Biological and clinical effects of interferon-beta ser at two doses. Treatment of advanced renal cell cancer with recombinant interferon alpha as a single agent and in combination with medroxyprogesterone acetate. A randomized multicenter trial. Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer. Interferon alfa and vinblastine versus medroxyprogesterone acetate in the treatment of metastatic renal cell carcinoma. Randomized multicenter phase II trial of subcutaneous recombinant human interleukin-12 versus interferon-alpha 2a for patients with advanced renal cell carcinoma. Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. Treatment of patients with metastatic renal carcinoma with a combination of subcutaneous interleukin-2 and interferon alfa with or without fluorouracil. Groupe Français d'Immunothérapie, Fédération Nationale des Centres de Lutte Contre le Cancer. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. A randomized study of low-dose interleukin-2 subcutaneous immunotherapy versus interleukin-2 plus interferon-alpha as first line therapy for metastatic renal cell carcinoma. Randomized phase II/III trial of interferon Alfa-2a with and without 13-cis-retinoic acid in patients with progressive metastatic renal cell Carcinoma: the European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EORTC 30951). Recombinant alfa interferon in renal cell carcinoma: a randomized trial of two routes of administration. Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma. Interferon therapy in disseminated renal cell carcinoma. A randomized phase II trial of interleukin 2 and interleukin 2-interferon alpha in advanced renal cancer. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. EORTC (30885) randomised phase III study with recombinant interferon alpha and recombinant interferon alpha and gamma in patients with advanced renal cell carcinoma. The EORTC Genitourinary Group. Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. Canadian Urologic Oncology Group. Interferon alternating with chemotherapy for patients with metastatic renal cell carcinoma. Abrogation of the negative influence of opioids on IL-2 immunotherapy of renal cell cancer by melatonin. Survival in renal cell carcinoma-a randomized evaluation of tamoxifen vs interleukin 2, alpha-interferon (leucocyte) and tamoxifen. A randomized study of low and high doses of leukocyte alpha-interferon in metastatic renal cell carcinoma: the American Cancer Society collaborative trial. Vinblastine fails to improve response of renal cancer to interferon alfa-n1: high response rate in patients with pulmonary metastases. A phase II study of interleukin-2 with and without beta-interferon in the treatment of advanced renal cell carcinoma. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. Phase II study of interferon-gamma versus interleukin-2 and interferon-alpha 2b in metastatic renal cell carcinoma. IL-2 in combination with IFN- alpha and 5-FU versus tamoxifen in metastatic renal cell carcinoma: long-term results of a controlled randomized clinical trial. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. A prospective randomized trial of alpha 2B-interferon/gamma-interferon or the combination in advanced metastatic renal cell carcinoma. Interleukin-2- and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: a Prospectively Randomized Trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie. Antitumor activity of recombinant-derived interferon alpha in metastatic renal cell carcinoma. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Recombinant leukocyte interferon alpha-2a and medroxyprogesterone in advanced renal cell carcinoma. A randomized trial. The use of polyethylene glycol-modified interleukin-2 (PEG-IL-2) in the treatment of patients with metastatic renal cell carcinoma and melanoma. A phase I study and a randomized prospective study comparing IL-2 alone versus IL-2 combined with PEG-IL-2. [Treatment of metastasizing renal adenocarcinoma with specific plasma transfusion. A controlled trial of the effects on metastases and survival time]. A randomized phase II trial of continuous infusion interleukin-2 or bolus injection interleukin-2 plus lymphokine-activated killer cells for advanced renal cell carcinoma. Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Effect of autolymphocyte therapy on survival and quality of life in patients with metastatic renal-cell carcinoma. Interleukin-2, interferon-alpha and interleukin-2 plus interferon-alpha in renal cell carcinoma. A randomized phase II trial. Cytoreductive nephrectomy: is it a realistic option in patients with renal cancer? A randomized prospective assessment of recombinant leukocyte A human interferon with or without aspirin in advanced renal adenocarcinoma. Combined treatment with low-dose interferon plus vinblastine is associated with less toxicity than conventional interferon monotherapy in patients with metastatic renal cell carcinoma. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. [Preoperative subcutaneous immunotherapy with interleukin-2 in renal carcinoma with synchronous metastasis: randomized clinico-biological study. Preoperative use of Il-2 in renal carcinoma]. Standard interleukin-2 (IL-2) and interferon-alpha immunotherapy versus an IL-2 and 4-epirubicin immuno-chemotherapeutic association in metastatic renal cell carcinoma. Active specific immunotherapy of renal cell carcinoma patients: a prospective randomized study of hormono-immuno-versus hormonotherapy. Preliminary report of immunological and clinical aspects. Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma.
To assess biological response, therapeutic activity, and side effects, a randomized, double-blind trial of two doses of interferon-beta ser (IFN-beta ser), differing by 20-fold 4.5 and 90 x 10(6) units), was undertaken in 64 patients with metastatic renal carcinoma. Patients were treated intravenously with injections daily for 10 days with an 11-day rest before treatment was reinitiated. The trial confirmed the relatively good toleration of IFN-beta ser; in the first cycle only 4/63 patients had anorexia of moderate or greater severity. Median weight change over the duration on study was -1.5 kg; in the first cycle only 7% of patients had performance status decline greater than 1 level. Statistically significant changes (p less than 0.05) occurred in granulocytes, lymphocytes, calcium, cholesterol, alkaline phosphatase, and aspartate transferase (AST); however, except for AST, overall clinical differences in the two doses were not great. Of 60 patients evaluated, 1 developed neutralizing antibody. When assessed 24 h after IFN-beta ser at 4.5 x 10(6) units, significant (p less than 0.05) augmentation had occurred in beta 2-microglobulin, HLA-DR, and HLA-DQ expression on monocytes, 2',5'-oligoadenylate (2-5A) synthetase in peripheral mononuclear cells, and natural killer (NK) and K cells functional activity. Although the 90 x 10(6) unit dose also resulted in stimulation of these responses, little additional augmentation of biological response occurred at the higher dose. Except for a decline in monocyte HLA-DR expression, biological responses remained increased at both doses over the 10-day period of treatment. However, no objective regressions of metastatic disease occurred. In view of objective responses in metastatic renal carcinoma in other trials with IFN-beta ser, consideration should be given to alternative schedules. The response rates in metastatic renal cell cancer (RCC) after chemotherapy, hormonal treatment, or immunotherapy rarely exceed 15%. Recently, interferon alpha (IFN alpha) was used for treatment of this disease in several studies which also demonstrated response rates of 15%. In order to test whether IFN therapy combined with hormones would result in higher response rates we compared single agent IFN therapy with a combined therapy of rIFN alpha 2C plus medroxyprogesterone acetate (MPA) in a randomized multicenter trial. The rIFN alpha 2C (2MU) was given s.c. 5 times per week for 8-12 weeks and subsequently once weekly until week 48. In the combined treatment, 750 mg MPA was given p.o. daily until week 48 in addition to the IFN as described. The overall response rate in 93 evaluable patients was 5.4% corresponding to 2 complete and 3 partial responses. Median survival was 7 months in both treatment groups. These data confirm the ineffectivity of low IFN doses for treatment of RCC. The low response rate is not increased by addition of MPA to IFN. The analysis of other IFN studies suggests that not only IFN doses but also IFN sources may influence response rates in metastatic RCC. Treatment results in patients with metastatic renal cell cancer (RCC) are still extremely unsatisfactory. Rates of response to IFN-alpha monotherapy and/or IL-2 mono/combination therapy vary between 10% and 20%. Coumarin (Cum) together with cimetidine (Cim) has yielded objective responses in 20%-33% of patients with RCC, according to two recent phase II studies.
