Randomized Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous Interleukin-2 and Interferon in Patients With Metastatic Renal Cel
http://www.100md.com
《临床肿瘤学》
the Beth Israel Deaconess Medical Center
Dana-Farber Cancer Institute, Boston, MA
Loyola University Chicago, Maywood
University of Illinois at Chicago, Chicago, IL
Wayne State University, Detroit, MI
University of Texas, San Antonio, TX
Pittsburgh Cancer Institute, Pittsburgh, PA
Indiana University, Indianapolis, IN
Dartmouth Hitchcock Medical Center, Hanover, NH
Earle Chiles Cancer Center, Portland, OR
City of Hope Comprehensive Cancer Center, Duarte, CA
Our Lady of Mercy, Bronx, NY
ABSTRACT
PATIENTS AND METHODS: Patients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5 MIU/m2 subcutaneously every 8 hours for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m2 subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks.
RESULTS: One hundred ninety-two patients were enrolled between April 1997 and July 2000. Toxicities were as anticipated for these regimens. The response rate was 23.2% (22 of 95 patients) for HD IL-2 versus 9.9% (nine of 91 patients) for IL-2/IFN (P = .018). Ten patients receiving HD IL-2 were progression-free at 3 years versus three patients receiving IL-2 and IFN (P = .082). The median response durations were 24 and 15 months (P = .18), and median survivals were 17.5 and 13 months (P = .24). For patients with bone or liver metastases (P = .001) or a primary tumor in place (P = .040), survival was superior with HD IL-2.
CONCLUSION: This randomized phase III trial provides additional evidence that HD IL-2 should remain the preferred therapy for selected patients with metastatic renal cell carcinoma.
INTRODUCTION
In an effort to confirm and extend these results, the Cytokine Working Group (CWG) conducted a series of phase II trials that evaluated HD bolus IL-2 alone, intravenous (IV) IL-2 and IFN, outpatient subcutaneous IL-2 and IFN, and subcutaneous IL-2 and IFN alternating with fluorouracil/IFN in patients with metastatic renal cell carcinoma.13-15 All patients on these studies had met the same eligibility criteria. The response rates (range, 11% to 17%) and median survivals (range, 15 to 20 months) were similar in these studies, although acute toxicity was less severe in the outpatient regimens. The addition of IV IFN to HD IL-2 and fluorouracil to outpatient IL-2 and IFN did not seem to improve efficacy but did increase toxicity. The median response duration and 3-year progression-free survival seemed to be longest with HD IL-2; however, because these studies were not randomized, patient selection bias could have influenced the results.
This phase II experience encouraged the CWG to formally investigate whether lower-dose IL-2 regimens were able to produce durable responses at a rate similar to HD IL-2 before accepting such regimens as standard therapy.
Therefore, a randomized phase III trial was initiated to compare HD IV bolus IL-2 with outpatient subcutaneous IL-2 and IFN in patients with advanced renal cancer. On the basis of the results of earlier CWG phase II studies, 3-year progression-free survival was chosen as the primary study end point.
PATIENTS AND METHODS
Treatment Plan
Outpatient subcutaneous IL-2 and IFN. On treatment day 1, patients received a subcutaneous IL-2 loading dose of 5 x 106 U/m2 every 8 hours for three doses. This was followed by a 5 x 106 U/m2 dose via subcutaneous injection, one dose per day on treatment days 2, 3, 4, and 5 (week 1), and then daily 5 days per week for the remaining 3 weeks as outpatients. During the first 4 weeks of treatment, patients also received subcutaneous IFN 5 x 106 U/m2/dose thrice weekly. Cycles were repeated every 6 weeks. One cycle consisted of 4 weeks of treatment followed by 2 weeks of rest. Up to 2 weeks of additional rest were allowed for the resolution of adverse events. A maximum of six 6-week cycles were given.
Patients were premedicated with acetaminophen 500 to 650 mg orally every 4 hours (total 2,600 mg to 3,000 mg/d). Oral nonsteroidal anti-inflammatory drugs were administered to patients whose fever was unresponsive to acetaminophen. Opioid analgesia (meperidine 25 to 50 mg orally) was given for severe rigors. Patients were evaluated for tumor response after cycles 1, 2, 4, and 6. Patients with disease progression at any time were ineligible for further treatment. All patients were treated for at least two 6-week cycles unless progressive disease or unacceptable toxicity was encountered. To be eligible for more than two cycles, patients had to have at least stable disease, with some evidence of tumor regression or an objective response, and had to meet baseline eligibility criteria for organ function.
High-dose IV IL-2. Patients received IL-2 600,000 U/kg/dose (Chiron) IV every 8 hours for 5 days (maximum of 14 doses) beginning on day 1 and again on day 15. One cycle consisted of 5 days of treatment, 9 days of rest, 5 more days of treatment, and 9 weeks of rest. A treatment delay of up to 4 weeks was allowed for resolution of side effects between cycles. Patients were eligible to receive a maximum of three cycles of treatment.
