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10.1245/ASO.2005.03.063
Annals of Surgical Oncology 12:381-390 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Initial Clinical Response Predicts Outcome and Is Associated With Dose Schedule in Metastatic Melanoma and Renal Cell Carcinoma Patients Treated With High-Dose Interleukin 2

Kathryn Spanknebel, MD1, Kenneth Y. Cheung, PhD2, John Stoutenburg, MD3, Karl Hurst-Wicker, BS1, Charles Hesdorffer, MD1,3, Gail DeRaffele, RN1 and Howard L. Kaufman, MD1

1 Department of Surgery, Columbia University College of Physicians and Surgeons, 177 Fort Washington Avenue, MHB-7SK 20, New York, New York 10032
2 Department of Biostatistics, Columbia University Mailman School of Public Health, 722 West 168th Street, New York, New York 10032
3 Department of Medicine, Division of Hematology and Oncology, Columbia University College of Physicians and Surgeons, 6Knuckle Building, Room 435, New York, New York 10032

Correspondence: Address correspondence and reprint requests to: Kathryn Spanknebel, MD; E-mail: ks2166{at}columbia.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: High-dose interleukin (IL)-2 is an effective agent for the treatment of metastatic malignant melanoma and renal cell carcinoma. This study evaluated the outcomes of patients receiving two commonly used intravenous IL-2 schedules that have never been directly compared.

Methods: Forty-seven metastatic malignant melanoma and renal cell carcinoma patients were identified from a prospective database who underwent high-dose IL-2 therapy (720,000 or 600,000 IU/kg) during 1999 to 2003. Disease-specific survival (DSS) was calculated by the Kaplan-Meier method with the log-rank test on an intention-to-treat basis. Multivariate Cox regression analysis of prognostic variables associated with outcome was performed. Factors associated with initial response and prevention of disease progression were determined.

Results: Objective response (5 partial and 5 mixed) or disease stabilization was noted in 9 (20%) and 10 (22%), respectively, of 46 assessable patients after 1 course of therapy. Four patients (22%) achieved disease-free status after the third course of IL-2 (n = 1) or surgical resection of confined metastatic disease (n = 3). At 19.1 months’ median follow-up, factors associated with improved DSS included an initial clinical response to IL-2 therapy (P < .001) and a higher administered dose (P = .04). Patients who received 720,000 IU/kg were more likely to experience an initial major objective response (P = .03) and disease stabilization (P = 0.03) independent of the tumor treated. Objective response early in the course of therapy was the only independent predictor of tumor-related mortality (P = .004).

Conclusions: The initial clinical response to IL-2 therapy is an independent predictor of improved outcome associated with DSS and the 720,000 IU/kg dose. These results support further prospective trials with increased IL-2 dose schedules in a larger cohort of patients.

Key Words: Melanoma • Renal cell carcinoma • Immunotherapy • Interleukin 2 • Metastatic


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
High-dose bolus intravenous (IV) interleukin (IL)-2 is one of the most effective agents for the treatment of patients with metastatic malignant melanoma (MM) and renal cell carcinoma (RCC).1 IL-2 remains the only cytokine approved for therapy of MM and the only drug approved for treatment of metastatic RCC.2,3

In 1992, the Food and Drug Administration (FDA) approved the use of high-dose IL-2 in metastatic RCC patients on the basis of the pooled results of 7 phase II trials performed at 21 institutions.4 In these studies, IL-2 720,000 or 600,000 IU/kg was administered as an IV bolus every 8 hours for up to 14 consecutive doses as tolerated, with a period of rest followed by an additional cycle. Courses (composed of two cycles) were repeated in patients who demonstrated tumor response or disease stabilization. Overall response rates of 20%, with a complete and durable response in 9%, have been reported.1 Similarly, in 1998, IL-2 was also approved for use in MM patients on the basis of the durability of response in 270 patients entered onto 8 clinical trials.5 In seven of the trials, IL-2 was administered by using the same high-dose bolus method previously reported in RCC, with overall response rates of 17% and a durable complete response in 7% of patients.5 Most MM6 and RCC7 patients who responded to therapy in these trials have not relapsed according to mature follow-up data extending to 17 years.8

