dose bolus therapy was originally proposed by Keilholz et al. in their initial report of this same combination/schedule of IFN and IL-2 in patients with metastatic melanoma [29]. In this report, responses were more common in patients receiving the unique decrescendo IL-2 infusion in combination with s.c. outpatient IFN, while toxicity was less severe than in those patients receiving the same IFN dose and schedule followed by a standard continuous infusion of IL-2 at 1 mg/m2/24 h for 5 days. These results were felt most likely to be due to lower levels of circulating tumor necrosis factor alpha (TNF-{alpha}) in the decrescendo IL-2 population. We did not measure circulating TNF-{alpha} levels in our patients and therefore cannot confirm this hypothesis.

Overall, the patients treated in this study would be considered an unfavorable population [39]. That is, 25 of 44 eligible patients had their primary tumor intact. More than half (23) had a performance status of 1; 25 (57%) had bone and/or visceral metastases, excluding the lung; and only two of the 44 patients had lung-only disease, traditionally considered a favorable prognostic feature. Recent data suggest that patients who undergo nephrectomy prior to receiving IFN have improved survival [40]. Nephrectomy was not performed prior to enrollment for a number of reasons, including: primary tumors were considered unresectable; patients were considered inappropriate candidates for nephrectomy; and nephrectomy in patients with documented metastatic disease was still considered somewhat controversial at the time this study was designed and run. The median time from prior nephrectomy, for those who had undergone resection of their primary tumors in this study, was 6 months. Others have reported a better long-term outcome in those patients who have undergone nephrectomy for >6 months from the time of development of metastases [41]. With these factors in mind, it would appear then that this particular sequential combination may in fact be more suitable for those patients not considered optimal candidates for high-dose bolus i.v. IL-2 (600 000–720 000 IU/kg), and/or that it might rival that of high-dose IL-2 in the favorable population. Such an extrapolation could only be validated in a randomized phase III head-to-head comparison, however. Whether patient resources are best utilized with such a phase III trial is debatable.

This study helps to define another combination cytokine based approach to the treatment of advanced RCC with IL-2 and IFN. Although toxicity can be considered reasonable, the overall response rate remains suboptimal. That is, this combination can induce durable remissions, exceeding 3 years in some individuals, yet the vast majority of patients treated did not benefit. Much room for improvement remains in the treatment of this disease and we must therefore continue to seek new treatment approaches. This regimen may provide a base upon which to add new agents, especially those that attempt to overcome the tumor factors that are barriers to more effective immunotherapy (e.g. anti-VEGF, Flt3L, etc.)


    Acknowledgements
 
Supported in part by grants to each institution from Chiron Therapeutics, Division of Chiron Corporation, Emeryville, CA, and Schering Plough Corporation, Kenilworth, NJ.


    Footnotes
 
+ Correspondence to: Dr J. I. Clark, Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA. Tel: +1-708-327-3236; Fax: +1-708-327-3218; E-mail: jclark@lumc.eduPresented in part at the 35th annual meeting of the American Society of Clinical Oncology, May 1999, Atlanta, Georgia. Back


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