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Originally published as JCO Early Release 10.1200/JCO.2003.02.014 on June 16 2003 © 2003 American Society for Clinical Oncology Adjuvant High-Dose Bolus Interleukin-2 for Patients With High-Risk Renal Cell Carcinoma: A Cytokine Working Group Randomized Trial
From the Loyola University Chicago, Maywood, IL; Beth Israel Deaconess Medical Center, Boston, MA; Earle A. Chiles Research Institute/Providence Portland Medical Center, Portland, OR; University of California at Los Angeles, Los Angeles; City of Hope National Medical Center, Duarte, CA; Our Lady of Mercy Comprehensive Cancer Center, New York, NY; Wayne State University, Detroit; University of Michigan, Ann Arbor, MI; Vanderbilt University, Nashville, TN; Indiana University, Indianapolis, IN; Carolinas Medical Center, Charlotte, NC; University of Texas/South Texas Veterans Health Care System, San Antonio, TX; Dartmouth Hitchcock Medical Center, Lebanon, NH; and Arizona Health Sciences Center, Phoenix, AZ. Address reprint requests to Joseph I. Clark, MD, Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153; email: jclark{at}lumc.edu.
Purpose: This prospective, randomized, controlled phase III trial assessed high-dose bolus interleukin-2 (IL-2) postoperatively in patients with high-risk renal cell carcinoma (RCC). Patients and Methods: Eligibility requirements were resected locally advanced (LA; T3b-4 or N1–3) or metastatic (M1) RCC, no prior systemic therapy, and excellent organ function. Randomized assignment was to one course of IL-2 (600,000 U/kg every 8 hours on days 1 to 5 and days 15 to 19 [maximum 28 doses]) or observation. The study was designed and powered to show an improvement in predicted 2-year disease-free survival (DFS) from 40% for the observation group to 70% for the treatment group. The accrual goal was 68 patients with LA disease, with 34 patients per treatment arm. Metastasectomy patients were to be analyzed separately because of their unpredictable natural history. Results: Sixty-nine patients were enrolled onto the study (44 LA and 25 M1 patients). Toxic effects of IL-2 were as anticipated; no unexpected serious adverse events or treatment-related deaths occurred. Early closure occurred when an interim analysis determined that the 30% improvement in 2-year DFS could not be achieved despite full accrual. Sixteen of 21 LA patients receiving IL-2 experienced relapse, compared with 15 of 23 patients in the observation arm (P = .73); in the LA group, three deaths occurred in the IL-2 arm, and five deaths occurred in the observation arm (P = .38). Analysis including metastasectomy patients made no difference in DFS or overall survival. Conclusion: One course of high-dose bolus IL-2, though feasible, did not produce the ambitious clinically meaningful benefit anticipated when administered postoperatively to patients with resected high-risk RCC.
DURING THE year 2003, an estimated 31,900 new patients with renal cell carcinoma (RCC) will be identified, and 11,900 RCC deaths will occur in the United States.1 One third of RCC patients have metastatic disease at the time of diagnosis.2 The 5-year overall survival of all RCC patients is 40% to 45% and has not appreciably improved in 25 years.3 The median survival of patients with metastatic RCC is 10 months, with less than 2% long-term survival.4 Locally advanced RCC is associated with a poor prognosis. Recurrence rates range from 50% to 85% depending on the tumor (T) stage and nodal (N) status for locally advanced RCC,5,6 and approach 100% in distant metastatic (M) disease that has been surgically removed. To date, no effective adjuvant therapy has been developed for patients with resected high-risk locally advanced or metastatic RCC. This includes local radiation to the tumor bed, systemic cytotoxic chemotherapy, or systemic immunotherapy.7–12 High-dose bolus interleukin-2 (IL-2) remains the only United States Food and Drug Administration–approved systemic therapy for metastatic RCC. Approval was based largely on the small percentage of durable complete remissions induced with such treatment.13–15 Because of its well-established and extensively reported toxicity profile,16,17 treatment with high-dose IL-2 is confined to patients who have excellent functional status and who are treated at a few institutions that have experience with this treatment. The Cytokine Working Group has extensive experience with high-dose IL-2.18–20 Given its proven efficacy in the setting of metastatic disease, we hypothesized that treatment with high-dose IL-2 might effectively limit recurrences in minimal disease states of RCC after complete surgical resection of locally advanced or distant metastatic disease. We hypothesized that if one course of high-dose bolus IL-2 could decrease this predicted recurrence rate significantly, it would be a reasonable adjuvant approach in this high-risk population, despite its toxicity. We therefore performed a prospective, randomized phase III trial comparing one course of high-dose bolus IL-2 versus observation (which is the standard of care for resected RCC) with the option of using an IL-2–based therapy at the time of recurrence.
