High-dose Interleukin-2 Therapy Research Articles

Current advances and perspectives in the treatment of advanced melanoma

Melanoma has long been considered as an extremely therapy-resistant tumour. Recent developments in the area of immunotherapy as well as targeted therapy showed rapid development and excellent results. The anti-CTLA-4 antibody ipilimumab, which was approved in the USA and Europe in 2011, was the first substance in melanoma therapy to demonstrate an overall survival benefit. Another approval is expected in Europe for the specific BRAF-inhibitor vemurafenib, which has shown a significant impact on progression-free survival and overall survival in patients with the BRAF(V600E) mutation. In this review the relevant agents in the substance classes of immunomodulatory drugs and small molecules are presented and discussed, and future prospects for combination therapies and developments in melanoma treatment are outlined.

Syndrome of Inappropriate Antidiuretic Hormone Secretion Caused by High-Dose Bolus Interleukin-2 Therapy for Metastatic Melanoma

Melanoma is a relatively common cancer and is often associated with a dire prognosis once diagnosed as metastatic. Immunomodulatory therapy with high-dose bolus interleukin-2 may provide durable responses, albeit in a small subset of those afflicted with metastatic melanoma. High-dose interleukin-2 is well-known to cause substantial toxicities, both acute and delayed. We report on a single case of syndrome of inappropriate antidiuretic hormone secretion in a patient with metastatic melanoma with metastases to the lung and liver which was associated with high-dose bolus interleukin-2 therapy.

Fulminant myocarditis owing to high-dose interleukin-2 therapy for metastatic melanoma

High-dose interleukin-2 (IL-2) therapy may cause acute myocarditis characterised by diffuse myocardial involvement and occasionally fulminant heart failure. Cardiac MRI (CMRI) provides a comprehensive assessment of myocardial function, inflammation and injury in a single examination and has shown value in the diagnosis of myocarditis. We report a case of a 54-year-old male with metastatic melanoma who developed acute severe myocarditis with fulminant heart failure after high-dose IL-2 therapy. CMRI using a combination of T(2) weighted imaging and T(1) weighted late post-gadolinium enhancement techniques played a key role in establishing the diagnosis. To our knowledge we present the first case report of the combined use of T(1) and T(2) weighted CMRI techniques to diagnose IL-2 induced myocarditis.

Changes in Dendritic Cell Phenotype After a New High-dose Weekly Schedule of Interleukin-2 Therapy for Kidney Cancer and Melanoma

High-dose intravenous interleukin-2 (IL-2) therapy (14 doses/course, 2 courses/cycle) for metastatic melanoma or kidney cancer induces infrequent, although major responses. In this trial, we evaluated a new schedule (dose of 600,000 IU/kg, 8 h between doses, 5 doses/course, 4 courses at weekly intervals/cycle) of high-dose IL-2, in which we inserted more planned breaks while maintaining high cumulative dose delivery, and investigated the relationship between dendritic cells (DC) and response to treatment. Target dose delivery was attained: median IL-2 cumulative dose per patient was 11.4 and 10.8 million units/kg (cycles 1 and 2, respectively). Major responses were observed in patients with kidney cancer (n=20; 3 complete and 2 partial responses) and melanoma (n=16; 1 partial response). Adverse events appeared comparable with those typically associated with high-dose IL-2. From this data set, we introduce the hypothesis-generating observation that patients who had more favorable outcomes had high pretreatment DC-to-myeloid-derived suppressor cell (MDSC) ratios, similar to the ratio observed in healthy individuals. However, even in patients with the most favorable outcome, after treatment, there were IL-2-induced changes in the DC-to-MDSC ratio, specifically increases in MDSCs. This modified IL-2 schedule is a feasible option, with a more uniform dose delivery over the treatment cycle, a similar toxicity profile, and observed complete, durable response in patients with renal cancer. Pretreatment assessment of DC phenotypic or maturational status may be a starting point to predicting response to high-dose IL-2 cytokine immunotherapy in patients with melanoma and kidney cancer.