Patients underwent placement of a central venous catheter before each course of therapy and received antibiotic prophylaxis with ciprofloxacin 250 mg orally bid on days 1 to 10 and 15 to 24 of each cycle. All antihypertensive therapy was discontinued at least 24 hours before initiating each cycle of IL-2. Patients also received acetaminophen (650 mg orally every 4 hours) and indomethacin (25 mg every 6 hours) to reduce febrile reactions, ranitidine (150 mg) or famotidine (20 mg) orally every 12 hours for prophylaxis of gastrointestinal bleeding, hydroxyzine hydrochloride (25 to 50 mg orally every 6 hours) or diphenhydramine (25 mg orally every hours) for pruritus, meperidine (25 to 50 mg orally every 6 hours) for chills and rigors, an antidiarrheal agent, antiemetics, anxiolytics, diuretics, and vasopressors as needed.
Patients were evaluated for response during week 6 and 12 of the first cycle. To be eligible for more than one cycle of treatment, patients must have had at least stable disease with evidence of some minor tumor regression or objective response and had to meet baseline eligibility criteria for organ function.
Dose Modification and Toxicity Monitoring
Toxicity was evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria version 2.0.
Dose modification for toxicity: IL-2 and IFN. Dose-limiting toxicity (DLT) was defined as grade 3 to 4 toxicity with the exception of cardiac and neurologic toxicity (≥ grade 2) and hematologic and liver toxicity (grade 4). If a patient developed a DLT during weeks 1 to 4 of any cycle, both IL-2 and IFN were held until recovery took place (ie, the DLT improved to grade 1 or less) and then reinstituted with no change in dose. If a DLT recurred, doses for both drugs were reduced by 40% thereafter. If a DLT recurred at the lower dose, treatment was stopped and the patient was taken off treatment.
Dose modification for toxicity: HD IL-2. Treatment with HD IL-2 was modified by withholding doses of IL-2 rather than continuing therapy at a reduced dose. Doses of IL-2 were withheld for hypotension refractory to fluids and pressors or requiring unacceptably high pressor doses, anuria for more than 24 hours and unresponsive to fluid replacement and low-dose dopamine, respiratory distress requiring more than 4 L of oxygen to maintain O2 saturation greater than 95%, confusion, sustained ventricular tachycardia or any sign or symptom of myocardial ischemia or myocarditis, metabolic acidosis with HCO3 less than 18 despite attempts to correct with IV HCO3; atrial fibrillation, documented systemic infection, or any other serious toxicity that was not controlled at time of next dose.
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 a greater than 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 was defined as less than 50% but more than 25% reduction, but was in fact considered stable disease. Stable disease was defined as including minor response, no change, or less than 25% increase in disease and no new disease. Clinically relevant stable disease had to exceed 6 months. Progressive disease was defined as a greater than 25% increase in the sum of the products of perpendicular diameters of all lesions or the appearance of any new lesion. All patients who achieved a CR or PR had their computed tomography scans audited by independent radiologists to confirm their response and response duration.
Statistical Methods
The primary objective of this phase III study was to determine whether HD IL-2 was superior to outpatient subcutaneous IL-2 and IFN in terms of 3-year progression-free survival. Based on prior studies, it was assumed that the percentage of patients who would remain progression-free at 3 years was 10% for those receiving HD IL-2% and 2% in the IL-2 and IFN arm. The sample size was calculated to detect a difference in 3-year progression-free survival of 8% between the arms with 90% power. We presumed that 5% of enrolled patients would be found to be ineligible. The accrual of 174 patients was required to achieve this power.
After the study was underway, data began to emerge that suggested that patients with non–clear-cell primary tumors did not respond to biologic therapy. The accrual goal was then increased by 10% to permit subset analysis of only clear-cell patients at a later date, thus bringing the final total to 193 patients. Registration and randomization of eligible patients was performed at Beth Israel Deaconess Medical Center. Patients were randomly assigned to one of the two treatment arms in equal proportions using a stratified permuted block randomization. Before randomization, patients were stratified based on Eastern Cooperative Oncology Group performance status (0 or 1), liver or bone metastasis (yes or no), and primary tumor in place (yes or no). Additional prognostic criteria, as described by Motzer et al, 16 were collected from patient records after study completion.
Baseline continuous variables were summarized as median and range and compared between treatment arms using the Wilcoxon rank sum test. Binary baseline and response variables were compared between arms using Fisher's exact test; exact binomial CIs were reported. Three-year progression-free survival and 3-year durable CR were observed for all patients and are analyzed as binary end points. Time-to-event variables were summarized using Kaplan-Meier curves. Response duration was defined from date of documented tumor response to date of documented progressive disease or was censored at date of last follow-up visit; a log-rank test was used to compare treatment arms. Survival end points were defined from date of randomization to date of documented progressive disease (for progression-free survival) or death from any cause or were censored at date of last follow-up visit. Cox proportional hazards regression models were used to estimate hazard ratios and calculate log-rank tests (ie, score test) comparing treatment arms. The model among all patients was stratified by the three randomization strata. For the models by randomization variables, each was stratified for the other two randomization variables. The assumption of proportionality between treatment arms was assessed by plots of log of the cumulative hazard versus time and by testing for an interaction term of treatment arm with time in the model. For patients without liver or bone metastases, the assumption seemed violated, and time-varying hazard ratios were calculated for selected clinically relevant time points. Two-sided P values were reported for all analyses. The statistical analysis used SAS 8.2 (SAS Institute Inc, Cary, NC) and StatXact-5 (Cytel Software Corp, Cambridge, MA).
