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© 2001 American Society for Clinical Oncology Factors Associated With Response to High-Dose Interleukin-2 in Patients With Metastatic MelanomaByFrom the Surgery Branch and Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD. Address reprint requests to Steven A. Rosenberg, MD, PhD, Surgery Branch, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 2B42, 9000 Rockville Pike, Bethesda, MD 20892-1502; email: steven_rosenberg{at}nih.gov
PURPOSE: The present study attempted to identify characteristics that correlated with clinical response to interleukin (IL)-2 therapy in patients with metastatic melanoma. PATIENTS AND METHODS: We retrospectively evaluated laboratory and clinical characteristics of 374 consecutive patients with metastatic melanoma treated with high-dose intravenous bolus IL-2 (720,000 IU/kg) from July 1, 1988, to December 31, 1999, at the Surgery Branch of the National Cancer Institute. RESULTS: The overall objective response rate was 15.5%. Pretreatment parameters such as patient demographics, laboratory values, and prior therapy did not correlate with response; however, 53.6% of patients with only subcutaneous and/or cutaneous metastases responded, compared with 12.4% of patients with disease at other sites (P2 = .000001). During therapy, patients who were responders tended to have received more doses during course 1 (16.2 ± 0.3 doses v 14.5 ± 0.2 doses; P2 = .0095); however, when limited to patients who were able to complete both cycles of course 1, there was no statistically significant difference (P2 = .27). Responders had a higher maximum lymphocyte count immediately after therapy compared with nonresponders (P2 = .0026). The development of abnormal thyroid function tests and vitiligo after therapy was associated with response (thyroid-stimulating hormone, P2 = .01; free T4, P2 = .0049; vitiligo, P2 < 10-6), although thyroid dysfunction may have been related more to the length of IL-2 therapy than to response. CONCLUSION: The presence of metastases only to subcutaneous and/or cutaneous sites, lymphocytosis immediately after treatment, and long-term immunologic side effects, especially vitiligo, were associated with antitumor response to IL-2 therapy.
THE INCIDENCE OF cutaneous malignant melanoma continues to increase faster than any other cancer in the United States. Approximately 51,000 new cases of invasive malignant melanoma will be diagnosed this year. Approximately one in 74 Americans will develop this malignancy in his or her lifetime.1 The death rate is also increasing. Nearly 8,000 Americans will die this year from malignant melanoma.2 Survival is directly related to staging. The 5-year survival rate for those with stage I is more than 95% and decreases significantly to less than 2% for those with stage IV. The median survival time for patients with stage IV disease is approximately 7 months.3 The only chemotherapy agent approved by the Food and Drug Administration for the treatment of patients with metastatic melanoma is dacarbazine, which may have a response rate of up to 25%. However, durable responses are extremely unusual, with the majority of patients relapsing within several weeks to months. Treatment with interleukin-2 (IL-2), also approved by the Food and Drug Administration, is associated with a 15% objective response rate. About a third of these patients experience a complete response, the majority of which are durable and probably curative.4 IL-2 is a 15-kd glycoprotein produced by helper T-lymphocytes that plays a varied and critical role in immunoregulation. Early experimental studies demonstrating the ability of IL-2 to mediate the regression of established metastases in mice5 led to clinical trials in patients with metastatic cancer that showed the effectiveness of IL-2 treatment in humans as well.6,7 By 1994, the Surgery Branch at the National Cancer Institute (NCI) had established a standard dosing regimen for patients with high-dose IL-2 (720,000 IU/kg intravenously [IV] every 8 hours as tolerated for up to 5 days) and reported a series of 283 patients with metastatic melanoma and renal cell cancer.8 Melanoma patients had an objective response rate of 17%, with 7% having complete disappearance of assessable metastases; patients with renal cell cancer had a response rate of 20%, with 7% being complete. Follow-up in 1998 showed that over 70% of those complete responders remain ongoing4; in fact, no relapses occurred in melanoma patients who maintained a complete response more than 30 months.9,10 This high-dose bolus IV IL-2 (HD IV IL-2) regimen was approved by the Food and Drug Administration in 1998 for the treatment of patients with metastatic melanoma. Despite these durable responses, a significant factor limiting the use of HD IV IL-2 is the toxicity caused by IL-2. Although the side effects are transient and resolve when IL-2 administration is stopped, they can involve most organ systems. However, HD IV IL-2 can be safely administered, and in a series of patients treated at the NCI since 1987, treatment-related mortality was 0.3%.11 Because of these potential toxicities, we attempted in this study to identify characteristics of patients with metastatic melanoma who responded to treatment with HD IV IL-2 alone (in comparison to those who did not respond) which may be useful in identifying more appropriate IL-2 candidates. This article updates a previous publication12 from this institution that included patients with renal cell cancer and those receiving lower-doses of IL-2, lymphokine-activated killer cells, and IL-2 conjugated to polyethylene glycol, all of which may have affected the prior analysis and were not included in this study.