                In the present study 148 patients with metastatic RCC were randomised to receive either IFN-alpha (5 MU 5 x weekly s.c.) + coumarin (100 mg/d p.o.) + cimetidine (3 x 400 mg/d p.o.), or IFN-alpha-monotherapy (5 MU 5 x weekly s.c.).
                Of the 148 patients in the study 137 were evaluable for response. No differences in remission rates (RR IFN-alpha + Cum + Cim 17.1% and IFN-alpha 20.8%) or survival times (median survival 9 months and 8 months, respectively) were found between these two treatment arms.
                This study confirms that INFN-alpha has antitumoral activity in RCC. Adding coumarin + cimetidine to IFN-alpha in the dose and regimen prescribed in this study did not increase response rates or survival. Since the beginning of the 1980s, when gene technology provided sufficient amounts of cytokines, numerous Phase II studies in metastatic renal cell carcinoma were carried out mostly with interferon alfa (IFN-alpha) and interleukin-2 (IL-2). So far, no randomized prospective trials including untreated control groups have been reported. We present a prospective study comparing IFN-alpha and vinblastine (VBL) versus medroxyprogesterone acetate (MPA).
                Immunochemotherapy schedule consists of IFN-alpha 8 million U/day subcutaneously for 3 days per week and VBL 0.1 mg/kg body weight intravenously at 3-week intervals. MPA was administrated intramuscularly at a dosage of 500 mg/week. The response rates, toxicities, and actuarial overall survival were analyzed.
                The overall response rate in 41 patients receiving IFN-alpha and VBL treatment was 20.5% (95% confidence interval, 9% to 33%). Four patients reached a complete and 5 patients reached a partial remission. No remissions were observed in 35 patients of the control group. A statistically significant survival benefit for the IFN-alpha and VBL group could not be demonstrated. Excluding fever, mild to moderate toxicities were observed. About one third of patients refused the proposed schedule due to general malaise and fatigue.
                A survival benefit or a favorable outcome of patients with metastatic renal cell carcinoma, treated with IFN-alpha and VBL, could not be demonstrated. As judged from this analysis, IFN-alpha and VBL therapy does not sufficiently meet the requirements of a palliative treatment of renal cell carcinoma. Recombinant human interleukin-12 (rHuIL-12) is a pleiotropic cytokine with anticancer activity against renal cell carcinoma (RCC) in preclinical models and in a phase I trial. A randomized phase II study of rHuIL-12 compared with interferon-alpha (IFN-alpha) evaluated clinical response for patients with previously untreated, advanced RCC. Patients were randomly assigned 2:1 to receive either rHuIL-12 or IFN-alpha2a. rHuIL-12 was administered by subcutaneous (s.c.) injection on days 1, 8, and 15 of each 28-day cycle. The dose of IL-12 was escalated during cycle 1 to a maintenance dose of 1.25 microg/kg. IFN was administered at 9 million units by s.c. injection three times per week. Serum concentrations of IL-12, IFN-gamma, IL-10, and neopterin were obtained in 10 patients treated with rHuIL-12 after the first full dose of 1.25 microg/kg given on day 15 (dose 3) of cycle 1 and again after multiple doses on day 15 (dose 6) of cycle 2. Thirty patients were treated with rHuIL-12, and 16 patients were treated with IFN-alpha. Two (7%) of 30 patients treated with rHuIL-12 achieved a partial response, and the trial was closed to accrual based on the low response proportion. IL-12 was absorbed rapidly after s.c. drug administration, with the peak serum concentration appearing at approximately 12 h in both cycles. Serum IL-12 concentrations remained stable on multiple dosing. Levels of IFN-gamma, IL-10, and neopterin increased with rHuIL-12 and were maintained in cycle 2. rHuIL-12 is a novel cytokine with unique pharmacologic and pharmacodynamic features under study for the treatment of malignancy and other medical conditions. The low response proportion associated with rHuIL-12 single-agent therapy against metastatic RCC was disappointing, given the preclinical data. Further study of rHuIL-12 for other medical conditions is underway. For RCC, the study of new cytokines is of the highest priority. A randomized phase III trial was conducted to determine whether combination therapy with 13-cis-retinoic acid (13-CRA) plus interferon alfa-2a (IFNalpha2a) is superior to IFNalpha2a alone in patients with advanced renal cell carcinoma (RCC).
                Two hundred eighty-four patients were randomized to treatment with IFNalpha2a plus 13-CRA or treatment with IFNalpha2a alone. IFNalpha2a was given daily subcutaneously, starting at a dose of 3 million units (MU). The dose was escalated every 7 days from 3 to 9 MU (by increments of 3 MU), unless >/= grade 2 toxicity occurred, in which case dose escalation was stopped. Patients randomized to combination therapy were given oral 13-CRA 1 mg/kg/d plus IFNalpha2a. Quality of life (QOL) was assessed.