RESULTS
Treatment arms were evenly balanced for the stratification criteria and were reasonably well balanced for prior therapy, sex, age, and the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic criteria.16 Forty-five percent of all patients had liver or bone metastases, 31% had their primary tumors in place, and 87% were intermediate or poor risk by the (MSKCC) prognostic criteria.
Treatment
Treatment information is listed in Table 2. During the first 12 weeks of therapy, patients received most of the planned doses of IL-2 and IFN and 68% of the planned doses of HD IL-2.
Toxicity
The incidence of grade 3 and 4 toxicity in cycle 1 of treatment is listed in Table 3. Grade 3 and 4 toxicities were more common with HD IL-2. In general, the side effects with both treatment regimens were typical of our prior published experience with these regimens.4,13-15 However, one patient receiving IL-2 and IFN developed acute renal failure while on treatment and required permanent hemodialysis. In addition, two treatment-related deaths were noted, one on each treatment arm. A 44-year-old male patient died during cycle 1, week 4 of IL-2 and IFN of acute respiratory distress syndrome and progressive lung metastases. A 60-year-old male died during cycle 1, week 1 of HD IL-2 as a result of complications from capillary leak syndrome.
Response Data
Tumor response data by treatment arm are listed in Table 4. The overall response rate to HD IL-2 was 23.2% (95% CI, 15.1% to 32.9%), compared with 9.9% (95% CI, 4.6% to 18.0%) with IL-2 and IFN (P = .018). There were eight complete responses (8.4%) with HD IL-2, compared with only three responses (3.3%) on the IL-2 and IFN arm (P = .214).
Tumor response data by treatment arm for each of the three stratification criteria are listed in Table 5. Statistically significant differences in response rate favoring the HD IL-2 regimen were seen for patients with liver or bone metastasis (P = .008) and primary tumor in place (P = .024).
The median response duration for HD IL-2 was 24 months, compared with 15 months for IL-2 and IFN (P = .180; Fig 1). The median progression-free survival was 3.1 months for each treatment arm (Fig 2). Ten patients (nine responders and one patient with stable disease) receiving HD IL-2 remained progression-free at 3 years, compared with three patients (two responders and one patient with stable disease) who received IL-2 and IFN (P = .082). Nine of 22 patients who responded to HD IL-2 remain progression-free at 38 to 63 months, whereas only one of nine patients who responded to IL-2 and IFN (a PR) remain progression-free (51 months). There are seven ongoing CRs on HD IL-2 and none on IL-2 and IFN (P = .014).
Survival Data
One hundred ninety-two patients were followed up for survival. Survival by treatment arm, stratification subset, and MSKCC prognostic criteria is shown in Table 6. Median survival from time on-study was 13 months for patients assigned to IL-2 and IFN therapy and 17 months for those assigned to HD IL-2. This trend in survival benefit favoring HD IL-2 was not statistically significant (P = .211; Fig 3).
A statistically significant survival benefit was noted for patients with liver or bone metastases (P = .001) and for patients with primary tumors in place (P = .040) with HD IL-2 therapy (Fig 4A through 4F).
Broadly similar results were found when the analysis was limited to the 165 patients with clear-cell histology (77 patients receiving IL-2 and IFN; 88 patients receiving HD IL-2). There was still a significant response difference for patients with liver or bone metastases (P = .036), a trend in the number of patients progression-free at 3 years (P = .067), and a survival benefit for patients with liver or bone metastases (P = .002) or primary tumors in place (P = .034) all favoring HD IL-2.
DISCUSSION
In this study, HD IL-2 produced a statistically significant improvement in response rate (23.2% v 9.9% P = .018) compared with IL-2 and IFN. The response quality, as reflected by the CR rate (8% v 3%), durable CR rate (7.4% v 0%), and response duration (median 24 v 15 months) also favored HD IL-2 treatment, although only durable CR rate was statistically significant. HD IL-2 did not have a significant impact on median progression-free survival or median overall survival. Given that IL-2–based therapy for metastatic renal cell carcinoma benefits a minority of patients, we did not expect to see significant differences in these survival end points. However, this study confirmed the observation from prior CWG phase II studies, showing a trend in the number of patients free of disease progression at 3 years (10 v three patients; P = .082) favoring HD IL-2 therapy.
Patients with performance status ≥ 1, primary tumor in place, or liver or bone metastases have been reported to be less likely to respond to IL-2–based therapy.17 Consequently, we stratified study patients for these variables. Of note, patients with liver or bone metastases and patients treated with their primary tumor in place had significantly improved response rates and survival with HD IL-2 relative to lower-dose IL-2 and IFN. The current study represents the first time a survival advantage has ever been shown for any stratified subset of patients receiving IL-2–based therapy. However, the results of the subset analyses should be seen as hypothesis generating and will need to be confirmed in future trials.