Although two high-dose bolus schedules (720,000 and 600,000 IU/kg) have proven effective in the treatment of MM and RCC, neither retrospective comparison nor prospective evaluation has been performed to assess potential differences in efficacy or toxicity profiles. Clinicians recommending therapy in this patient group initiate a particular IV dose based on personal preference, institutional bias, or cost with the assumption that the doses are therapeutically equivalent. In addition, the FDA-approved dose of 600,000 IU/kg IV is an influencing factor for clinicians administering therapy; investigators at the National Cancer Institute and collaborators at extramural institutions use the 720,000 IU/kg IV dose. Moreover, significant treatment-related toxicity and potential mortality limit the delivery of this therapy to highly selected patients at specialized centers.9–11 As a result, researchers have focused a great deal of effort on investigating alternative treatment strategies12 and significantly reduced dose regimens13–15 to limit toxicity and enable more convenient and cost-effective delivery of therapy to more MM16–18 and RCC19,20 patients.

An illustration of these efforts is a recent prospective trial that randomized 400 RCC patients to high-dose (720,000 IU/kg), low-dose (72,000 IU/kg), or subcutaneous IL-2. The outcome of this trial suggested that reduced-dose schedules, although they demonstrated fewer treatment-related toxicities, resulted in decreased objective response rates compared with high-dose schedules.21 Response durability was improved for patients who received a higher dose regimen; however, this did not result in an overall survival advantage.21 Similar prospective trials do not exist for MM, and, in general, reduced-dose schedules of single-agent IL-2 immunotherapy (with or without interferon alfa) have been disappointing.18,22,23 Alternative strategies testing IL-2 in combination with chemotherapy (biochemotherapy) have demonstrated overall response rates from 25% to 48%16,20,24–26; however, trials have been hindered by small sample sizes and have not been powered to detected an overall survival benefit. A recent large phase III cooperative group trial powered to address this question found no survival advantage to biochemotherapy over chemotherapy alone.27

Currently, high-dose bolus IV IL-2 therapy seems to be more effective than IL-2 administered by alternative routes and schedules or in combination with other agents.2 Because two published high-dose regimens are available, we were interested in comparing the efficacy of the two doses (720,000 or 600,000 IU/kg) administered to a cohort of MM and RCC patients over 4 years at two tertiary referral centers. This exploratory analysis focuses on differences in objective response rates, potential factors associated with response, treatment-related toxicity, and overall patient outcomes. This serves as a first step toward a better understanding of two commonly used high-dose IL-2 schedules not previously compared.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Review of a prospective database from June 1999 through May 2003 identified patients with MM or RCC who received high-dose IV bolus IL-2 therapy. Patients selected for therapy had histologically confirmed disease that was clinically or radiographically measurable. Patients were not offered therapy if they had poor performance status (Eastern Cooperative Oncology Group status >1), active central nervous system involvement, recent corticosteroid therapy, or active autoimmune disease. Patients were screened for coronary artery disease by history and stress thallium evaluations if indicated. In general, patients with significant cardiopulmonary, renal, or hepatic insufficiency were not offered therapy.

Doses of 720,000 or 600,000 IU/kg were used during the first 33 months and last 15 months of the study period, respectively, according to the local practices of two major tertiary referral centers where the senior author (H.L.K.) was employed during the period of study. Patients received high-dose IL-2 at 720,000 IU/kg IV (group 720K) every 8 hours to the maximum number of tolerated doses (not to exceed 15 consecutive doses in any given cycle) or 600,000 IU/kg IV (group 600K) at the same dose schedule and limits. Toxicities of IV IL-2 were managed according to published guidelines and algorithms.28 All treatments were divided into two cycles of therapy, with a rest period between cycles of approximately 10 days and up to 3 weeks’ duration. At the end of two cycles of therapy (which constituted one course), patients were assessed by physical examination and radiographic staging for objective treatment response. Those with a favorable response (stable or regressing disease) underwent additional courses of IL-2 therapy. In general, patients were assessed every 2 to 4 months for 2 years and at increasing intervals thereafter.