                Complete or partial responses were achieved by 12% of patients treated with IFNalpha2a plus 13-CRA and 6% of patients treated with IFNalpha2a (P =.14). Median duration of response (complete and partial combined) in the group treated with the combination was 33 months (range, 9 to 50 months), versus 22 months (range, 5 to 38 months) for the second group (P =.03). Nineteen percent of patients treated with IFNalpha2a plus 13-CRA were progression-free at 24 months, compared with 10% of patients treated with IFNalpha2a alone (P =.05). Median survival time for all patients was 15 months, with no difference in survival between the two treatment arms (P =.26). QOL decreased during the first 8 weeks of treatment, and a partial recovery followed. Lower scores were associated with the combination therapy.
                Response proportion and survival did not improve significantly with the addition of 13-CRA to IFNalpha2a therapy in patients with advanced RCC. 13-CRA may lengthen response to IFNalpha2a therapy in patients with IFNalpha2a-sensitive tumors. Treatment, particularly the combination therapy, was associated with a decrease in QOL. Subcutaneous recombinant interleukin-2 (rIL-2) and recombinant interferon alfa-2a (rIFNalpha-2a) have been used extensively in the treatment of metastatic renal cancer. Most results, coming from noncontrolled phase II trials, showed inconsistent rates of response. More recently, the addition of fluorouracil (FU) was proposed to improve the efficacy of these regimens.
                The role of a subcutaneous combination of rIL-2 and rIFNalpha-2a with or without FU was investigated. Patients were randomly assigned to receive a combination of rIL-2 and rIFNalpha-2a at weeks 1, 3, 5, and 7 or the same combination together with a continuous infusion of FU at weeks 1 and 5. The major end points of this multicenter, randomized trial were progression-free survival, response rate, and toxicity. Overall survival was a secondary end point. Tumor responses were reviewed by an independent committee. Analysis of the results was performed on an intention-to-treat basis.
                One hundred thirty-one patients were enrolled. There was no difference in toxicity between the arms, and no toxic death was observed. One partial response was observed in arm A and five in arm B. Progression-free survival did not differ between the arms, and rates at 1 year were 12% and 15% in arms A and B, respectively. No statistically significant differences were detected in any end point.
                The subcutaneous combination of rIL-2 and rIFNalpha-2a with or without FU does not benefit patients with metastatic renal carcinoma. Neither of these regimens can be recommended as standard treatment. The results of the subcutaneous cytokine regimen seem disappointing. The value of nephrectomy in metastatic renal-cell cancer has long been debated. Several nonrandomized studies suggest a higher rate of response to systemic therapy and longer survival in patients who have undergone nephrectomy.
                We randomly assigned patients with metastatic renal-cell cancer who were acceptable candidates for nephrectomy to undergo radical nephrectomy followed by therapy with interferon alfa-2b or to receive interferon alfa-2b therapy alone. The primary end point was survival, and the secondary end point was a response of the tumor to treatment.
                The median survival of 120 eligible patients assigned to surgery followed by interferon was 11.1 months, and among the 121 eligible patients assigned to interferon alone it was 8.1 months (P=0.05). The difference in median survival between the two groups was independent of performance status, metastatic site, and the presence or absence of a measurable metastatic lesion.
                Nephrectomy followed by interferon therapy results in longer survival among patients with metastatic renal-cell cancer than does interferon therapy alone. IL-2 given subcutaneously in combination with interferon-alpha 2b (IFN) appears to induce a response rate comparable to that obtained with IL-2 intravenous injection in patients with metastatic renal cell carcinoma (RCC) but with lower toxicity. The role of IFN when combined with IL-2 has however still to be defined. The present study was performed to draw some preliminary conclusions about the effect of IFN in combination with IL-2 in metastatic RCC.
                The study included 30 consecutive patients with metastatic RCC who were randomized to treatment with IL-2 subcutaneous therapy (3 million IU twice/daily for 5 days/week for 6 weeks) or with IL-2 plus IFN (5 million U/m2 subcutaneously thrice weekly). In patients without progressive disease, a second cycle was repeated after a 28-day rest period.
                No significant difference in partial response rate was found between patients treated with IL-2 alone and those given IL-2 plus IFN (5/15 vs 4/15). Similarly, no difference was seen in the percentage of stable disease (7/15 vs 7/15). Toxicity was higher in patients who received IL-2 plus IFN. Lymphocyte and eosinophil mean increase was higher in patients treated with IL-2 alone than in those treated with IL-2 plus IFN, without however any significant difference.
                The present results, which require confirmation in a larger series, indicate that combination with IFN does not increase the efficacy of IL-2 subcutaneous immunotherapy in metastatic RCC but only the toxicity of treatment. A randomized phase II/III trial was conducted to determine whether combination treatment with 13-cis-retinoic acid (13-CRA) plus interferon alfa-2a (IFN-alpha-2a) was superior to IFN-alpha-2a alone in patients with progressive metastatic renal cell carcinoma.
                Three hundred twenty patients were randomly assigned to treatment with IFN-alpha-2a plus 13-CRA or to IFN-alpha-2a alone. IFN-alpha-2a was given daily subcutaneously, starting at a dose of 3 million units (MU). The dose was escalated every 7 days from 3 to 9 MU by increments of 3 MU. Patients randomly assigned to combination therapy received oral 13-CRA 1 mg/kg/d plus IFN-alpha-2a.
                Median time to progression was 5.1 months for patients treated with the combination and 3.4 months for patients on IFN-alpha-2a alone (P = .008). Progression-free survival rates at 6 months were 43% for patients receiving combined therapy and 30% for patients on IFN-alpha-2a, and at 12 months, 27% and 17%, respectively. Median overall survival was 17.3 months for patients on IFN-alpha-2a and 13-CRA, and 13.2 months for patients treated with IFN-alpha-2a (P = .048). Twenty-two percent of the patients receiving the combination stopped treatment due to toxicity, as compared with 16% on IFN-alpha-2a.