Although the response rate for patients receiving HD IL-2 remained relatively constant across all prognostic variables (21% to 24%), IL-2 and IFN was essentially inactive in patients who had liver or bone metastases or their primary tumor in place. The explanation for this unanticipated result is not readily apparent. It is possible that higher serum or tissue IL-2 levels are needed either to overcome the immune suppression associated with greater tumor burden or to activate T cells in sites of disease other than lung and soft tissue. Consequently, it seems that patients with liver or bone metastases or unresected primaries represent a group of patients who seem to require a more intensive IL-2 regimen to achieve clinical benefit, whereas the impact of dose is less critical in patients with resected primaries and tumor confined to lung.
In contrast to earlier CWG phase II trials, the response rate to HD IL-2 in this study was significantly higher than the response rate with IL-2 and IFN. Considered in the light of this trial, the previously observed similarities in response rates might have been the consequence of less rigorous auditing of the responses in the prior IL-2 and IFN studies than was performed for the HD IL-2 data set that was prepared for United States Food and Drug Administration submission. Although the median response duration seen for patients on the HD IL-2 arm of this study was shorter than in the prior CWG phase II HD IL-2 trial (54 v 24 months), the fact that the plateau on the response duration curve falls just below the 50% mark probably accounts for this difference. As expected, HD IL-2 produced more acute toxicity than outpatient IL-2 and IFN. However, holding therapy rapidly reversed most toxicity, and treatment-related mortality occurred in only one patient on each arm.
Other investigators have previously studied the relative value of IL-2–based regimens in patients with metastatic renal cancer. In 1998, the French Immunotherapy Group reported on a large, phase III randomized study that compared inpatient continuous-infusion IL-2 alone with either IFN alone or the combination of IL-2 and IFN.10 They concluded that the combination of IL-2 and IFN was superior in terms of response rate and 1-year progression-free survival as compared with monotherapy with either agent. This study used an IL-2 regimen that was less intensive than bolus HD IL-2, which may explain the low level of antitumor activity in the IL-2 alone arm (8% response rate). In addition, although IL-2 and IFN produced a superior response rate, this did not translate into more durable responses or an improvement in median or overall survival. In 2003, NCI Surgery Branch investigators reported results of a randomized phase III trial that compared the efficacy and toxicity of HD IV IL-2 to a lower-dose IV regimen (10% of high dose) using an otherwise identical administration schedule.18 In that study, patients who received HD IL-2 had a significantly higher response rate (21% v 13%; P = .048) and were more likely to have durable responses than those who received the lower-dose IV regimen. However, there were no significant differences in overall survival between the two groups. Despite the more acute toxicity with the high-dose regimen, quality-of-life assessments showed no differences between the two treatment arms. In an overlapping three-arm study, a third group of patients were randomly assigned to receive a low-dose outpatient subcutaneous IL-2 regimen. In this three-arm comparison, the response rates were 21% for HD IL-2, 11% for lower-dose IV IL-2%, and 10% for subcutaneous IL-2. Once again there were no significant survival differences. In this study, the vast majority of patients had an excellent performance status and had undergone prior nephrectomy, and relatively few had liver or bone metastases, making subset analyses difficult to perform. In the CWG study, most of the trend in survival difference favoring HD IL-2 was attributable to the patient populations with liver or bone metastases and primary tumor in place, perhaps explaining why the survival difference was less pronounced in the NCI Surgery Branch trial. Taking these three randomized studies into consideration, one can conclude that HD IL-2 is superior to both lower doses of IL-2 or IL-2 and IFN in terms of response rates and response quality.
This CWG phase III randomized trial provides additional evidence that HD IL-2 should remain the preferred therapy for selected patients with access to such treatment. Furthermore, it suggests that patients with bone or liver metastases or a primary tumor in place may receive little benefit from a lower-dose IL-2 regimen. Given the toxicity and expense associated with HD IL-2 therapy, and the still-low overall response rate, these results suggest that better criteria for selecting patients for HD IL-2 therapy are necessary. Although some progress has been made in this regard, even with the best selection criteria, the majority of patients will not respond to IL-2 therapy.19-22 Consequently, new treatment options that focus on important targets (eg, angiogenesis and signal transduction) will still be necessary for those with unfavorable selection features or who experience disease progression after IL-2–based therapy.
Authors' Disclosures of Potential Conflicts of Interest
Acknowledgment
We thank Judi Manola and Robert Parker for their input on statistical considerations; Susan Graham-McLaughlin and Toneika Allen for assistance in manuscript preparation; and Amanda Youmans, Daniel Clancy, Laura Ruttner, and Christine Connolly for their invaluable assistance with management of the central database.
NOTES
Supported in part by grants to each institution from Chiron Therapeutics, Division of Chiron Corporation, Emeryville, CA; and Schering Plough Corporation, Kenilworth, NJ.
Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
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14. Dutcher JP, Fisher RI, Weiss G, et al: Outpatient subcutaneous interleukin-2 and interferon-alpha for metastatic renal cell cancer: Five-year follow-up of the Cytokine Working Group Study. Cancer J Sci Am 3:157-162, 1997
15. Dutcher JP, Atkins M, Fisher R, et al: Interleukin-2-based therapy for metastatic renal cell cancer: The Cytokine Working Group experience, 1989-1997. Cancer J Sci Am 1:S73-S78, 1997 (suppl)
16. Motzer RJ, Bacik J, Murphy BA, et al: Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289-296, 2002
17. Fyfe GA, Fisher RI, Rosenberg SA, et al: Long-term response data for 255 patients with metastatic renal cell carcinoma treated with high-dose recombinant interleukin-2 therapy. J Clin Oncol 14:2410-2411, 1996
18. Yang JC, Sherry RM, Steinberg SM, et al: A randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cell cancer. J Clin Oncol 21:3127-3132, 2003
19. Upton MP, Parker RA, Youmans A, et al: Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. Proc Am Soc Clin Oncol 22:851, 2003 (abstr 3420)
20. Bui MHT, Seligson D, Han K, et al: Carbonic anhydrase IX is an independent predictor of survival in advanced renal cell carcinoma: Implications for prognosis and therapy. Clin Cancer Res 9:802-811, 2003
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Dana-Farber Cancer Institute, Boston, MA
Loyola University Chicago, Maywood
University of Illinois at Chicago, Chicago, IL
Wayne State University, Detroit, MI
University of Texas, San Antonio, TX
Pittsburgh Cancer Institute, Pittsburgh, PA
Indiana University, Indianapolis, IN
Dartmouth Hitchcock Medical Center, Hanover, NH
Earle Chiles Cancer Center, Portland, OR
City of Hope Comprehensive Cancer Center, Duarte, CA
Our Lady of Mercy, Bronx, NY
ABSTRACT
PATIENTS AND METHODS: Patients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5 MIU/m2 subcutaneously every 8 hours for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m2 subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks.
RESULTS: One hundred ninety-two patients were enrolled between April 1997 and July 2000. Toxicities were as anticipated for these regimens. The response rate was 23.2% (22 of 95 patients) for HD IL-2 versus 9.9% (nine of 91 patients) for IL-2/IFN (P = .018). Ten patients receiving HD IL-2 were progression-free at 3 years versus three patients receiving IL-2 and IFN (P = .082). The median response durations were 24 and 15 months (P = .18), and median survivals were 17.5 and 13 months (P = .24). For patients with bone or liver metastases (P = .001) or a primary tumor in place (P = .040), survival was superior with HD IL-2.
CONCLUSION: This randomized phase III trial provides additional evidence that HD IL-2 should remain the preferred therapy for selected patients with metastatic renal cell carcinoma.
INTRODUCTION
In an effort to confirm and extend these results, the Cytokine Working Group (CWG) conducted a series of phase II trials that evaluated HD bolus IL-2 alone, intravenous (IV) IL-2 and IFN, outpatient subcutaneous IL-2 and IFN, and subcutaneous IL-2 and IFN alternating with fluorouracil/IFN in patients with metastatic renal cell carcinoma.13-15 All patients on these studies had met the same eligibility criteria. The response rates (range, 11% to 17%) and median survivals (range, 15 to 20 months) were similar in these studies, although acute toxicity was less severe in the outpatient regimens. The addition of IV IFN to HD IL-2 and fluorouracil to outpatient IL-2 and IFN did not seem to improve efficacy but did increase toxicity. The median response duration and 3-year progression-free survival seemed to be longest with HD IL-2; however, because these studies were not randomized, patient selection bias could have influenced the results.
This phase II experience encouraged the CWG to formally investigate whether lower-dose IL-2 regimens were able to produce durable responses at a rate similar to HD IL-2 before accepting such regimens as standard therapy.
Therefore, a randomized phase III trial was initiated to compare HD IV bolus IL-2 with outpatient subcutaneous IL-2 and IFN in patients with advanced renal cancer. On the basis of the results of earlier CWG phase II studies, 3-year progression-free survival was chosen as the primary study end point.
PATIENTS AND METHODS
Treatment Plan
Outpatient subcutaneous IL-2 and IFN. On treatment day 1, patients received a subcutaneous IL-2 loading dose of 5 x 106 U/m2 every 8 hours for three doses. This was followed by a 5 x 106 U/m2 dose via subcutaneous injection, one dose per day on treatment days 2, 3, 4, and 5 (week 1), and then daily 5 days per week for the remaining 3 weeks as outpatients. During the first 4 weeks of treatment, patients also received subcutaneous IFN 5 x 106 U/m2/dose thrice weekly. Cycles were repeated every 6 weeks. One cycle consisted of 4 weeks of treatment followed by 2 weeks of rest. Up to 2 weeks of additional rest were allowed for the resolution of adverse events. A maximum of six 6-week cycles were given.
Patients were premedicated with acetaminophen 500 to 650 mg orally every 4 hours (total 2,600 mg to 3,000 mg/d). Oral nonsteroidal anti-inflammatory drugs were administered to patients whose fever was unresponsive to acetaminophen. Opioid analgesia (meperidine 25 to 50 mg orally) was given for severe rigors. Patients were evaluated for tumor response after cycles 1, 2, 4, and 6. Patients with disease progression at any time were ineligible for further treatment. All patients were treated for at least two 6-week cycles unless progressive disease or unacceptable toxicity was encountered. To be eligible for more than two cycles, patients had to have at least stable disease, with some evidence of tumor regression or an objective response, and had to meet baseline eligibility criteria for organ function.