Patients Patients were eligible for enrollment onto this trial if they were older than 16 years and had completely resected advanced high-risk RCC as defined by one of the following pathologic stages: T3b-c, T4, N1–3, or M1 disease resected to no evidence of disease (NED; Table 1  ).21 Patients must have recovered from any effects of surgery, which must have been performed within 12 weeks of enrollment. The patients had to meet the following eligibility criteria: an excellent performance status (Eastern Cooperative Oncology Group performance status of 0 or 1); adequate organ function defined as WBC count  4,000/µL, platelet count 100,000/µL, hemoglobin 10 g/dL, serum creatinine  1.5 mg/dL or creatinine clearance 60 mL/min, and direct bilirubin 1.5 mg/dL; and forced expiratory volume at 1 second more than 2.0 L or 75% of predicted for height and age from pre-enrollment pulmonary function testing. No history or evidence of cardiac disease on ECG was allowed, and a normal cardiac stress test was required for all patients older than 40 years of age. No prior systemic treatment for RCC was allowed, but patients may have received prior locoregional radiation therapy to solitary resectable metastases, which must have undergone surgical resection before enrollment. No prior history of invasive malignancy in the past 5 years or human immunodeficiency virus positivity was allowed; female patients were required to have a negative pregnancy test; and all patients were required to give written informed consent to participate. The institutional review boards for the protection of human subjects at each participating institution approved the study.
Randomization, Treatment, and Follow-Up At the time of enrollment, patients were assigned to one of four stratification groups on the basis of the pathologic stage of their disease: T3b or N1 disease, T3c-4 disease, N2–3 disease, or M1 disease resected to NED. Histologic categorization of the primary RCC was not used prospectively as a stratification criterion. Patients were then randomly assigned in a 1:1 fashion to treatment with one course of high-dose bolus IL-2 or observation. Disease characteristics between the two treatment groups were compared at randomization using the  2 test and the Student’s t test for categorical and continuous variables, respectively. The IL-2 (Proleukin; Chiron Corp, Emeryville, CA) was administered in standard fashion: 600,000 U/kg as an intravenous bolus over 15 minutes every 8 hours on days 1 to 5, and again on days 15 to 19, for a maximum of 28 doses as an inpatient, often on a unit with intensive care–level monitoring capabilities. Standard supportive therapy was used to treat the typical IL-2–induced capillary leak syndrome, including low-dose vasopressor support, antipyretics, antinausea, and antidiarrheal medications.20 Follow-up was identical for the two study arms: patients underwent evaluation with office visits, laboratory work-ups, and radiographic imaging (computed tomography scan and bone scan) every 3 months for 2 years, then every 4 months for 1 year, then every 6 months during years 4 and 5, then yearly until recurrence or death. Documentation of recurrence was based on radiographic and clinical findings.
Objectives and Statistical Analysis
Interim Data and Safety Monitoring
Between September 1997 and June 2002, 69 patients at 15 institutions were accrued to this trial. Enrollment was expected to occur over a 3-year period; however, initial accrual of the primary subjects of interest (ie, those with T3c-4 primary tumors or N2–3 nodal involvement) was much slower than anticipated. To increase accrual, in June 1998, the study was amended to include patients with slightly lower risk disease (T3b or N1). Accrual of the target population was subsequently anticipated to require 5 years from trial initiation.