                Progression-free and overall survival for patients with progressive metastatic renal cell carcinoma treated with IFN-alpha-2a plus 13-CRA were significantly longer compared with patients on IFN-alpha-2a alone (P = .007 and P = .048, respectively). Improvement in efficacy in the combination arm was accompanied by increased, though not serious, toxicity. Ninety-seven patients with recurrent or metastatic renal cell carcinoma were randomized to receive recombinant interferon (IFN) alfa-2b (Intron A; Schering-Plough, Kenilworth, NJ) by either the subcutaneous (SC) or intravenous (IV) route. The SC dosage was 2 X 10(6) IU/m2 three times weekly, and the IV dose 30 X 10(6) IU/m2 for five consecutive days every 3 weeks. Dose escalation to a maximum of 10 X 10(6) IU/m2 SC and 50 X 10(6) IU/m2 IV was allowed for patients with minimal or absent toxicity. Five of 51 of the SC-treated patients (10%) and three of 46 of the IV-treated patients (7%) had a partial response (PR) or complete response (CR). Patients with prior nephrectomy, no prior treatment, and lack of bone metastases were most likely to respond, and a retrospective analysis of this subgroup revealed a 23% response rate. Achievement of response took from 3 weeks to 11 months, while response duration lasted from 3 to 31+ months. All responders had prior nephrectomy; six of eight had no prior chemotherapy or hormonal therapy; five had lung metastases, and none had bone metastases. Regardless of route, almost all patients developed a flu-like syndrome; however, grade 3 or greater toxicity was much more common for IV-treated patients. This trial demonstrates modest, but definite antitumor activity for recombinant interferon in advanced renal cell carcinoma. SC administration with lower dose and toxicity is as effective as treatment administered IV. Histamine inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). Two randomised phase II trials of IL-2 with or without histamine dihydrochloride (HDC) in patients with metastatic renal cell carcinoma (mRCC) were run in parallel. A total of 41 patients were included in Manchester, UK and 63 in Aarhus, Denmark. The self-administered, outpatient regimen included IL-2 as a fixed dose, 18 MIU s.c. once daily, 5 days per week for 3 weeks followed by 2 weeks rest. Histamine dihydrochloride was added twice daily, 1.0 mg s.c., concomitantly with IL-2. A maximum of four cycles were given. The Danish study showed a statistically significant 1-year survival benefit (76 vs 47%, P = 0.03), a trend towards benefit in both median survival (18.3 vs 11.4 months, P = 0.07), time to PD (4.5 vs 2.2 months, P = 0.13) and clinical benefit (CR + PR + SD) (58 vs 37%, P = 0.10) in favour of IL-2/HDC, whereas the UK study was negative for all end points. Only three patients had grade 4 toxicity; however, two were fatal. A randomised phase III trial is warranted to clarify the potential role of adding histamine to IL-2 in mRCC. Twenty patients with pulmonary metastases of renal cell carcinomas have been treated in a randomized study with either leucocyte interferon in daily doses of 3 x 10(6) I.U.i.m or irradiation of both lungs in a calculated mean central dose of 10 Gy in 4 weeks in combination with bleomycin and vincristine. Most patients had a short time to progression of their disease. Three patients in the interferon group had complete response (CR) and partial response (PR) and one patient in the other group had PR. The numbers of patients in both arms of the study are too small to allow any conclusions whether beneficial effects are more frequent in one group than in the other, but there is a more favourable tendency in the interferon group. A randomized phase II trial was performed to compare the efficacy and toxicity of interleukin 2 (IL-2) with an IL-2 and interferon alpha (IFN-alpha) regimen for the treatment of metastatic renal carcinoma. Sixty patients with recurrent renal cell carcinoma (RCC) who had previously undergone a nephrectomy were randomized to receive three cycles of IL-2 or IL-2 with IFN-alpha2b. Eighteen MU of IL-2 were administered subcutaneously on Mondays-Fridays for 3 weeks out of 4. Those patients randomized to receive the combination received the same regimen of IL-2 with 9 MU of IFN-alpha2b subcutaneously on Mondays, Wednesdays and Fridays for 3 weeks out of 4. Thirty patients were randomized to receive each arm. Twenty-nine were evaluable in each arm. Twenty-two patients received three cycles of IL-2 but only 14 patients received three cycles of IL-2/IFN-alpha because of the greater toxicity of the combination. The principal toxicities included nausea, fatigue and fever. There were no complete responses in either arm and only two patients who were treated with IL-2 attained a partial response. Twelve patients in each arm had stable disease and 15 patients in the IL-2 arm and 16 patients in the IL-2/IFN-alpha arm progressed through treatment. There were no significant differences in survival. Ten patients who received IL-2 are alive with a median follow-up of 266 days, whereas six patients who received IL-2/IFN-alpha are alive after a median of 278 days. The median survival from the time of identification of metastatic disease is 444 days in the IL-2 arm and 381 days in the IL-2/IFN-alpha arm. The IL-2/IFN-alpha combination is more toxic than IL-2 alone and this resulted in a reduced number of cycles of treatment. However, the median survival of the two groups was the same, suggesting that further evaluation of the IL-2/IFN-alpha combination should be confined to large prospective randomized clinical trials. Metastatic renal carcinoma has a 2-year survival of around 20% and is largely resistant to chemotherapy. The use of interferons in the treatment of metastatic renal carcinoma remains controversial. Although non-randomised studies suggest that biological therapy with interferons produces a small number of tumour responses, most clinicians judge such treatment to be ineffective. We have investigated the effect of treatment with interferon-alpha on survival in patients with metastatic renal carcinoma.
                In a multicentre, randomised trial, patients with metastatic renal carcinoma were randomly assigned subcutaneous interferon-alpha (three doses--5 MU, 5 MU, 10 MU--for the first week, then 10 MU three times per week for a further 11 weeks; n=174) or oral medroxyprogesterone acetate (MPA; 300 mg once daily for 12 weeks; n=176). The primary endpoint was overall survival. Analysis was by intention to treat. The trial used a triangular sequential design for early termination as soon as results were conclusive. The trial was stopped in November, 1997, when data were available for 335 patients (167 interferon-alpha, 168 MPA).
                A total of 111 patients have died in the interferon-alpha group, and 125 patients have died in the MPA group. There was a 28% reduction in the risk of death in the interferon-alpha group (hazard ratio 0.72 [95% CI 0.55-0.94], p=0.017). Interferon-alpha gave an improvement in 1-year survival of 12% (MPA 31% survival, interferon-alpha 43%), and an improvement in median survival of 2.5 months (MPA 6 months, interferon-alpha 8.5 months).