High-dose IV IL-2. Patients received IL-2 600,000 U/kg/dose (Chiron) IV every 8 hours for 5 days (maximum of 14 doses) beginning on day 1 and again on day 15. One cycle consisted of 5 days of treatment, 9 days of rest, 5 more days of treatment, and 9 weeks of rest. A treatment delay of up to 4 weeks was allowed for resolution of side effects between cycles. Patients were eligible to receive a maximum of three cycles of treatment.
Patients underwent placement of a central venous catheter before each course of therapy and received antibiotic prophylaxis with ciprofloxacin 250 mg orally bid on days 1 to 10 and 15 to 24 of each cycle. All antihypertensive therapy was discontinued at least 24 hours before initiating each cycle of IL-2. Patients also received acetaminophen (650 mg orally every 4 hours) and indomethacin (25 mg every 6 hours) to reduce febrile reactions, ranitidine (150 mg) or famotidine (20 mg) orally every 12 hours for prophylaxis of gastrointestinal bleeding, hydroxyzine hydrochloride (25 to 50 mg orally every 6 hours) or diphenhydramine (25 mg orally every hours) for pruritus, meperidine (25 to 50 mg orally every 6 hours) for chills and rigors, an antidiarrheal agent, antiemetics, anxiolytics, diuretics, and vasopressors as needed.
Patients were evaluated for response during week 6 and 12 of the first cycle. To be eligible for more than one cycle of treatment, patients must have had at least stable disease with evidence of some minor tumor regression or objective response and had to meet baseline eligibility criteria for organ function.
Dose Modification and Toxicity Monitoring
Toxicity was evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria version 2.0.
Dose modification for toxicity: IL-2 and IFN. Dose-limiting toxicity (DLT) was defined as grade 3 to 4 toxicity with the exception of cardiac and neurologic toxicity (≥ grade 2) and hematologic and liver toxicity (grade 4). If a patient developed a DLT during weeks 1 to 4 of any cycle, both IL-2 and IFN were held until recovery took place (ie, the DLT improved to grade 1 or less) and then reinstituted with no change in dose. If a DLT recurred, doses for both drugs were reduced by 40% thereafter. If a DLT recurred at the lower dose, treatment was stopped and the patient was taken off treatment.
Dose modification for toxicity: HD IL-2. Treatment with HD IL-2 was modified by withholding doses of IL-2 rather than continuing therapy at a reduced dose. Doses of IL-2 were withheld for hypotension refractory to fluids and pressors or requiring unacceptably high pressor doses, anuria for more than 24 hours and unresponsive to fluid replacement and low-dose dopamine, respiratory distress requiring more than 4 L of oxygen to maintain O2 saturation greater than 95%, confusion, sustained ventricular tachycardia or any sign or symptom of myocardial ischemia or myocarditis, metabolic acidosis with HCO3 less than 18 despite attempts to correct with IV HCO3; atrial fibrillation, documented systemic infection, or any other serious toxicity that was not controlled at time of next dose.
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 a greater than 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 was defined as less than 50% but more than 25% reduction, but was in fact considered stable disease. Stable disease was defined as including minor response, no change, or less than 25% increase in disease and no new disease. Clinically relevant stable disease had to exceed 6 months. Progressive disease was defined as a greater than 25% increase in the sum of the products of perpendicular diameters of all lesions or the appearance of any new lesion. All patients who achieved a CR or PR had their computed tomography scans audited by independent radiologists to confirm their response and response duration.
Statistical Methods
The primary objective of this phase III study was to determine whether HD IL-2 was superior to outpatient subcutaneous IL-2 and IFN in terms of 3-year progression-free survival. Based on prior studies, it was assumed that the percentage of patients who would remain progression-free at 3 years was 10% for those receiving HD IL-2% and 2% in the IL-2 and IFN arm. The sample size was calculated to detect a difference in 3-year progression-free survival of 8% between the arms with 90% power. We presumed that 5% of enrolled patients would be found to be ineligible. The accrual of 174 patients was required to achieve this power.
After the study was underway, data began to emerge that suggested that patients with non–clear-cell primary tumors did not respond to biologic therapy. The accrual goal was then increased by 10% to permit subset analysis of only clear-cell patients at a later date, thus bringing the final total to 193 patients. Registration and randomization of eligible patients was performed at Beth Israel Deaconess Medical Center. Patients were randomly assigned to one of the two treatment arms in equal proportions using a stratified permuted block randomization. Before randomization, patients were stratified based on Eastern Cooperative Oncology Group performance status (0 or 1), liver or bone metastasis (yes or no), and primary tumor in place (yes or no). Additional prognostic criteria, as described by Motzer et al, 16 were collected from patient records after study completion.