Response to therapy is defined as complete, partial, mixed, stable, or progressive according to the following criteria:

  1. Complete response: disappearance of all known measurable disease.
  2. Partial response: 50% decrease in tumor mass with no evidence of progression in any lesion or development of new lesions.
  3. Mixed response: 50% decrease in tumor mass at any site and 25% increase in tumor mass at any other site with no development of new lesions.
  4. Stable response: increase less than 25% and no evidence of new lesions.
  5. Progressive disease: 25% increase in tumor mass or development of new lesions. Patients with stable disease, partial response, mixed response, or complete response after a course of IL-2 were considered to have an objective response to therapy.

Patient characteristics and treatments administered were analyzed according to dose schedule by using descriptive statistics; differences between groups were determined with Fisher’s exact test and the Mann-Whitney test. Disease-specific survival (DSS) was calculated with the Kaplan-Meier method with the log-rank test for patients who received 720,000 or 600,000 IU/kg doses on an intention-to-treat basis (SPSS version 10.0; SPSS Inc., Chicago, IL). Prognostic variables associated with outcome were subjected to multivariate Cox regression analysis. An evaluation of factors associated with clinical response was determined by using Fisher’s exact test. Variables associated with the prevention of progressive disease after an initial course of therapy were determined by the likelihood ratio test. Significance was defined as P < .05, and all tests were two tailed.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Between June 1999 and May 2003, a total of 47 patients with MM or RCC were treated with IV high-dose bolus IL-2. Demographic data for all patients are listed in Table 1Go. Clinically significant parameters were not different between the two groups, thus indicating consistent patient selection and treatment at the different institutions over the course of the study. Overall, the population had a good performance status with a predominance of MM patients. Both groups had undergone multiple previous treatments, including resection of primary tumors in four RCC and all MM patients with known primary tumors. One third (14 of 47) of patients received IL-2 as initial therapy for metastatic disease. Treatment details are listed in Table 1Go and demonstrate comparable delivery of IL-2 therapy between patient groups, as measured by the number of doses delivered per course and the total cumulative dose per course. Clinically significant toxicity in each group required that more than half of the treatment courses be stopped before the maximum allowable number of doses was given. Overall, more courses were delivered to patients who received the 720,000 IU/kg dose (P = .03 vs. 600,000 IU/kg; Fisher’s exact test), and this seemed to be a function of treatment response rather than associated toxicity.


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  		TABLE 1. Patient features and treatments administered according to interleukin (IL)-2 dose
 
Patients experienced similar associated grade 3 and 4 toxicities (Table 2Go). With the exception of reduced hypotension with the 600,000 IU/kg dose, there seemed to be no benefit associated with a reduced dose with respect to toxicity. In fact, patients who received doses of 600,000 IU/kg experienced increased central nervous system toxicity and gastrointestinal symptoms compared with those who received the higher 720,000 IU/kg dose. Thrombocytopenia was more common with 720,000 IU/kg, but this did not correlate with clinically significant bleeding episodes, which occurred in a minority of patients. There was no treatment-related mortality in either group, and all toxicities resolved with discontinuation of IL-2 therapy.