                The benefit of treatment with interferon-alpha should be weighed against the drug's toxic effects. Combination regimens of biological therapy and chemotherapy should now be compared with interferon-alpha monotherapy in randomised controlled trials. In the treatment of renal cell carcinoma both complete (CRs) and partial remissions (PRs) have been obtained using recombinant (r) interferon alpha (IFN-alpha), with response rates ranging from 0 to 31% (mean 16%). rIFN-gamma is a potent immunostimulating agent, but the clinical experience of its use is limited and results are conflicting. In a phase II study with the combination of rIFN-alpha 2c (Boehringer Ingelheim) and rIFN-gamma (Genentech, supplied by Boehringer Ingelheim) in 31 eligible patients, a response rate of 25% was recorded. Based on this observation a randomised phase III study was initiated to investigate the possible advantage of the addition rIFN-gamma to rIFN-alpha 2c treatment. Treatment consisted of rIFN-alpha 2c 30 micrograms m-2 = 10 x 10(6) IU m-2 s.c. twice weekly in arm A and the same dose of rIFN-alpha combined with rIFN-gamma 100 micrograms m-2 = 2 x 10(6) IU m-2 in arm B. Eligibility criteria included documented progression of disease; patients with bone lesions only and overt central nervous system metastases were excluded. Between November 1988 and September 1990, 102 patients were entered into the study. An interim analysis showed a response in 7/53 (13%) patients (two CRs and five PRs) in the rIFN-alpha 2c monotherapy arm and in 2/45 (4%) (one CR and one PR) patients in the combination arm. This difference was not statistically significant (P = 0.17). The probability of missing an eventual 10% advantage for the combination is 0.001. The numbers are insufficient to rule out a negative effect of the addition of rIFN-gamma. The dose intensity of IFN-alpha 2c for the two treatment arms was the same. The addition of rIFN-gamma does not improve the response rate of rIFN-alpha 2c monotherapy. A possible detrimental effect cannot be excluded. Most trials of immunomodulators in metastatic renal-cell carcinoma have been uncontrolled and subject to selection bias. The objective of this blinded, placebo-controlled study was to compare overall response rates, time to disease progression, and survival of patients with metastatic renal-cell carcinoma treated with recombinant human interferon gamma-1b or placebo.
                Patients with biopsy-proved metastatic renal-cell carcinoma were randomly assigned to receive interferon gamma-1b (60 microg per square meter of body-surface area subcutaneously once weekly) or placebo. The primary tumor had been treated by nephrectomy or angioinfarction at least three weeks previously. Patients were evaluated for radiologic evidence of progression, and all responses were independently reviewed by a committee that was unaware of the treatment.
                A total of 197 patients with metastatic renal-cell carcinoma were enrolled at 17 centers in Canada. One hundred eighty-one patients could be evaluated; of these, 91 were assigned to receive interferon gamma-1b and 90 were given placebo. The groups were well balanced in terms of prognostic factors. Two thirds of all patients had Karnofsky scores of 90 or 100, and more than half had two or more metastatic sites. Grade I and II toxicity, mostly chills, fever, asthenia, or headaches, was reported in 91 percent and 61 percent, respectively, of the patients in the interferon group, as compared with 76 percent and 63 percent in the placebo group. Life-threatening drug-related events were rare, occurring in 1 percent of patients in the interferon group. No significant differences between groups were observed in overall response rates, time to disease progression, or survival. The overall response rate was 4.4 percent (3.3 percent complete response and 1.1 percent partial response) in the interferon group and 6.6 percent (3.3 percent complete response and 3.3 percent partial response) in the placebo group (P=0.54), with a rate of durable complete response of 1 percent in both groups. The median time to disease progression was 1.9 months in both groups (P=0.49), and there was no significant difference in median survival (12.2 months with interferon vs. 15.7 months with placebo, P=0.52).
                No difference in outcome was observed in patients with metastatic renal-cell carcinoma who were treated with interferon gamma-1b as compared with placebo. These results emphasize the necessity of testing the efficacy of immunomodulators in randomized studies. A prospective randomized trial tested the hypothesis that interferon and cytotoxic chemotherapy delivered sequentially would be synergistic and would increase the response rate in metastatic renal cell carcinoma. Thirty-six patients were entered and randomized to chemotherapy only (5-fluorouracil, doxorubicin, mitomycin, and cis-platin) vs. interferon alternating with the same chemotherapy. Only 4 of 32 evaluable patients (13%), 2 in each arm, had a major response. Three patients in the alternating arm had minor responses. Complete, partial, and minor responses totaled 7 (22%). All four patients whose only disease was lung metastasis had some evidence of response (p = 0.001). Interferon alternating with chemotherapy did not appear to improve the major response rate over chemotherapy alone. Responses in metastatic renal cell carcinoma appear confined to a favorable subset of patients. IL-2 immunotherapy has been proven to be effective in the treatment of metastatic renal cell cancer (RCC). However, several drugs commonly used in the palliative therapy of cancer may potentially influence IL-2 efficacy, since the anticancer immunity has appeared to depend on complex interactions between immune system and psychoneuroimmunomodulation. In particular, experimental studies and preliminary clinical investigations have shown that the opioid substances, namely morphine, may suppress the anticancer immunity and the efficacy of IL-2 itself. In contrast, other neuroactive substances, in particular the pineal hormone melatonin (MLT), have been proven to stimulate the immune response, including the anticancer immunity, and to abrogate opioid-induced immunosuppression. On this basis, a study was planned to evaluate the effect of a concomitant MLT administration on the efficacy of IL-2 immunotherapy in advanced cancer patients chronically treated with morphine for cancer-related pain. The study was carried out in 30 metastatic RCC patients under chronic therapy with morphine at oral doses ranging from 60 to 120 mg/day. Patients were randomized to receive morphine alone or morphine plus MLT (20 mg/day orally in the evening). The immunotherapeutic cycle consisted of IL-2 subcutaneous administration at a dose of 6 million IU/day for 6 days/week for 4 consecutive weeks. In nonprogressing patients, a second cycle was planned after a 21-day rest period. The percent of partial responses achieved in patients treated with morphine alone was significantly lower than that observed in patients concomitantly treated with MLT (1/16 vs. 4/14, p<0.05). Moreover, the 3-year percent of survival was significantly higher in patients concomitantly treated with MLT (p<0.01). In contrast, no diminished analgesic efficacy of morphine occurred in patients concomitantly treated with MLT. This preliminary study