Patients were stratified according to stage, and the various subsets of disease were evenly distributed between treatment arms (Table 2
The toxicity of the high-dose IL-2 was as expected. There were no unexpected adverse events or treatment-related deaths as a result of this therapy (Table 3 ). Eighty-eight percent of the 33 patients treated with IL-2 experienced at least one grade 3 or 4 toxicity. The most common grade 3 or 4 toxicity was hypotension, which required vasopressor support and occurred in 52% of patients. Serious cardiac or CNS toxicities were rare. All toxicities resolved after discontinuation of therapy. The median number of doses received in the treatment arm was 20 of a maximum of 28 (range, 6 to 28 doses), which is consistent with dosing experienced in advanced disease trials.24 The range and median number of doses were similar for patients with locally advanced disease and those with resected metastases.
After 38 patients with locally advanced high-risk disease (T3b-4 or N1–3) were enrolled and had undergone adequate follow-up, an interim analysis of DFS was performed by the DSMC, as called for in the protocol. At the time of the analysis, 23 of these patients had disease progression or death. The expected total number of events at 2 years of follow-up was 32 in the target population of 68 patients with locally advanced disease, or 34 patients in each arm (21 events in the observation arm and 11 events in the treatment arm, respectively). Thus, 72% of the expected events had occurred at the time of the interim analysis. The conditional probability calculation for comparison of DFS revealed a less than 1% chance of observing the minimum 30% actual improvement in 2-year DFS, which was prospectively defined, if the trend of events continued with full accrual. It was therefore concluded by the DSMC that there was no evidence to indicate that IL-2 would have the projected 30% absolute increase in 2-year DFS over that of observation (Table 4 ). The same conclusion was reached whether the entire patient population (Fig 1) or only patients with locally advanced high-risk disease were analyzed (Fig 2). Figure 3 indicates the DFS for those patients having undergone metastasectomy before enrollment. The median DFS for all patients enrolled was 28 months. The investigators unanimously concluded, therefore, that given the minimal likelihood that one course of IL-2 adjuvant therapy would demonstrate the clinically significant benefit projected, continued accrual to the trial was not justified. The totals outlined in all Tables and Figures indicate all patients enrolled and thus are different from those used in the interim analysis because not all patients accrued had undergone adequate follow-up at the time of the DSMC analysis.
Overall survival was similar between treatment arms and stratification groups (Table 4  and Fig 4, 5, and 6), with a median follow-up for all enrolled patients of 22 months. Sites of recurrence were similar in each group; the lung was the most common site of recurrence (observed in 30% of patients with recurrent disease). Of the 20 patients randomly assigned to observation who developed recurrence, five patients went on to receive standard high-dose bolus IL-2 systemic therapy. Most patients were enrolled onto another clinical trial during which they received another form of an IL-2–based systemic immunotherapy regimen. One patient underwent surgical resection of his recurrent disease; four other patients were still contemplating treatment options at last follow-up.
In this trial, we set out to evaluate the potential role of high-dose bolus IL-2 as systemic adjuvant therapy for patients with resected high-risk RCC. We assessed the efficacy and tolerability of this approach in a patient population with known poor long-term outcome. Although the trial was terminated early according to recommendations of an official DSMC after an interim analysis performed at a predetermined evaluation time point, it was clear that even if full accrual to the trial had occurred, the projected improvement in DFS would not be observed. Overall survival was not affected by this treatment. Toxicity, although significant, was typical for one course of systemic high-dose bolus IL-2 and was completely reversible. The number of doses of IL-2 administered to patients was consistent with prior published series for patients with unresected advanced RCC.24 The study did confirm that the patients selected for this trial were at high risk for recurrence. Many other treatments have been evaluated in the adjuvant setting for RCC.6–12 Thus far, none have resulted in an improvement in outcome. The largest trial to date tested lymphoblastoid interferon as adjuvant postoperative treatment in patients with resected stage III RCC.6,11 Although no benefit was observed in progression-free or overall survival, the study did identify a subgroup of patients who were at high-risk for recurrence.5,6 Among the 294 patients enrolled, those with T3c or N2 disease had only a 25% and 18% 2-year DFS, respectively. We initially chose to target this subgroup of high-risk patients in our study to minimize exposure of a lower risk population to the substantial toxicity of high-dose IL-2. As outlined above, however, because of poor accrual we expanded the eligibility criteria 1 year later to include somewhat lower risk patients with T3b or N1 disease. In the prior study, the 2-year DFS for these populations was 50% and 43%, respectively. In another large randomized