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  		TABLE 2. Toxicities of patients receiving a 720,000 IU/kg (group 720K) or 600,000 IU/kg (group 600K) intravenous bolus of interleukin 2, n (%)
 
There were 10 objective responses in 46 assessable patients after 1 course of IL-2 therapy, for an overall initial response rate of 23%. Patients who received the 720,000 IU/kg dose experienced higher objective response rates after one course of therapy compared with those who received 600,000 IU/kg (26% vs. 17%, respectively); however, this was not statistically significant (P = .72, Mann-Whitney test). Patients who received the higher dose schedule were, however, more likely to experience stabilization of disease after one course of therapy compared with patients who received the 600,000 IU/kg dose (35% vs. 4%, respectively; Table 3Go). As a result, patients who received higher doses were more likely to have additional cycles and courses of IL-2 therapy administered than were those who received the 600,000 IU/kg dose (P = .03; Fisher’s exact test; Table 2Go). Factors associated with prevention of disease progression after one course of IL-2 therapy included a higher dose (P = .006 vs. 600,000 IU/kg, likelihood ratio test; odds ratio, 2.37; 95% confidence interval [CI], 1.24–4.53) but not the tumor being treated (P = .08, RCC vs. MM, likelihood ratio test; odds ratio, 1.83; 95% CI, .90–3.71) or the logarithmic value of the total dose delivered (P = .15, likelihood ratio test; odds ratio, 3.68; 95% CI, .59–22.8).


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  		TABLE 3. Patient responses after each course of interleukin (IL)–2 therapy according to 2 different doses administered to 46 assessable patients
 
A trend toward improved durability of response in patients who received a higher dose schedule was demonstrated. Table 4Go summarizes the status and duration of response for 18 of 19 patients with long-term follow-up available who exhibited an initial favorable response to IL-2 therapy. In all, 46% (6 of 13) of group 720K patients were alive at a median follow-up of 33.6 months, and 3 patients achieved a complete response: 1 RCC patient after the third course of IL-2 therapy and 2 MM patients after surgical resection of isolated metastatic disease. Both melanoma patients experienced an initial stable response to one course of IL-2 therapy, and partial regression of disease occurred after a second course of IL-2. One patient underwent resection of confined gastrointestinal metastases after regression of other peritoneal and soft tissue disease. The other patient underwent resection of isolated pulmonary metastasis. Both patients crossed over to the 600,000 IU/kg group for an additional consolidation course of IL-2 after surgical cure and remain with no evidence of disease at last follow-up. Eighty percent of responding patients (four of five) in the 600K group are alive at a median follow-up of 17.2 months and are currently enrolled in ongoing IL-2 therapy protocols. One melanoma patient received IL-2 as an initial therapy for metastases to lung, mediastinal lymph nodes, and spleen and had a mixed response after two courses. After systemic chemotherapy with thalidomide and gefitinib and a course of external beam radiotherapy to the mediastinum, disease was confined to the spleen and a single parenchymal lung nodule. The patient subsequently underwent splenectomy and resection of the isolated lung mass and remains in remission at last follow-up. The median follow-up for responding patients was significantly different between the two groups of patients, favoring a potential improved durability in the 600K group (P < .001; log-rank test; Table 4Go). Additional follow-up is necessary to know the true benefit of a higher dose with respect to response durability.


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  		TABLE 4. Response duration in months and status of all assessable patients at last follow-up after interleukin 2 therapy with intravenous 720,000 IU/kg (group 720K) or 600,000 IU/kg kg (group 600K)
 
At a median follow-up of 19.1 months and with 32% of all patients (14 of 44) surviving at last follow-up, there was an associated improvement in DSS for patients who received 720,000 vs. 600,000 IU/kg on an intention-to-treat basis (P = .044; log-rank test; Fig. 1Go). Moreover, patients with any objective response to an initial course of IL-2 had significantly improved DSS compared with those with progressive disease (P < .001; log-rank test; Fig. 2Go). On multivariate analysis, any initial favorable clinical response to IL-2 therapy was determined as the most important independent predictor of DSS (P = .004), whereas dose schedule (P = .38) and the tumor being treated (P = .61) were not predictive of patient outcome (Table 5Go).


Figure 1
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  		FIG. 1. Disease-specific survival of all patients receiving either 720,000 IU/kg (group 720K) or 600,000 IU/kg (group 600K) of interleukin 2 on an intention-to-treat basis, analyzed by the Kaplan-Meier method with log-rank test.