Patients Consecutive patients with assessable metastatic melanoma treated between January 1, 1988, and December 31, 1999, with HD IV bolus IL-2 (720,000 IU/kg every 8 hours as tolerated for up to 15 doses) were included in this study. Patients were enrolled with the intention to complete at least two cycles (one course) of therapy, although some did not complete both cycles because of either toxicity or progressive disease. All patients signed informed consent before protocol enrollment. The institutional review board of the NCI approved all protocols. Patients were not included if they had any previous exposure to IL-2, if they had received IL-2 conjugated to polyethylene glycol, or received any concurrent cell therapy (lymphokine-activated killer cells, tumor-infiltrating lymphocytes, or dendritic cells), other cytokines (including interferon alfa or tumor necrosis factor), chemotherapy, NG-monomethyl-L-arginine, monoclonal antibodies, or corticosteroids. At least 4 weeks were required between undergoing any systemic therapy and the first cycle of IL-2 therapy. In the past several years, we started using vaccine therapy directed against melanoma-associated antigens (such as gp100, MART-1, tyrosinase, and TRP1). These vaccines were given as an IV, subcutaneous, or intramuscular injection every 2 to 4 weeks, either before the patient advanced to HD IV IL-2 therapy or in conjunction with HD IV IL-2. No grade 3 or 4 toxicity was noted from the vaccines themselves. Thus these patients who also received HD IV IL-2 were included in this analysis.
IL-2 Therapy
Response Evaluation
Statistical Analysis
Patient Demographics Three hundred seventy-four patients were analyzed, consisting of 243 (65%) men and 131 (35%) women, with ages ranging from 16 to 81 years (median, 44 years). Three hundred eighteen patients (85%) had an Eastern Cooperative Oncology Group (ECOG) score of 0; 49 (13%) had an ECOG score of 1; and seven (2%) had an ECOG score of 2. Only 2% of patients were nonwhite.
Response
Pretreatment Factors Versus Response
The most predictive pretherapy factor for response was the presence of only subcutaneous and/or cutaneous metastases (Table 2). These patients had a response rate of 53.6%, compared with 12.4% in the remaining patients (P2 = .000001). Of note, a negative trend was noted for patients with brain metastases; only one of these patients had an objective response (P2 = .056).