Cytokine Working Group Study of Lymphodepleting Chemotherapy, Interleukin-2, and Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Metastatic Melanoma: Clinical Outcomes and Peripheral-Blood Cell Recovery

Recovery of lymphocyte populations after lymphocyte depletion is implicated in therapeutic immune pathways in animal models and in patients with cancer. We sought to evaluate the effects of chemotherapy-induced lymphodepletion followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and high-dose interleukin-2 (IL-2) therapy on clinical response and the recovery of lymphocyte subcompartments in patients with metastatic melanoma. This was a two-stage phase II trial design. Patients with measurable metastatic melanoma were treated with intravenous cyclophosphamide (60 mg/kg, days 1 and 2) and fludarabine (25 mg/m(2), day 3 through 7) followed by two 5-day courses of intravenous high-dose bolus IL-2 (600,000 U/kg; days 8 through 12 and 21 through 25). GM-CSF (250 microg/m(2)/d beginning day 8) was given until granulocyte recovery. Lymphocyte recovery profiles were determined by flow cytometric phenotyping at regular intervals, and clinical outcome was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). The trial was stopped at the end of stage 1 with four of 18 objective responses noted. Twelve patients had detailed lymphocyte subcompartments evaluated. After lymphodepletion, we observed an induction of regulatory cells (CD4+ T regulatory cells; CD8+ T suppressor cells) and of T memory cells (CD8+ T central memory cells; T effector memory RA+ cells). Expansion of circulating melanoma-specific CD8(+) cells was observed in one of four HLA-A2-positive patients. Chemotherapy-induced lymphodepletion modulates the homeostatic repopulation of the lymphocyte compartment and influences recovering lymphocyte subpopulations. Clinical activity seems similar to standard high-dose aldesleukin alone.

Response to high-dose interleukin-2 (HD IL-2) therapy in patients with brain metastases from metastatic melanoma

e20007 Background: HD IL-2 has been shown to produce durable responses in patients with metastatic melanoma. The purpose of this study was to determine whether the University of Minnesota's outcomes were comparable to previously published data and to analyze subsets of patients to find further data on prognosis and response. Methods: A retrospective analysis was performed all adult patients with Stage IV melanoma treated with HD IL-2 from January 2000 to October 2008 at our institution. HD IL-2 was given I.V. every eight hours as a bolus over 15 minutes at a dose of 600,000 IU/kg. A maximum of 14 doses for each course was given. Results: A total of 15 patients with metastatic melanoma had been treated with HD IL-2 at our institution. Complete response (CR) was seen in 6.67% (N=1), partial response (PR) in 6.67% (N=1), mixed response (MR) in 6.67% (N=1), and stable disease (SD) in 13.33% (N=2). Average time to disease progression (TTDP) was 5.67 months in those with a PR or SD. Two patients with brain metastases had subsequently complete resolution of the brain lesions after HD IL-2 therapy. One of these patients has a CR and is disease free 34 months out from therapy. The other had PR and is currently alive with disease, but has no recurrence of the brain lesion after over 19 months. Twelve of the fifteen patients were able to receive 2 courses of therapy. On average patients tolerated 10.5 HD IL-2 doses with the first course and 8.8 doses with the second course. Common grade (G) 3 and 4 adverse events included hyperbilirubinemia (G 3 = 26.67%), hypotension (G 3 = 6.67%, G 4 = 6.67%), peripheral edema (G 3 = 26.67%), pulmonary edema (G 3 = 13.33%), and hypophosphatemia (G 3 = 6.67%, G 4 = 6.67%). Conclusions: The CR rate of 6.67% and TTDP in those with SD or a PR are comparable to previously published studies. Observed adverse events were also similar to other reports. HD IL-2 has typically been avoided in patients with brain metastases due to concern for neurologic complications from the capillary leak syndrome caused by treatment. We propose further evaluation of this ineligibility for HD IL-2, since carefully selected patients with brain metastases may derive benefit from this treatment. No significant financial relationships to disclose.

Biomarkers of Therapeutic Response in Melanoma and Renal Cell Carcinoma: Potential Inroads to Improved Immunotherapy

Biomarkers of Therapeutic Response in Melanoma and Renal Cell Carcinoma: Potential Inroads to Improved Immunotherapy

Serum Vascular Endothelial Growth Factor and Fibronectin Predict Clinical Response to High-Dose Interleukin-2 Therapy

High-dose interleukin-2 (IL-2) induces durable therapeutic responses in a small subset of patients with metastatic melanoma and renal cell carcinoma, but simple pretreatment predictors of response have not been identified. To identify predictive biomarkers of clinical response, sera from patients treated with high-dose IL-2 were collected for analysis using a customized, multiplex antibody-targeted protein array platform that surveyed expression of soluble factors associated with tumor immunobiology. Soluble factors associated with clinical responses were analyzed using a multivariate permutation test, and survival outcomes were determined using Kaplan-Meier and log-rank tests. A training set from 10 patients identified 68 potentially relevant soluble factors that were then tested in an independent validation set of 49 patients. Class comparison revealed a cluster of 11 biomarkers that were associated with therapeutic outcome. Vascular endothelial growth factor (VEGF) and fibronectin were identified as independent predictors of response. In particular, high levels of these proteins were correlated with lack of clinical response and decreased overall survival. Serum VEGF and fibronectin are easily measured pretreatment biomarkers that could serve to exclude patients unlikely to respond to IL-2 therapy.