study, a similarly lower risk group of 247 patients with resected stage II and III RCC were assigned to treatment with interferon alfa-2b or observation.12 Again, no benefit from postoperative adjuvant immunotherapy was observed. One potential limitation to our study may have been the restriction of postoperative therapy to one course of high-dose bolus IL-2. High-dose bolus IL-2 remains the only United States Food and Drug Administration–approved treatment for advanced or metastatic RCC. Because of the documented durable complete responses observed with this dose and schedule of IL-2 in patients with metastatic disease,13–15 we believed that testing high-dose bolus IL-2 as adjuvant therapy was justified in the identified high-risk population, despite its toxicity. The choice of only one course of therapy as adjuvant treatment was based on the following rationales. First, the vast majority of responders with advanced RCC do so after one course of therapy; no definitive evidence exists that more than one course of this treatment offers a significant benefit in the setting of metastatic or unresectable disease because most patients still show interval shrinkage at the time of the second course of therapy. It has been well documented that the total IL-2 administered to patients on a second course is substantially less than that administered in the first course.13,14 Second, the patients to be treated on this study would have had resection of all clinically detectable disease; it would therefore be impossible to document whether individual patients had benefited at all, let alone sufficiently to justify the expense and risk of a second course of therapy. Given this minimal residual disease state and our unwillingness to subject patients to excessive risk, we presumed that one course of IL-2 would be adequate. Another potential limitation might be the highly selected patient population on which we focused. Limiting initial accrual to patients with resected T3c or N2 or greater disease led to slow enrollment. It became clear to us that patients with such locally advanced disease do not commonly undergo surgical resection for curative intent or are rarely referred for potential adjuvant therapy. Expansion of enrollment to include a lower risk group allowed for enhanced accrual; nevertheless, the other obstacles to accrual, such as physician or patient bias about randomized trials and the fact that high-dose IL-2 is only administered in specialized centers, led to continued slow accrual.
The potential impact of unbalanced randomization with regard to tumor histologic subtype may have been a contributing factor to the negative outcome of this study, although this is unlikely. Histologic subtype was not prospectively defined as a stratification factor; thus, Table 2 It is likely that an absolute improvement in DFS as large as 30% (75% relative improvement) was far too ambitious, considering that high-dose bolus IL-2 is associated with an objective overall response rate of only 15% to 20% in high-performance patients with advanced RCC. However, we believed that only a large improvement in DFS could justify the potential risk and expense of IL-2 therapy in this patient population. Our study failed to show the anticipated significant clinical advantage to postoperative systemic IL-2 in patients with resected RCC at high-risk for recurrence. On the basis of our results, however, a benefit of less magnitude that might still be of clinical benefit cannot be ruled out. The question arises as to whether it was appropriate to study the efficacy of high-dose bolus IL-2 in patients with resected regional nodal metastases. In one retrospective review, patients presenting with distant metastatic disease along with regional lymphadenopathy experienced a decreased survival compared with those patients without nodal involvement.26 These patients with locally advanced and distant disease did not appear to benefit from IL-2–based immunotherapy after cytoreductive surgery.26 Another question is whether high-dose IL-2 is the proper agent to study. As noted, overall response rates in advanced RCC are 15% to 20%. The likelihood, therefore, of observing a meaningful advantage using this agent in the adjuvant setting might have been predicted to be low. Evaluation of adjuvant therapy using a more effective systemic immunotherapy in advanced disease RCC patients makes more sense. Unfortunately, to date, no such therapy exists. Active immunotherapeutic regimens reported for advanced RCC generally have no greater overall response rates or durable remissions than those reported for high-dose IL-2.27–30 A more relevant question then becomes whether adjuvant trials in RCC should even be considered until more effective agents or at least an effective immune regimen that induces an immune response in a majority of patients becomes available. Until such a time, the standard of care for fully resected RCC remains observation.
We thank Susan Fisher for her initial input on statistical considerations; Bruce Roth and Robert Dreicer for their important contribution to the Data Safety Monitoring Committee; Marc S. Ernstoff for assistance in manuscript preparation; and Lisa Deabel, Renata Mulhall, and Ann Lau-Schwabe for their invaluable assistance with data management.
Supported by an unrestricted educational grant from Chiron Corp, Emeryville, CA. Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, June 1, 2003, Chicago, IL.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