Baseline continuous variables were summarized as median and range and compared between treatment arms using the Wilcoxon rank sum test. Binary baseline and response variables were compared between arms using Fisher's exact test; exact binomial CIs were reported. Three-year progression-free survival and 3-year durable CR were observed for all patients and are analyzed as binary end points. Time-to-event variables were summarized using Kaplan-Meier curves. Response duration was defined from date of documented tumor response to date of documented progressive disease or was censored at date of last follow-up visit; a log-rank test was used to compare treatment arms. Survival end points were defined from date of randomization to date of documented progressive disease (for progression-free survival) or death from any cause or were censored at date of last follow-up visit. Cox proportional hazards regression models were used to estimate hazard ratios and calculate log-rank tests (ie, score test) comparing treatment arms. The model among all patients was stratified by the three randomization strata. For the models by randomization variables, each was stratified for the other two randomization variables. The assumption of proportionality between treatment arms was assessed by plots of log of the cumulative hazard versus time and by testing for an interaction term of treatment arm with time in the model. For patients without liver or bone metastases, the assumption seemed violated, and time-varying hazard ratios were calculated for selected clinically relevant time points. Two-sided P values were reported for all analyses. The statistical analysis used SAS 8.2 (SAS Institute Inc, Cary, NC) and StatXact-5 (Cytel Software Corp, Cambridge, MA).
RESULTS
Treatment arms were evenly balanced for the stratification criteria and were reasonably well balanced for prior therapy, sex, age, and the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic criteria.16 Forty-five percent of all patients had liver or bone metastases, 31% had their primary tumors in place, and 87% were intermediate or poor risk by the (MSKCC) prognostic criteria.
Treatment
Treatment information is listed in Table 2. During the first 12 weeks of therapy, patients received most of the planned doses of IL-2 and IFN and 68% of the planned doses of HD IL-2.
Toxicity
The incidence of grade 3 and 4 toxicity in cycle 1 of treatment is listed in Table 3. Grade 3 and 4 toxicities were more common with HD IL-2. In general, the side effects with both treatment regimens were typical of our prior published experience with these regimens.4,13-15 However, one patient receiving IL-2 and IFN developed acute renal failure while on treatment and required permanent hemodialysis. In addition, two treatment-related deaths were noted, one on each treatment arm. A 44-year-old male patient died during cycle 1, week 4 of IL-2 and IFN of acute respiratory distress syndrome and progressive lung metastases. A 60-year-old male died during cycle 1, week 1 of HD IL-2 as a result of complications from capillary leak syndrome.
Response Data
Tumor response data by treatment arm are listed in Table 4. The overall response rate to HD IL-2 was 23.2% (95% CI, 15.1% to 32.9%), compared with 9.9% (95% CI, 4.6% to 18.0%) with IL-2 and IFN (P = .018). There were eight complete responses (8.4%) with HD IL-2, compared with only three responses (3.3%) on the IL-2 and IFN arm (P = .214).
Tumor response data by treatment arm for each of the three stratification criteria are listed in Table 5. Statistically significant differences in response rate favoring the HD IL-2 regimen were seen for patients with liver or bone metastasis (P = .008) and primary tumor in place (P = .024).
The median response duration for HD IL-2 was 24 months, compared with 15 months for IL-2 and IFN (P = .180; Fig 1). The median progression-free survival was 3.1 months for each treatment arm (Fig 2). Ten patients (nine responders and one patient with stable disease) receiving HD IL-2 remained progression-free at 3 years, compared with three patients (two responders and one patient with stable disease) who received IL-2 and IFN (P = .082). Nine of 22 patients who responded to HD IL-2 remain progression-free at 38 to 63 months, whereas only one of nine patients who responded to IL-2 and IFN (a PR) remain progression-free (51 months). There are seven ongoing CRs on HD IL-2 and none on IL-2 and IFN (P = .014).
Survival Data
One hundred ninety-two patients were followed up for survival. Survival by treatment arm, stratification subset, and MSKCC prognostic criteria is shown in Table 6. Median survival from time on-study was 13 months for patients assigned to IL-2 and IFN therapy and 17 months for those assigned to HD IL-2. This trend in survival benefit favoring HD IL-2 was not statistically significant (P = .211; Fig 3).
A statistically significant survival benefit was noted for patients with liver or bone metastases (P = .001) and for patients with primary tumors in place (P = .040) with HD IL-2 therapy (Fig 4A through 4F).
Broadly similar results were found when the analysis was limited to the 165 patients with clear-cell histology (77 patients receiving IL-2 and IFN; 88 patients receiving HD IL-2). There was still a significant response difference for patients with liver or bone metastases (P = .036), a trend in the number of patients progression-free at 3 years (P = .067), and a survival benefit for patients with liver or bone metastases (P = .002) or primary tumors in place (P = .034) all favoring HD IL-2.
DISCUSSION
In this study, HD IL-2 produced a statistically significant improvement in response rate (23.2% v 9.9% P = .018) compared with IL-2 and IFN. The response quality, as reflected by the CR rate (8% v 3%), durable CR rate (7.4% v 0%), and response duration (median 24 v 15 months) also favored HD IL-2 treatment, although only durable CR rate was statistically significant. HD IL-2 did not have a significant impact on median progression-free survival or median overall survival. Given that IL-2–based therapy for metastatic renal cell carcinoma benefits a minority of patients, we did not expect to see significant differences in these survival end points. However, this study confirmed the observation from prior CWG phase II studies, showing a trend in the number of patients free of disease progression at 3 years (10 v three patients; P = .082) favoring HD IL-2 therapy.