Left Posterior Fascicular Block Due to High-Dose lnterleukin-2

To report a case of reversible left posterior fascicular block (LPFB) associated with high-dose interleukin-2 (IL-2) therapy. A 50-year-old white, nonsmoking male with a history of hypertension, hyperlipidemia, paroxysmal atrial fibrillation, and hypothyroidism had been recently diagnosed with metastatic clear cell-type renal cell carcinoma. He was started on high-dose IL-2 therapy (600,000 IU/kg/dose by 15-min intravenous infusion every 8 h for up to 14 consecutive doses over 5 days, as tolerated). He developed new-onset LPFB after the second dose of IL-2, which was diagnosed electrocardiographically with right axis deviation; deep S waves in lead I; and qR waves in leads II, III, and aVF. He denied chest pain, palpitations, or syncope. The LPFB resolved 18 hours after discontinuation of IL-2 without any potential complications or delay of hospital discharge. The patient completed 9 of 14 doses of IL-2 therapy. Similar electrocardiogram changes were noticed during 2 subsequent cycles of high-dose IL-2 treatment, both of which resolved spontaneously. High-dose IL-2 is a Food and Drug Administration-approved biological agent used as monotherapy for the treatment of metastatic renal cell carcinoma and metastatic melanoma. Capillary leak syndrome has been associated with IL-2 therapy and many of its cardiac and noncardiac toxicities. In our patient, LPFB was observed as a reversible adverse reaction to high-dose IL-2 therapy. The Naranjo probability scale indicates a probable relationship between LPFB and high-dose IL-2 in this patient. LPFB has not previously been reported as an adverse reaction associated with high-dose IL-2 therapy. LPFB may be a reversible cardiac complication associated with high-dose IL-2 therapy. Healthcare professionals should be aware of this potential adverse effect.

Immunotherapy for Renal Cell Carcinoma

Since spontaneous regression of metastatic renal cell carcinoma (mRCC) has been reported, immunotherapy for mRCC has been the therapeutic option. The goal of modulating an immune response to the tumor cell with passive and/or active immunotherapy can be achieved through the increasing technological sophistication and the understanding of the immune system. Currently, among the several available cytokines to treat mRCC, high-dose interleukin-2 (IL-2) administration is the only way to obtain complete remission. However, due to the lack of prominent benefit and toxicity of high dose IL-2 therapy, cytokine-based immunotherapy for the treatment of mRCC is threatened by the intriguing molecularly targeted agents, which are still under the trials. Different types of cellular (autologous tumor cell, gene modified tumor cell, dendritic cell) and non-cellular therapeutic vaccines of mRCC have been applied in the clinical setting, and the success of clinical effectiveness in selected population has been reported. Future treatment approaches for mRCC or locally advanced RCC would be directed with combined therapy with immunotherapy and targeted agent. Additionally, molecularly targeted agents and vaccines modulating tumor immunology cascade will be another immunotherapeutic approach for RCC.

Expression of CXCR3 on Mononuclear Cells and CXCR3 Ligands in Patients With Metastatic Renal Cell Carcinoma in Response to Systemic IL-2 Therapy

Chemokines play an important role in regulating tumor-mediated immunity, angiogenesis, and tumor cell metastasis. The chemokine receptor, CXCR3, is expressed in various human tumors, including renal cell carcinoma (RCC). CXCR3 is also associated with antiangiogenic effects in multiple tumors, and we hypothesized that interleukin-2 (IL-2) treatment of patients with metastatic clear cell RCC could augment CXCR3 levels on circulating mononuclear cells and correlate to outcome. The kinetics of CXCR3 expression on circulating mononuclear cells and its ligands (CXCL9, CXCL10, and CXCL11) in plasma were evaluated in 20 patients with metastatic clear cell RCC during cycles 1 and 2 of high dose IL-2 therapy. Subpopulations of peripheral blood mononuclear cells (PBMCs) were studied by dual color flow cytometry. Angiogenic ligands were measured and an "angiogenic ratio" was calculated prehigh and posthigh dose IL-2. CXCR3 expression on PBMC at baseline was similar in patients with metastatic RCC and normal controls. PBMC CXCR3 expression increased during treatment, and peaked during cycle 2. Plasma from RCC patients displayed similar baseline levels of CXCR3 ligands to normal controls. However, the angiogenic ratio was significantly increased in patients with metastatic RCC at baseline. Plasma levels of CXCR3 ligands increased during treatment, resulting in a reversal in the angiogenic ratio to favor angiostatic chemokines. The CXCR3/CXCR3 ligand biologic axis and angiogenic ratio may be important biomarkers in clear cell RCC patients who are undergoing high dose IL-2 therapy.