seems to suggest that the negative influence of morphine therapy for cancer-related pain on the clinical efficacy of IL-2 cancer immunotherapy may be abrogated by the concomitant administration of the immunomodulating pineal neurohormone MLT. Metastatic renal cell carcinoma (RCC) has a poor prognosis. Conventional treatment strategies, including chemotherapy and hormonal therapy, have limited value. Although encouraging results have been achieved in terms of objective response using immunological manipulations, no conclusive studies yet exist with a controlled comparative evaluation of survival. Therefore, the present study was undertaken, which compared one of the present (and presumed best) treatments, interleukin 2/interferon-alpha (IL-2/IFN-alpha) and tamoxifen, with a control arm of tamoxifen only. Tamoxifen has been shown to potentiate in vivo anti-tumour activity of IL-2, and because of its non-toxic behaviour it was included in both groups. The study was open, randomized and included seven institutions in Sweden. The patients were stratified according to the different centres involved. An interim analysis was planned when a minimum of 100 patients were evaluable. The 128 patients finally included had a histologically documented metastatic RCC, with a life expectancy of more than 3 months, a performance status WHO 0-2 and no prior chemo- or immunotherapy. Informed consent was obtained from each patient. The patients randomized to the control arm (n = 63) received only tamoxifen 40 mg p.o. daily for at least 1 year or until progression. The patients (n = 65) randomized to biotherapy received subcutaneous recombinant IL-2, leucocyte IFN-alpha in a treatment cycle of 42 days, as well as tamoxifen p.o. In the absence of undue toxicity or disease progression, these patients received one additional treatment cycle of 42 days followed by maintenance treatment, consisting of 5 days therapy every 4 weeks, for 1 year, or until proven progression. Only two patients in the tamoxifen-only group received immunotherapy when the disease progressed, but without any beneficial effect. All patients received appropriate local treatment when indicated. The interim analysis demonstrated no survival advantage for either group, and therefore further inclusion of patients was stopped. The median follow-up was 11 months (range 0.4-48 months). The final survival analysis showed no significant differences between the two treatment arms in so far as comparison from the day of diagnosis of primary disease, from the day of first evidence of metastatic spread, or from the onset of treatment. This was valid both when the evaluation was performed with regard to intention to treat and when the analysis was directed only to patients that managed at least one treatment cycle (42 days) of IL-2/IFN-alpha. The adverse effects were more pronounced in the IL-2/IFN-alpha group. Although the number of patients is limited, the results raise doubt concerning immunotherapy with IL-2 and IFN-alpha as a routine treatment in the management of advanced RCC. The difference in cost of drugs and health care (drug costs per patient: IL-2/IFN-alpha $27000 vs tamoxifen $360) as well as adverse effects caused by IL-2/IFN-alpha are also factors of importance. The study emphasizes the need for more effort to find the 'optimal schedule' of immunotherapy, as well as the need for randomized controlled studies before approval of a new treatment in the routine setting. A prospective randomized trial of low versus high doses of human leukocyte alpha-interferon (1 X 10(6) units/day for 28 days versus 10 X 10(6) units/day for 28 days) was carried out in 30 patients with metastatic renal cell carcinoma, to test the tolerance and relative antitumor effects of these interferon doses. Both doses were tolerated well, and responses to the human leukocyte alpha-interferon were observed overall in seven individuals, including complete, partial, and minimal tumor regressions. Six of the seven responses occurred in patients who received the high dosage, and three of these responses were major responses. While not statistically significant, this result suggested a dose-response relationship. One minimal response was observed in a patient treated at low dosage. Nine individuals who were stable after 1 month of therapy at low dosage were randomized to a further month of therapy at low or high dosage, during which one of four at high dosage had a partial response, and none of five at low dosage manifested response. Regression of pulmonary disease in one individual was delayed, occurring 3 months after therapy at the high dose and enduring for a period of 28 months. Major objective responses in other patients were of 4 and 15 months duration. Human leukocyte alpha-interferon is an active agent in renal cell carcinoma at the dosage of 10 million units daily. No relationship of toxicity to response was evident in this trial. Optimum dosage and duration of treatment have yet to be established. One hundred sixty-five patients were randomized to receive either interferon alfa-n1 (Wellferon; Burroughs Wellcome Co, Research Triangle Park, NC) alone or with vinblastine. An initial six-cycle induction treatment consisted of interferon given at daily doses of 3, 5, 20, 20, and 20 x 10(6) U/m2 every 2 weeks. Vinblastine at a dose of 10 mg/m2 (later decreased to 5 mg/m2) was given on day 1 of alternate cycles. Toxicities were generally well tolerated. The overall response rate was 10% with no significant difference between treatment arms. Survival was also not significantly different for the arms. A small subset of patients (16) with metastases only to the lungs had a high complete response (CR) and partial response (PR) rate of 44%. Responses were durable, and overall survival of this group was much better than that of the other patients. Biologic response modifiers have activity in renal cell carcinoma. The combination of interleukin-2 (IL-2) and beta-interferon (B-IFN) is synergistic in vitro. This trial was initiated to determine the efficacy of IL-2 alone and with B-IFN in advanced RCC.
                Ambulatory patients with advanced RCC were randomly allocated to either IL-2 6 x 10(6) units/M2 intravenously (IV) three days a week for four weeks or IL-2 5 x 10(6) units/M2 IV plus B-IFN 6 x 10(6) units/M2 IV three days a week for 4 weeks. This induction phase was followed by a maintenance phase of the same drugs and doses administered for two weeks out of every four.
                84 patients were entered onto this phase II trial with 75 considered eligible for response and survival. Toxicity is reported for the 81 patients on whom data was received, irrespective of eligibility. The overall response rate (RR) was 9.3% (7/75). Of the 3 responses in the IL-2 arm (RR = 8.3%), one was a complete response. 4 patients in the IL-2 + B-IFN arm (RR = 10.3%) achieved a partial response. Median survival was estimated to be 8.4 months for patients given IL-2 and 8.0 months for patients given the IL-2 and B-IFN combination. Multivariate analysis of survival data identified initial performance status, metastases of > 1 site, and weight loss as being important prognostic factors for survival. There were 2 lethal and 3 life threatening toxicities with the IL-2 treatment. While there were no lethal toxicities on the combination arm, there were 4 life threatening toxicities.