In-Treatment Factors Versus Response Among all 374 patients, responders averaged more doses of IL-2 per course 1 (16.2 ± 0.3; median, 16; range, 10 to 23) than nonresponders (14.5 ± 0.2; median, 15; range, three to 26; P2 = .0095). However, when limited to those who were able to complete both cycles of course 1 (331 patients), there was no significant difference. In addition, the development of grade 3 or 4 toxicity (hypotension, tachycardia, arrhythmia, myocarditis or abnormal creatinine kinase, pulmonary insufficiency, oliguria, diarrhea, and neurologic/mental status changes) and the reasons for the cessation of IL-2 dosing (hypotension; arrhythmia; pulmonary insufficiency; neurologic/mental status changes; renal insufficiency; malaise; diarrhea; abnormal creatinine kinase, bilirubin, or platelets; and patient refusal) were not associated with response. Most notable, however, was the difference in lymphocytosis between responders and nonresponders (Table 3). The absolute lymphocyte counts were recorded immediately before therapy and daily from the initial administration of IL-2 to the time of discharge. In general, the lymphocyte count peaked 2 to 5 days after cessation of IL-2. Responders had a higher mean maximum lymphocyte count immediately after therapy (by 984/µL compared with nonresponders; P2 = .0026) as well as a higher change in lymphocyte count (maximum value minus pretreatment value), with responders having a greater change (by 869/µL compared with nonresponders; P2 = .007). There was no significant association between response and WBC counts, platelet counts, bilirubin, creatinine, and calcium levels.
Posttreatment Factors Versus Response In comparing long-term posttreatment parameters, responders were more likely to develop abnormal thyroid-stimulating hormone levels (thyroid-stimulating hormone [TSH]; P2 = .01), abnormal free T4 (FT4) levels (P2 = .0049), and vitiligo (P2 < 10-6) (Table 4). Given the confounding factor that these long-term immunologic side effects could be due to prolonged IL-2 therapy, which would not occur unless the patient continued to respond to IL-2, we then limited our evaluation to the presence of abnormal TSH or FT4 or the presence of vitiligo by day 60 after the start of IL-2 therapy or before the initiation of course 2. Twenty-two patients developed abnormal TSH levels; three were responders, and 19 were nonresponders (P2 = .46). Twenty-seven patients developed abnormal FT4 levels; four of them were responders, and 23 were nonresponders (P2 = .47). Only one patient (a nonresponder) developed new vitiligo by day 60.
Given that a high percentage of patients developed abnormal TSH (58.9%; 219 of 372 assessable patients) and abnormal FT4 (53.8%; 200 of 372 patients) during and after IL-2 therapy, we attempted to find out whether these abnormalities persisted. Limited by the fact that many nonresponders were not evaluated at long-term follow-up, with at least 6 months after the administration of the last IL-2 dose of course 1, 51.0% (26 of 51 assessable patients) had abnormal TSH, and 49.0% (25 of 51 assessable patients) had abnormal FT4. At least 1 year after course 1, 39.1% (nine of 23 assessable patients) continued to have abnormal TSH, and 52.2% (12 of 23 assessable patients) continued to have abnormal FT4.
Several prior studies have attempted to identify predictive factors for IL-2 response. One study reported the negative correlation with serum IL-6 and C-reactive protein levels in patients with renal cell cancer.13 In a study of 81 patients receiving various IL-2 regimens, increased C-reactive protein levels and the presence of visceral metastases were found to be negatively associated with response.14 The current study represents the largest single institution series of patients with metastatic melanoma receiving HD IV IL-2. A previous report from this institution evaluating predictive factors included 112 of these 374 patients.12 Overall, the strongest statistical predictor of response was the presence of only subcutaneous and/or cutaneous metastases. This finding has been previously noted from this institution.12,15 Prior studies12,16 have shown an increased response rate in melanoma patients receiving higher total doses of IL-2. When assessable patients were limited to those who were able to receive both cycles of therapy (331 of 374 patients) to correct for the confounding factor that nonresponders were less likely to return for subsequent cycles and those with poor status secondary to tumor burden were less able to complete both cycles, we did not find any significant association between response and the number of IL-2 doses. The number of doses between the two groups showed significant overlap (Table 2). Rebound lymphocytosis is one of the many hematologic side effects of IL-2.17 Lymphopenia occurs within minutes of an infusion of IL-2,18 probably due to margination of