Effects of the Administration of High-Dose Interleukin-2 on Immunoregulatory Cell Subsets in Patients with Advanced Melanoma and Renal Cell Cancer

High-dose recombinant human interleukin-2 (IL-2) therapy is of clinical benefit in a subset of patients with advanced melanoma and renal cell cancer. Although IL-2 is well known as a T-cell growth factor, its potential in vivo effects on human immunoregulatory cell subsets are largely unexplored. Here, we studied the effects of high-dose IL-2 therapy on circulating dendritic cell subsets (DC), CD1d-reactive invariant natural killer T cells (iNKT), and CD4(+)CD25(+) regulatory-type T cells. The frequency of both circulating myeloid DC1 and plasmacytoid DC decreased during high-dose IL-2 treatment. Of these, only a significant fraction of myeloid DC expressed CD1d. Although the proportion of Th1-type CD4(-) iNKT increased, similarly to DC subsets, the total frequency of iNKT decreased during high-dose IL-2 treatment. In contrast, the frequency of CD4(+)CD25(+) T cells, including CD4(+)Foxp3(+) T cells, which have been reported to suppress antitumor immune responses, increased during high-dose IL-2 therapy. However, there was little, if any, change of expression of GITR, CD30, or CTLA-4 on CD4(+)CD25(+) T cells in response to IL-2. Functionally, patient CD25(+) T cells at their peak level (immediately after the first cycle of high-dose IL-2) were less suppressive than healthy donor CD25(+) T cells and mostly failed to Th2 polarize iNKT. Our data show that there are reciprocal quantitative and qualitative alterations of immunoregulatory cell subsets with opposing functions during treatment with high-dose IL-2, some of which may compromise the establishment of effective antitumor immune responses.

P239: CCR5 polymorphism as a predictor of clinical resonse to high-dose IL-2 therapy in melanoma and renal cell carcinoma

Introduction: High-dose Interleukin-2 (IL-2) therapy confers a 16-20% clinical response in patients with malignant melanoma (MM) and renal cell carcinoma (RCC) through activation and proliferation of tumor-specific T lymphocytes. IL-2 has also been shown to induce regulatory T cells (Tregs), whose function is to suppress T cell activation and proliferation, which may explain, in part, why the clinical response rate to IL-2 is not better. We have previously shown that patients who respond clinically to high dose IL-2 demonstrate significant decreases in Treg levels (9.0% to 1.2%) compared to non-responders (7.72% to 16.7%).

The Role of Nephron Sparing Surgery for Metastatic (pM1) Renal Cell Carcinoma

Studies have demonstrated increased time to progression when cytoreductive nephrectomy is performed for metastatic renal cell carcinoma. We evaluated the role of nephron sparing surgery in these patients. We selected all patients with pM1 renal cell carcinoma treated with nephron sparing surgery or radical nephrectomy, and all patients with pM0 renal cell carcinoma undergoing nephron sparing surgery for solitary kidney from 1970 to 2002 from the Mayo Clinic Nephrectomy Registry. We identified 16 patients who underwent nephron sparing surgery for pM1 renal cell carcinoma. Solitary kidney was present in 12, 3 had bilateral synchronous disease and 1 had elective nephron sparing surgery. Cancer specific survival rates at 1, 3 and 5 years were 81%, 49% and 49%, respectively. We identified 404 patients who underwent radical nephrectomy for pM1 renal cell carcinoma. Cancer specific survival rates at 1, 3 and 5 years were 51%, 21% and 13%, respectively. The pM1 nephron sparing surgery for solitary kidney cases were more likely to have early (33% vs 10%, p = 0.009) or late (50% vs 19%, p = 0.018) complications compared with pM1 radical nephrectomy cases. There were no significant differences in early (p = 0.475) or late (p = 0.350) complications between pM1 nephron sparing surgery cases and 139 pM0 nephron sparing surgery cases. Cancer specific survival rates in pM1 nephron sparing surgery cases were comparable to pM1 radical nephrectomy cases. Although there were differences in early and late complications between the pM1 nephron sparing surgery and pM1 radical nephrectomy groups, there were no differences when compared with imperative pM0 nephron sparing surgery cases. This study demonstrates that nephron sparing surgery can achieve adequate cytoreductive therapy while preserving renal function, with postoperative complication rates similar to those of pM0 nephron sparing surgery cases.