 

Figure 2
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  		FIG. 2. Disease-specific survival of all patients receiving either 720,000 IU/kg or 600,000 IU/kg of interleukin 2 on an intention-to-treat basis according to the initial response to therapy, analyzed by the Kaplan-Meier method with log-rank test. PD, progressive disease.

 

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  		TABLE 5. Multivariate Cox regression analysis of factors associated with disease-specific survival after therapy with either 720,000 or 600,000 IU/kg intravenous doses of interleukin 2
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
High-dose IV bolus IL-2 is one of the most effective treatments for either MM or RCC and imparts the chance for complete and durable response in a small subgroup of patients.8 The FDA-approved dose of IL-2 for this patient group is 600,000 IU/kg, although a higher dose (720,000 IU/kg) is commonly used by many clinicians.4,5 Because toxicity of therapy is significant, cost is high, and the number of patients who may benefit from this treatment overall is low, researchers have justified the implementation of reduced-dose schedules and alternative strategies to decrease associated toxicity and reduce cost. These regimens, however, are acceptable only if clinical outcomes are maintained; they have been the subject of prospective randomized trials21 and ongoing investigation29 suggesting that IL-2 is most effective only at high doses. However, the two accepted high-dose IV regimens have not been directly compared in retrospective analysis or prospective trials. In this report, two accepted high-dose IL-2 regimens were analyzed in a cohort of MM and RCC patients to determine whether improved outcomes may be realized with higher administered doses.

In this comparison, toxicity profiles were similar between the two groups and allowed for a comparable number of doses per course and cumulative overall dose to be delivered. On the basis of previously reported dose-escalation data, it was necessary to reduce IL-2 IV bolus doses by 90% to achieve a clinical reduction in measured toxicity21; therefore, it is not surprising that no significant difference in treatment-related toxicity was demonstrated. Because the treatment effects of high-dose IL-2 are manageable,28,30 with no reported treatment-related mortality in as many as 809 consecutively treated patients31 and no associated long-term effects after discontinuation of therapy,31 strategies should strive to maintain high activity levels as measured by response rate and durability and should not compromise the effectiveness of therapy with reduced doses. In general, a reduced dose of 600,000 IU/kg (although this is considered a high-dose regimen by those using this therapy) did not impart an advantage of fewer toxicities and thus should not be considered an important factor in choosing which high-dose regimen to use.

Patients in this study experienced major objective responses with both treatment regimens; however, patients who received 720,000 IU/kg were more likely to have an initial response after a single course of IL-2 therapy. Furthermore, an initial favorable response was associated with ongoing prevention of progressive disease (i.e., response durability), and this resulted in more courses delivered to patients who received 720,000 vs. 600,000 IU/kg. The concept of an improved response rate and durability with higher IV bolus schedules is in agreement with the results of large prospective randomized trials comparing either of two high-dose bolus regimens with alternative strategies that use markedly reduced schedules. This observation was interesting in that a seemingly small reduction of 16.6% (600,000 IU/kg IV every 8 hours) was associated with similar significant differences in response rate and durability in our study. This result is inconsistent with other reported trials.

Yang et al.21 tested the effectiveness of a reduced-dose regimen (72,000 IU/kg IV) and an alternative route of administration (subcutaneous IL-2) and compared this with an established high-dose schedule (720,000 IU/kg IV) in 400 randomized RCC patients. Major objective response rates to the high-dose regimen were nearly twice those for low-dose or subcutaneous schedules (21% vs. 11% vs. 10%, respectively; P = .033).21 In addition, the only prognostic treatment variable associated with response rate was the number of doses delivered, which was important only for patients who received higher administered doses.21 Furthermore, other investigators in a preliminary report of 193 patients with metastatic RCC randomized to receive either 600,000 IU/kg IV or subcutaneous IL-2 with interferon alfa demonstrated a trend toward improved initial major objective response (25% vs. 12%, respectively) with high-dose regimens.15 These reports focused on homogeneous groups of patients with respect to tumor diagnosis. In our exploratory analysis, most patients had a diagnosis of MM, although response rates were shown to be independent of the tumor being treated (MM vs. RCC).