                The results of this study indicate that further investigation of IL-2 with or without B-IFN at this dose and schedule as treatments for renal cell carcinoma is probably not warranted. This three-arm randomized study compares response rates and overall survival of patients with metastatic renal cell cancer (RCC) receiving high-dose or one of two low-dose interleukin-2 (IL-2) regimens.
                Patients with measurable metastatic RCC and a good performance status were randomized to receive either 720,000 U/kg (high-dose [HD]) or 72,000 U/kg (low-dose [LD]), both given by intravenous (IV) bolus every 8 hours. After randomly assigning 117 patients, a third arm of low-dose daily subcutaneous IL-2 was added, and an additional 283 patients were randomly assigned.
                A total of 156 patients were randomly assigned to HD IV IL-2, and 150 patients to LD IV IL-2. Toxicities were less frequent with LD IV IL-2 (especially hypotension), but there were no IL-2-related deaths in any arm. There was a higher response proportion with HD IV IL-2 (21%) versus LD IV IL-2 (13%; P =.048) but no overall survival difference. The response rate of subcutaneous IL-2 (10%, partial response and complete response) was similar to that of LD IV IL-2, differing from HD IV (P =.033). Response durability and survival in completely responding patients was superior with HD IV compared with LD IV therapy (P =.04).
                Major tumor regressions, as well as complete responses, were seen with all regimens tested. IL-2 was more clinically active at maximal doses, although this did not produce an overall survival benefit. The immunological factors which constrain the curative potential of IL-2 to only a small percentage of patients need to be further elucidated. In a randomized phase II study we evaluated response, survival and side effects of low dose recombinant interferon-gamma in 30 patients (group 1) versus recombinant interleukin-2 and interferon-alpha 2b in 30 (group 2) with metastatic renal cell carcinoma.
                Group 1 received 200 micrograms interferon-gamma subcutaneously once a week. Group 2 received 4 x 4.8 x 10(6) IU/m.2 interleukin-2 subcutaneously on days 1 and 22, 2 x 4.8 x 10(6) IU/m.2 on days 2 and 23, and 2 x 2.4 x 10(6) IU/m.2 combined with interferon-alpha 2b subcutaneously at 3 x 10(6) IU/m.2 on days 3, 5, 24 and 26, and 6 x 10(6) IU/m.2 3 times weekly for 6 weeks.
                Toxicity grades 2 and 3 (World Health Organization) were observed in group 2 only. After followup of 13 months there was no remission in group 1 compared to 7 remissions in group 2, with 23 cases of progressive disease detected.
                Combination therapy showed an objective response rate of 23% (p = 0.01). Although survival was not a primary aim of the study, there was a tendency toward no significant difference in survival when evaluating these relatively small groups (p = 0.49). We conducted a prospectively randomized clinical trial to compare the efficacy and safety of subcutaneous interferon-alpha2a, subcutaneous interleukin-2 and intravenous 5-fluorouracil as home therapy against oral tamoxifen in 78 patients with progressive metastatic renal cell carcinoma. Treatment courses consisted of interferon-alpha2a 5 x 10(6) IU m(-2), day 1 weeks 1 + 4; days 1, 3, 5 weeks 2 + 3; 10 x 10(6) IU m(-2), days 1, 3, 5 weeks 5-8; interleukin-2 10 x 10(6) IU m(-2), twice daily days 3-5 weeks 1 + 4; 5 x 10(6) IU m(-2), days 1, 3, 5 weeks 2 + 3; and 5-fluorouracil 1000 mg m(-2), day 1 weeks 5-8. The tamoxifen group received tamoxifen 80 mg twice daily over 8 weeks. Among 41 patients treated with interleukin-2, interferon-alpha2a and 5-fluorouracil there were 7 complete (17.1%) and 9 partial responders (21.9%), with an overall objective response rate of 39.1% (95% CI, 24.2-55.5). An additional 15 patients (36.6%) were stable throughout therapy. The overall survival was 24 months (range 5-76+). In 37 patients receiving tamoxifen no objective remissions occurred. 13 patients (35.1%) had stable disease and 24 patients (64.9%) showed continued disease progression. The overall survival was 13 months (range 3-73+). In summary, this home-based therapy regimen of interferon-alpha2a, interleukin-2 and 5-fluorouracil demonstrated significant therapeutic efficacy in patients with progressive renal cell carcinoma when compared to hormonal therapy.
                Copyright 2001 Cancer Research Campaign http://www.bjcancer.com. The Cytokine Working Group conducted a randomized phase III trial to determine the value of outpatient interleukin-2 (IL-2) and interferon alfa-2b (IFN) relative to high-dose (HD) IL-2 in patients with metastatic renal cell carcinoma.
                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/m(2) subcutaneously every 8 hours for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m(2) 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.
                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 [corrected] months (P = .18) [corrected] 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.
                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. Eighty-nine patients with advanced measurable metastatic renal cell carcinoma were entered into a prospective randomized trial comparing alpha-interferon to gamma-interferon and to the combination. The trial was performed in order to confirm the activity of gamma-interferon and assess the potential clinical synergism. Response rates were 5, 10, and 5%, respectively. The low response rate may have been due to the inability to raise the doses of the interferons to higher levels. Clinical synergy at this dose, route, and schedule of administration in renal cell carcinoma does not exist. We conducted a prospectively randomized clinical trial to compare the efficacy of three outpatient therapy regimens in 341 patients with progressive metastatic renal cell carcinoma.
                Patients were stratified according to known clinical predictors and were subsequently randomly assigned. Treatment arms were: arm A (n = 132), subcutaneous interferon alfa-2a (sc-IFN-alpha-2a), subcutaneous interleukin-2 (sc-IL-2), and intravenous (IV) fluorouracil; arm B (n = 146): arm A treatment combined with per oral 13-cis-retinoic acid; and arm C (n = 63), sc-IFN-alpha-2a and IV vinblastine.
                Treatment (according to the standard 8-week Hannover Atzpodien regimen) arms A, B, and C yielded objective response rates of 31%, 26%, and 20%, respectively. Arm B, but not arm A, showed a significantly improved progression-free survival (PFS) compared with arm C (P =.0248). Both arm A (median overall survival, 25 months; P =.0440) and arm B (median overall survival, 27 months; P =.0227) led to significantly improved overall survival (OS) compared with arm C (median OS, 16 months). All three sc-IFN-alpha-2a-based therapies were moderately or well tolerated.