lymphocytes. Approximately 24 hours after cessation of IL-2 therapy, a rebound lymphocytosis occurs that persists for 2 to 7 days.19,20 Although some studies with smaller cohorts did not show an association with lymphocytosis,20,21 we found a strong positive association between response and lymphocytosis, as did some other reports.4,22 Thyroid dysfunction, mainly hypothyroidism, has been found to be common in patients receiving IL-2 therapy. Among initially euthyroid patients, 32% developed hypothyroidism during and 14% after IL-2 therapy.23 The mechanism seems to be autoimmune, as elevated levels of antithyroglobulin and antithyroid microsomal antibodies have been found.23,24 Although thyroid dysfunction seemed to be related to response in our initial data, a significant bias exists because patients who respond continue to receive IL-2, which can increase the incidence of abnormal TSH and FT4. When limited to an evaluation checkpoint of less than 60 days or before the initiation of course 2, no significant association existed between thyroid dysfunction and response. In fact, the frequency of thyroid dysfunction has been found to be significantly associated with IL-2 treatment duration.24,25 The presence of vitiligo has been reported in patients with metastatic melanoma without any treatment and has been found to be a good prognostic indicator in some patients.26-28 Since some melanoma-associated antigens (such as MART-1, gp100, and tyrosinase) have been found in normal melanocytes, the incidence of vitiligo suggests that the cellular mechanisms responsible for IL-2 response (activated T lymphocytes) can potentially cross-react with normal tissue. A previous study from this institution evaluating 74 patients with metastatic melanoma found a strong relationship (P2 < .005) between vitiligo and IL-2 response.29 Interestingly, no patients with renal cell cancer in that study exhibited vitiligo (P2 < .0001), strongly suggesting that vitiligo was due to cross-reactivity, with T cells reacting against one of the melanoma-associated antigens. The current study strengthens this association (P2 < 10-6). Because vitiligo takes time to develop, it is difficult to separate whether there is a real association with response or if vitiligo is purely due to prolonged treatment with IL-2 (which would occur in responders) and the ability to observe responding patients for longer periods of time. In summary, this single-institution experience with 374 consecutive patients with metastatic melanoma treated with HD IV IL-2 shows that factors strongly related to response include having metastases to only subcutaneous and/or cutaneous sites, lymphocytosis immediately after IL-2 treatment, and the development of vitiligo. Abnormal thyroid function tests may be related to response but the issue is complicated by the fact that continual IL-2 therapy (as would occur in continual responders) increases the incidence of thyroid dysfunction.
Presented at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, May 12-15, 2001, San Francisco, CA.
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Atkins MB, Lotze MT, Dutcher JP, et al: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17: 2105-2116, 1999 10. Atkins MB, Kunkel L, Sznol M, et al: High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: Long-term survival update. Cancer J Sci Am 6: S11-S14, 2000 (suppl 1) 11. Kammula US, White DE, Rosenberg SA: Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer. Cancer 83: 797-805, 1998[Medline] 12. Royal RE, Steinberg SM, Krouse RS, et al: Correlates of response to IL-2 therapy in patients treated for metastatic renal cancer and melanoma. Cancer J Sci Am 2: 91-98, 1996[Medline]
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Kruit WJH, Bolhuis RLH, Goey SH, et al: Interleukin-2-induced thyroid dysfunction is correlated with treatment duration but not with tumor response. J Clin Oncol 11: 921-924, 1993 25. Krouse RS, Royal RE, Heywood G, et al: Thyroid dysfunction in 281 patients with metastatic melanoma or renal cell cancer treated with interleukin-2 alone. J Immunother 18: 272-278, 1996 26. Nordlund JJ, Kirkwood JM, Forget BM, et al: Vitiligo in patients with metastatic melanoma: A good prognostic sign. J Am Acad Dermatol 9: 689-695, 1983[Medline]
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50% of the sum of the products of the maximum perpendicular diameters of all assessable lesions lasting at least 1 month with no new or enlarging tumors. A complete response was defined as the disappearance of all assessable tumor sites lasting at least 1 month. Patients not achieving these criteria were deemed nonresponders. 
2 test or Fisher’s exact test. All P values are two-sided (P2). P2 values were not adjusted using Bonferroni’s correction. Statistical significance was considered only when P2 < .01. A possible noteworthy trend was considered when P2 < .05. 
