ABSTRACT: Interleukin-2 (IL-2, Proleukin) is one of the most effective agents in the treatment of metastatic renal cell carcinoma and metastatic melanoma. High-dose IL-2 therapy produces overall response rates of 15% to 20%; however, it is associated with significant toxicities that affect essentially every organ system. Although IL-2-related toxicities are usually reversible with therapy discontinuation, alternative IL-2 regimens have been evaluated. Several phase II studies have demonstrated that administering lower doses of IL-2 by IV bolus or continuous IV infusion or subcutaneously produces overall response rates similar to those with high-dose IL-2 therapy; however, randomized clinical trials have not yet been completed. In renal cell carcinoma, combining IL-2 with interferon alfa (Intron A, Roferon-A) or chemotherapy agents produces similar or increased overall response rates compared with the response rates of IL-2 alone, with no survival advantage. Combination IL-2 regimens in metastatic melanoma patients have produced variable results. The most promising regimens have included various IL-2-based biochemotherapy regimens in other patients. Randomized studies confirming the superiority of these regimens over high-dose IL-2 therapy are needed.
An estimated 32,000 new cases of renal cell carcinoma and 54,000 new cases of melanoma will be diagnosed in the United States in 2002. Although 70% of patients with renal cell carcinoma and 85% of patients with melanoma have local or locally advanced disease at diagnosis, many of these patients will develop metastatic disease.[2,3] The median survival time for metastatic renal cell carcinoma patients after diagnosis is 8 to 12 months; the 5-year survival rate is 0% to 20%.[4,5] Prognosis for metastatic melanoma patients is even more dismal; the median survival time is 6 to 8.5 months, with 5-year life expectancy less than 10%.
Traditionally, surgery has been the most effective therapy for renal cell carcinoma, but the poor survival rates (5-yr survival rate, 2%) in patients with distant metastases, have limited this approach. Radiation therapy has also yielded disappointing results and is only used palliatively in these patients.[2,5] Furthermore, renal cell carcinoma is resistant to chemotherapy. In a review of approximately 4,000 renal cell carcinoma patients receiving more than 40 chemotherapeutic agents in phase II clinical trials, the overall response rate was 0-15%.[7A]
Similarly, effective therapies for metastatic melanoma are also limited. Surgery and radiation therapy are used only for palliation and to improve quality of life.[7B] Single-agent chemotherapy produces modest overall response rates (10% to 20%) in metastatic melanoma patients, but complete responses are rare. Although combination chemotherapy produces higher overall response rates compared with single-agent chemotherapy, this approach produces greater toxicity and does not prolong survival time. Therefore, the use of chemotherapy in the treatment of metastatic melanoma remains controversial, and its use is often limited to clinical trials.
The resistance of both metastatic renal cell carcinoma and melanoma to traditional oncology-related treatments has generated widespread interest in developing and evaluating other effective therapies, such as immunotherapy. The relationship between the immune system and renal cell carcinoma and melanoma is suggested clinically; for example, spontaneous regression of renal cell carcinoma and melanoma in some patients suggests that these malignancies may be responsive to the patient’s immune system.[3,9] Thus, enhancing a patient’s immune system with cytokines is a rational treatment approach. Both interferon alfa (IFN-a, Intron A, Roferon-A) and interleukin-2 (IL-2, Proleukin) are effective therapies for these malignancies. Interferon alfa and IL-2 have produced overall response rates of 10% to 15% and 15% to 20%, respectively, in metastatic renal cell carcinoma and melanoma patients.
While IFN-a has been approved and is considered standard in the adjuvant treatment of melanoma, only IL-2 is approved by the US Food and Drug Administration for the treatment of metastatic renal cell carcinoma and melanoma.[2,7,10]
IL-2, first identified as a T-cell growth factor in 1976, is a 15-kd glycoprotein produced primarily by T-helper cells.[2,11,12] Interaction of IL-2 with the IL-2 receptor, which is expressed in increased amounts on activated T cells, results in proliferation and differentiation of both B and T cells, cytotoxic cells, and stimulation of a cascade of cytokines, including various interleukins, interferons, and tumor necrosis factors. The antitumor effect of IL-2 is mediated by its ability to cause proliferation of natural killer cells (NK), lymphokine-activated killer cells (LAK), and other cytotoxic cells.
IL-2 Doses and Administration Methods
Various administration schedules and doses of IL-2 have been evaluated. High dosage IL-2 (600,000-720,000 IU/kg IV q8h) is the most commonly used regimen in the United States. The FDA-approved dosage for treatment of metastatic renal cell carcinoma or melanoma is 600,000 IU/kg administered by IV bolus over 15 minutes every 8 hours for a maximum of 14 doses. Following 9 days of rest, the regimen is repeated, if tolerated by the patient. In Europe, the approved method of IL-2 administration is by continuous intravenous infusion (18 million IU/m²/d for two 4.5-5-day cycles, with 6-8 days of rest between cycles). Dosages up to 24 million IU/m²/d IV administered over 24 hours have also been evaluated. Low-dose subcutaneous IL-2 regimens (1-30 million IU/m²/d) have been investigated because they may reduce toxicity without compromising efficacy.