It is also important to keep in mind that various patient- and treatment-related variables have inconsistently been associated with response to IL-2 and are still poorly understood. Factors associated with improved response rates for MM patients have included subcutaneous metastatic sites,32,33 pre-treatment performance status,34 prior systemic therapy,5 hypotension requiring vasopressor support,35 and post-IL-2 lymphocytosis.36 One trial investigating IL-2-based biochemotherapy in metastatic RCC patients stratified patients according to pretreatment risk factors reported in other studies to be predictive of outcomes, including erythrocyte sedimentation rate, lactate dehydrogenase levels, neutrophil count, hemoglobin level, and site of metastatic disease (extrapulmonary or bone).37 In this study, stratification by risk factors into low- and intermediate-risk groups did not effectively predict which patients responded to biochemotherapy.37 With the absence of pretreatment- or treatment-related predictors of outcome, it becomes difficult to enrich prospective trials with patient groups who are most likely to derive a benefit from IL-2 therapy and to measure differences in treatment efficacy, such as administered dose. Although predictors of response would be helpful for selecting patients appropriate for high-dose IL-2 treatment, there are currently no confirmatory studies validating any of these factors.

In this trial, a trend was observed for improved DSS for patients who received 720,000 IU/kg compared with 600,000 IU/kg; however, this was not significant on multivariate analysis. At a median follow-up of 19.1 months, with 30% of patients still alive at the time of publication, the only independent predictor of improved overall survival was an initial response to IL-2 therapy. One should consider that this is a small retrospective study not appropriately randomized and powered to detect true differences between patient groups. Nonetheless, a recent large randomized study also failed to show a survival advantage with higher administered doses of IL-2 in metastatic RCC patients despite improved response rates and durability of response when compared with low-dose or subcutaneous schedules.21

This highlights the fact that it becomes difficult to prove survival advantages for treatments that result in such low cure rates. The observation that the patient group under study demonstrated higher overall response rates (41%) compared with other studies that administered high-dose schedules to MM and RCC patients1,4,5 may have enabled the detection of treatment-related associations that could be confirmed when tested in a larger cohort of patients with longer follow-up. In addition, it is of paramount importance to take a closer look at additional pretreatment and treatment parameters, as well as novel immunological and biological surrogates for response, that may be associated with response rate, durability, and survival, to select more appropriate patients for IL-2 therapy and prospective evaluation.

In summary, this study demonstrates that the two most common high-dose schedules of IV bolus IL-2 are capable of producing major objective tumor regression in patients with MM and RCC. Responses are durable and, when combined with other treatment modalities such as surgery, radiotherapy, chemotherapy, or other biologic therapy, have shown that patients may be cured of metastatic disease. It remains to be determined whether further modifications of IL-2-based regimens or the addition of newer agents to IL-2 will produce better tumor response and survival. A randomized trial investigating the treatment effects of these two dose schedules could be justified given the important association of improved response rates with higher administered doses. On the basis of our experience with these retrospective data, a trial randomizing 316 MM and RCC patients (in 2 strata) to 1 of 2 high-dose IV arms of therapy will give 80% power to detect a hazard ratio of 1.5, assuming a 2-year accrual period and a 1-year follow-up; power would increase if it took longer to enroll these patients. The feasibility of such a trial would be addressed optimally in the setting of a multi-institutional or cooperative group setting. It would be important to investigate biological and immunological correlates of response in such a proposed trial to further our understanding of those patients most likely to benefit from high-dose IL-2 immunotherapy.


   ACKNOWLEDGMENTS
 
Supported by grants from the National Institutes of Health (K08–79881), the National Cancer Institute (R01-093696), and the Doris Duke Charitable Foundation (T98052).

Received for publication March 19, 2004. Accepted for publication December 23, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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