Patients with performance status ≥ 1, primary tumor in place, or liver or bone metastases have been reported to be less likely to respond to IL-2–based therapy.17 Consequently, we stratified study patients for these variables. Of note, patients with liver or bone metastases and patients treated with their primary tumor in place had significantly improved response rates and survival with HD IL-2 relative to lower-dose IL-2 and IFN. The current study represents the first time a survival advantage has ever been shown for any stratified subset of patients receiving IL-2–based therapy. However, the results of the subset analyses should be seen as hypothesis generating and will need to be confirmed in future trials.
Although the response rate for patients receiving HD IL-2 remained relatively constant across all prognostic variables (21% to 24%), IL-2 and IFN was essentially inactive in patients who had liver or bone metastases or their primary tumor in place. The explanation for this unanticipated result is not readily apparent. It is possible that higher serum or tissue IL-2 levels are needed either to overcome the immune suppression associated with greater tumor burden or to activate T cells in sites of disease other than lung and soft tissue. Consequently, it seems that patients with liver or bone metastases or unresected primaries represent a group of patients who seem to require a more intensive IL-2 regimen to achieve clinical benefit, whereas the impact of dose is less critical in patients with resected primaries and tumor confined to lung.
In contrast to earlier CWG phase II trials, the response rate to HD IL-2 in this study was significantly higher than the response rate with IL-2 and IFN. Considered in the light of this trial, the previously observed similarities in response rates might have been the consequence of less rigorous auditing of the responses in the prior IL-2 and IFN studies than was performed for the HD IL-2 data set that was prepared for United States Food and Drug Administration submission. Although the median response duration seen for patients on the HD IL-2 arm of this study was shorter than in the prior CWG phase II HD IL-2 trial (54 v 24 months), the fact that the plateau on the response duration curve falls just below the 50% mark probably accounts for this difference. As expected, HD IL-2 produced more acute toxicity than outpatient IL-2 and IFN. However, holding therapy rapidly reversed most toxicity, and treatment-related mortality occurred in only one patient on each arm.
Other investigators have previously studied the relative value of IL-2–based regimens in patients with metastatic renal cancer. In 1998, the French Immunotherapy Group reported on a large, phase III randomized study that compared inpatient continuous-infusion IL-2 alone with either IFN alone or the combination of IL-2 and IFN.10 They concluded that the combination of IL-2 and IFN was superior in terms of response rate and 1-year progression-free survival as compared with monotherapy with either agent. This study used an IL-2 regimen that was less intensive than bolus HD IL-2, which may explain the low level of antitumor activity in the IL-2 alone arm (8% response rate). In addition, although IL-2 and IFN produced a superior response rate, this did not translate into more durable responses or an improvement in median or overall survival. In 2003, NCI Surgery Branch investigators reported results of a randomized phase III trial that compared the efficacy and toxicity of HD IV IL-2 to a lower-dose IV regimen (10% of high dose) using an otherwise identical administration schedule.18 In that study, patients who received HD IL-2 had a significantly higher response rate (21% v 13%; P = .048) and were more likely to have durable responses than those who received the lower-dose IV regimen. However, there were no significant differences in overall survival between the two groups. Despite the more acute toxicity with the high-dose regimen, quality-of-life assessments showed no differences between the two treatment arms. In an overlapping three-arm study, a third group of patients were randomly assigned to receive a low-dose outpatient subcutaneous IL-2 regimen. In this three-arm comparison, the response rates were 21% for HD IL-2, 11% for lower-dose IV IL-2%, and 10% for subcutaneous IL-2. Once again there were no significant survival differences. In this study, the vast majority of patients had an excellent performance status and had undergone prior nephrectomy, and relatively few had liver or bone metastases, making subset analyses difficult to perform. In the CWG study, most of the trend in survival difference favoring HD IL-2 was attributable to the patient populations with liver or bone metastases and primary tumor in place, perhaps explaining why the survival difference was less pronounced in the NCI Surgery Branch trial. Taking these three randomized studies into consideration, one can conclude that HD IL-2 is superior to both lower doses of IL-2 or IL-2 and IFN in terms of response rates and response quality.
This CWG phase III randomized trial provides additional evidence that HD IL-2 should remain the preferred therapy for selected patients with access to such treatment. Furthermore, it suggests that patients with bone or liver metastases or a primary tumor in place may receive little benefit from a lower-dose IL-2 regimen. Given the toxicity and expense associated with HD IL-2 therapy, and the still-low overall response rate, these results suggest that better criteria for selecting patients for HD IL-2 therapy are necessary. Although some progress has been made in this regard, even with the best selection criteria, the majority of patients will not respond to IL-2 therapy.19-22 Consequently, new treatment options that focus on important targets (eg, angiogenesis and signal transduction) will still be necessary for those with unfavorable selection features or who experience disease progression after IL-2–based therapy.
Authors' Disclosures of Potential Conflicts of Interest
Acknowledgment
We thank Judi Manola and Robert Parker for their input on statistical considerations; Susan Graham-McLaughlin and Toneika Allen for assistance in manuscript preparation; and Amanda Youmans, Daniel Clancy, Laura Ruttner, and Christine Connolly for their invaluable assistance with management of the central database.
NOTES
Supported in part by grants to each institution from Chiron Therapeutics, Division of Chiron Corporation, Emeryville, CA; and Schering Plough Corporation, Kenilworth, NJ.
Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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