Inflammatory protein profile during systemic high dose interleukin‐2 administration

Systemic interleukin-2 (IL-2) administration induces an assortment of downstream effects whose biological and therapeutic significance remains unexplored mostly because of the methodological inability to globally address their complexity. Protein array analysis of sera from patients with renal cell carcinoma obtained prior and during high-dose IL-2 therapy had previously revealed extensive alterations in expression of the soluble factors analyzed, whose discovery was limited by the number of capture antibodies selected for protein detection. Here, we expanded the analysis to SELDI-TOF-MS and quantitative protein analysis (nephelometry). All cytokines/chemokines detected by protein arrays were below the SELDI detection limit, while novel IL-2-specific changes in expression of acute-phase reactants and high-density lipoprotein metabolites could be identified. Serum amyloid protein A (SAA) and C-reactive protein expression were consistently up-regulated after four doses of IL-2, while other proteins were down-regulated. These findings were confirmed by SELDI immunoaffinity capture and nephelometry. Immunoaffinity capture revealed different, otherwise undetectable, isoforms of SAA. A linear correlation between peak area by SELDI and protein concentration by nephelometry was observed. Overall distinct yet complementary information was obtained using different platforms, which may better illustrate complex phenomena such as the systemic response to biological response modifiers.

Inflammatory Protein Profile During Systemic High Dose Interleukin-2 Administration

Systemic interleukin-2 (IL-2) administration induces an assortment of downstream effects whose biological and therapeutic significance remains unexplored mostly because of the methodological inability to globally address their complexity. Protein array analysis of sera from patients with renal cell carcinoma obtained prior and during high-dose IL-2 therapy had previously revealed extensive alterations in expression of the soluble factors analyzed, whose discovery was limited by the number of capture antibodies selected for protein detection. Here, we expanded the analysis to SELDI-TOF-MS and quantitative protein analysis (nephelometry). All cytokines/chemokines detected by protein arrays were below the SELDI detection limit, while novel IL-2-specific changes in expression of acute-phase reactants and high-density lipoprotein metabolites could be identified. Serum amyloid protein A (SAA) and C-reactive protein expression were consistently up-regulated after four doses of IL-2, while other proteins were down-regulated. These findings were confirmed by SELDI immunoaffinity capture and nephelometry. Immunoaffinity capture revealed different, otherwise undetectable, isoforms of SAA. A linear correlation between peak area by SELDI and protein concentration by nephelometry was observed. Overall distinct yet complementary information was obtained using different platforms, which may better illustrate complex phenomena such as the systemic response to biological response modifiers.

The MRC Randomised-controlled Trial of Interferon-α, Interleukin-2 and 5-Fluorouracil vs Interferon-α Alone in Patients with Advanced Renal cell Carcinoma (RE04): Rationale and Progress

Renal cell carcinoma is diagnosed in over 6000 people, and accounts for about 2% of malignant disease annually in the UK [1]. For early stage disease, surgery with curative intent is the treatment of choice, although 30–40% of patients diagnosed with disease, apparently limited to the kidney, subsequently will relapse systemically [2]. A further 25% of patients have metastatic disease at presentation. The prognosis for metastatic renal-cell carcinoma is poor, with a median survival of 6–8 months [3]. Response rates to combination chemotherapy [4] and hormonal agents [5] have been around 5–10%. It has been known for some time that the immune system has a role in the natural history of renal-cell carcinoma. For example, spontaneous regressions are rare but well documented [6,7]. Immunotherapy with interferon (IFN) in metastatic disease produces response rates of around 10–20%, with median response durations of 3–16 months [8]. Retrospective data have also shown that patients with a performance status of 0 or 1 are more likely to gain benefit (i.e. increase in median survival) from immunotherapy than are patients with a performance status of 2 or worse [9]. Randomisedcontrolled trials have shown a survival advantage to IFN compared with non-immunotherapy. A randomised trial comparing IFN-a plus vinblastine (VLB) with VLB alone reported a median survival of about 16 months for the 79 patients receiving IFN plus VLB, and 9 months for the 81 patients treated with VLB (PZ 0.0049). Overall response rates were 16.5% for patients treated with IFN plus VLB and 2.5% for patients treated with VLB alone (PZ 0.0025) [10]. The