The toxicity profile of IL-2 is dose, route, and administration dependent. This supplement includes an article titled Managing Toxicities of High-Dose IL-2, which more fully discusses the type, incidence, and management of toxicities associated with high-dose IL-2 therapy.
The 1992 FDA approval of high-dose IL-2 therapy for patients with metastatic renal cell carcinoma was based on the pooled results of seven phase II studies conducted at 21 institutions.[5,14] In these studies, IL-2 600,000 IU/kg (five studies) or 720,000 IU/kg (two studies) was administered as an IV bolus every 8 hours for 14 consecutive doses over 5 days, as tolerated. After 5 to 9 days of rest, an additional cycle was administered as tolerated. Courses (ie, two cycles) were repeated if patients displayed tumor response or disease stabilization.
Patients were continually monitored for response rates, remission durations, and survival times. The most recent overall response rate reported was 15%, and the complete response rate was 7%. Responses were durable, with a median duration of response of 54 months (range, 3-131+ months). Complete responders tended to have a longer duration of response than patients who achieved only a partial response (80+ vs 20 months, respectively), but the median duration of response for complete responders has not yet been reached. Baseline performance status (PS) was the only predictor of response: patients in relatively good health at therapy initiation, Eastern Cooperative Oncology Group (ECOG) performance status of 0, had almost twice the rate of overall response as that of patients with a poor baseline performance status, 17% for ECOG PS, 0 and 9% for ECOG PS, 1; P = .03. The median survival time was 16.3 months, which is higher than the historical median survival time for patients with metastatic renal cell carcinoma who do not receive high-dose IL-2.[4,14] This difference, however, may be attributed to the higher performance status and other favorable characteristics of patients who meet the rigorous eligibility requirements for high-dose IL-2 therapy. Additionally, 10% to 20% of patients are estimated to achieve a long-term (5-10 year) survival benefit. Baseline performance status (P < .01), prior nephrectomy (P < .01), and time from diagnosis to treatment (P = .01) were the most important predictors of survival.
Severe (grades 3/4) toxicities developed in most patients. The most common toxicity was hypotension, which occurred in 96% of patients (grades 3/4, 74%). Other severe toxicities resembled other clinical manifestations of septic shock. Most toxicities reversed rapidly after IL-2 discontinuation, and 89% of patients were discharged within 7 days of initial treatment. Despite the reversibility of toxicities, 4% of patients died of treatment-related toxicity in these early clinical trials. Since these trials were conducted, however, an understanding of the mechanism of the toxicity, improved patient selection, and better management techniques has evolved, contributing to the overall safety of high-dose IL-2 administration.
Continuous Intravenous IL-2
Because high-dose IL-2 therapy causes significant toxicity, various doses and routes of administration have been evaluated to achieve reduced toxicity without compromised efficacy. The short half-life and rapid clearance of IL-2 administered by IV bolus prompted investigators to administer IL-2 as a continuous IV infusion. Most studies administered IL-2 at 9 to 18 million IU/m²/d for 4 to 5 days, but doses up to 24 million IU/m²/d have also been evaluated. Overall response rates have varied, but the results of recent, multiple, phase I and II studies of 922 patients receiving IL-2 by continuous IV infusion showed an overall response rate of 13.3%.[10,15] Long-term survival following continuous IV infusion IL-2 therapy has also been reported recently. Negrier and colleagues conducted three phase II trials, in which 281 European patients receiving IL-2 18 million IU/m²/d by continuous IV infusion experienced a median survival time of 10 months. The overall 5-year survival rate was 6%, although 60% of patients with a complete response were alive at 5 years.
The results of a randomized, phase III study evaluating continuous IV infusion IL-2, subcutaneous IFN-a, and a combination of the two agents, showed an overall response rate of 6.5% in 138 patients receiving continuous IV infusion IL-2 (18 million IU/m²/d day 1-5 and 12-16) (see "Combination IL-2 Regimens: IL-2 and IFN-a" for more study details on page 8). Although the dose of IL-2 administered in this study was lower than those administered in high-dose IV bolus regimens, significant toxicity occurred. The most common severe (grades 3/4) adverse events were hypotension requiring maximal vasopressor support (68% of patients) and fever (43%). Grades 3/4 pulmonary, renal, and cardiac adverse events occurred in approximately 15% of patients. No treatment-related deaths were reported, and all patients recovered from toxicity after IL-2 discontinuation.
Similarly, the results of the only randomized study comparing the coadministration of LAK cells with either high-dose IL-2 (594,000 IU/kg q8h days 1-5 and 11-15) or continuous IV infusion IL-2 (18 million IU/m²/d days 1-5 and 22.5 million IU/m²/d days 11-16) in renal cell carcinoma patients showed a high incidence of life-threatening toxicities with continuous IV infusion IL-2 therapy coadministered with LAK cells. Fever, infection, and elevated alkaline phosphatase levels were more common in the continuous IV infusion group, and thrombocytopenia was more common in the high-dose IL-2 group. Overall response rates were similar: 20% in patients receiving high-dose IL-2 and 15% in the continuous IV infusion group.