Administration of High-Dose Continuous Infusion Interleukin-2 to Patients Age 70 or Over

High-dose bolus or continuous infusion interleukin-2-based therapy can cause capillary leak syndrome. Significant cardiovascular/hemodynamic events, including myocardial infarction, hypotension, pulmonary edema, and cardiac arrhythmia, have been described with such therapy. Concern over the toxicity of highdose interleukin-2 (IL-2) therapy has led to some clinicians excluding patients 70 years of age or over. We have treated 15 patients 70 years of age or over having an Eastern Conference Oncology Group (ECOG) performance status of 0 or 1, with therapy based on continuous infusion IL-2 18 MIU/sq m/24 hours for 72 hours. All patients underwent a pretreatment evaluation of cardiac status with a low-level stress or adenosine stress test. Cycles were typically repeated every 3 weeks for 4 cycles, then every 3-4 weeks thereafter. Patients were treated by oncology nurses in either the stem cell transplant (intermediate unit) or the oncology inpatient unit. Patient characteristics were: median age, 72 years (range, 70-83 years); tumor types: melanoma (10), kidney cancer (5); most common sites of disease: lung (11), lymph nodes (6), subcutaneous (3), liver (2); prior therapy included: none (8), outpatient IL-2 (5), other immunotherapy (4). Median number of cycles received: 3 (1-10). Most common toxicities were: fever, rigors, nausea, emesis, hypophosphatemia, and hypomagnesemia. Three patients required the use of dopamine for blood pressure support. Two patients declined further therapy. There were no treatment-related deaths. No patients required endotracheal intubation or transfer to an intensive care unit. One complete and 8 partial responses (60% response rate) have been seen. Responding sites include the lung, lymph node, intact kidney primary, and liver. Median survival has not been reached at over 14 months (range 3+-26+ months). Patients who are 70 years of age and older with an ECOG performance status of 0 or 1 are able to tolerate high-dose continuous infusion IL-2-based therapy and may respond to such treatment.

Characterization of bone metastases in patients with renal cell cancer.

To characterize the clinical features of bone metastases in patients with renal cell carcinoma (RCC) treated with interleukin-2 therapy. Bone lesions contribute to significant morbidity and mortality, and although present in up to half of patients with RCC, their behaviour and response to therapy have not been well characterized. We evaluated skeletal metastases in 19 patients with bone lesions who received either moderate- or high-dose interleukin-2 therapy. Data on bone disease, including location and number of bone lesions, need for bone-specific therapies and use of pain medications, were noted. The response of bone lesions to interleukin-2 was compared with the response of other systemic metastatic sites. Skeletal metastases resulted in significant morbidity by causing pain (75%) and other complications requiring surgical and/or radiotherapeutic intervention (94%) before beginning interleukin-2 therapy. In most patients the response of bone lesions to interleukin-2 was similar to that in their other systemic sites. Treatment with interleukin-2 had no significant effect on the requirement for pain medication for bone pain. However, it may have prevented skeletal complications requiring surgery or radiotherapy. None of the patients had hypercalcaemia; there was no significant association between bone metastases and elevated alkaline phosphatase levels. Skeletal metastases are a significant contributor to morbidity among patients with RCC. Bone lesions respond similarly to interleukin-2 therapy as other systemic sites. Bisphosphonates appear promising for these predominantly osteolytic lesions.

Interleukin-2: Clinical applications

Interleukin-2 (IL-2) is a promising immunotherapeutic agent for the treatment of metastatic melanoma, acute myelogenous leukemia, and metastatic renal cell carcinoma. While high-dose IL-2 regimens have shown clinical benefit in the treatment of melanoma and renal cell carcinoma, serious dose-limiting toxicities have limited their clinical use in a broader group of patients. Low-dose IL-2 therapy has produced disappointing clinical response rates in melanoma. While the response rates to low-dose IL-2 have been better in renal cell carcinoma, the quality of these responses relative to those seen with high-dose IL-2 therapy remains a concern. The addition of IL-2 to chemotherapeutic regimens (biochemotherapy) has been associated with overall response rates of up to 60% in patients with metastatic melanoma, but this has yet to be translated into a confirmed improvement in survival. 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. Semin Oncol 29 (suppl 7):12-17. Copyright 2002, Elsevier Science (USA). All rights reserved.