                Our results established the safety and improved long-term therapeutic efficacy of sc-IL-2 plus sc-INF-alpha-2a-based outpatient immunochemotherapies, compared with sc-INF-alpha-2a/IV vinblastine. Treatment using interleukin-2 (IL-2) alone or in conjunction with lymphokine-activated killer (LAK) cells has been shown to mediate disease regression in selected patients with advanced cancer.
                This prospective randomized trial was designed to determine whether the administration of LAK cells in conjunction with high-dose IL-2 alters response and survival rates, compared with those for IL-2 alone, in patients with advanced cancer.
                The 181 patients who had metastatic cancer that had failed to respond to standard therapy or who had disease for which no effective therapy existed received treatment with high-dose IL-2 alone or with LAK cells plus IL-2. Both treatment groups were to receive the same dose of IL-2 administered according to the same schedule. IL-2 doses were omitted depending on the tolerance of the patient. Of the 181 patients, 97 had renal cell cancer and 54 had melanoma.
                Median potential follow-up was 63.2 months. There were 10 complete responses among the 85 assessable patients who received IL-2 plus LAK cells, compared with four among the 79 who received IL-2 alone. There were 14 and 12 partial responses, respectively. Complete response continues in seven patients at 50-66 months. The 36-month actuarial survival with IL-2 plus LAK cells was 31%, compared with 17% with IL-2 alone (two-sided P value [P2] = .089). A trend toward improved survival was seen for patients with melanoma who received IL-2 plus LAK cells, compared with those who received IL-2 alone (24-month survival: 32% versus 15%; 48-month survival: 18% versus 4%; P2 = .064 [corrected]). None of 26 patients with melanoma who received IL-2 alone are alive; five of 28 who received IL-2 plus LAK cells are alive, and three continue in complete response. No difference in survival was seen in patients with renal cell cancer in the two treatment groups. There were six treatment-related deaths (3.3%); three were due to myocardial infarction. Other toxic effects resolved by discontinuation of IL-2. Many toxic effects were related to increased vascular permeability induced by IL-2.
                Some patients with metastatic cancer have prolonged remission when they are treated with high-dose IL-2 alone or in conjunction with LAK cells. Our results suggest a trend toward increased survival when IL-2 is given with LAK cells in patients with melanoma, but no trend was observed for patients with renal cell cancer.
                As these studies continue, efforts are underway to develop improved immunotherapies using tumor-infiltrating lymphocytes (TIL) and gene-modified TIL. The combination of interferon alfa-2a (IFNalpha2a) plus vinblastine (VLB) induces objective tumor responses in patients with advanced renal cell cancer. However, no prospective randomized trial has shown that this treatment prolongs overall survival. We compared overall survival after treatment with IFNalpha2a plus VLB versus VLB alone in patients with advanced renal cell cancer.
                We prospectively randomized 160 patients with locally advanced or metastatic renal cell cancer to receive either VLB alone or IFNalpha2a plus VLB for 12 months or until progression of disease. In both groups, VLB was administered intravenously at 0.1 mg/kg every 3 weeks, and in the combination group IFNalpha2a was administered subcutaneously at 3 million units three times a week for 1 week, and 18 million units three times a week thereafter for the second and subsequent weeks. For patients unable totolerate IFNalpha2a at 18 million units per injection, the dose was reduced to 9 million units.
                Median survival was 67.6 weeks for the 79 patients receiving IFNalpha2a plus VLB and 37.8 weeks for the 81 patients treated with VLB (P =.0049). Overall response rates were 16. 5% for patients treated with IFNalpha2a plus VLB and 2.5% for patients treated with VLB alone (P =.0025). Treatment with the combination was associated with constitutional symptoms and abnormalities in laboratory parameters, but no toxic deaths were reported.
                The combination of IFNalpha2a plus VLB is superior to VLB alone in the treatment of patients with locally advanced or metastatic renal cell carcinoma. This is the first study to demonstrate that survival can be prolonged by using IFNalpha2a for these patients. Recombinant human interleukin-2 (aldesleukin) and recombinant human interferon alfa can induce notable tumor regression in a limited number of patients with metastatic renal-cell carcinoma. We conducted a multicenter, randomized trial to determine the effect of each cytokine independently and in combination, and to identify patients who are best suited for this treatment.
                Four hundred twenty-five patients with metastatic renal-cell carcinoma were randomly assigned to receive either a continuous intravenous infusion of interleukin-2, subcutaneous injections of interferon alfa-2a, or both. The main outcome measure was the response rate; secondary outcomes were the rates of event-free and overall survival. Predictive factors for response and rapid progression were identified by multivariate analysis.
                Response rates were 6.5 percent, 7.5 percent, and 18.6 percent (P<0.01) for the groups receiving interleukin-2, interferon alfa-2a, and interleukin-2 plus interferon alfa-2a, respectively. At one year, the event-free survival rates were 15 percent, 12 percent, and 20 percent, respectively (P=0.01). There was no significant difference in overall survival among the three groups. Toxic effects of therapy were more common in patients receiving interleukin-2 than in those receiving interferon alfa-2a. Response to treatment was associated with having metastasis to a single organ and with receiving the combined treatment. The probability of rapid progression of disease was at least 70 percent for patients with at least two metastatic sites, liver metastases, and a period of less than one year between the diagnosis of the primary tumor and the appearance of metastases.
                Cytokines are active in a few patients with metastatic renal-cell carcinoma. The higher response rate and longer event-free survival obtained with a combination of cytokines must be balanced against the toxicity of such treatment. Fifty-six patients with metastatic renal cell carcinoma (RCC) were treated with recombinant DNA-derived interferon alpha (rIFN alpha A). The first 30 patients were randomized between doses of 2 X 10(6) U/m2 and 20 X 10(6) U/m2 intramuscularly daily. No complete (CR) or partial (PR) remissions were achieved in 15 patients receiving the low dose. In contrast, 27% of those receiving the high dose achieved CR or PR. Subsequently, 26 additional patients were given the high dose and achieved a 31% response rate. Remissions lasted from 1 to more than 12 months (median, 3 months). Responses occurred predominantly in lung parenchyma or mediastinal node metastases. Toxicity of the high dose required dose reduction in 50% of the patients. Neutralizing antibodies to rIFN alpha A developed in seven of 12 responsive (58%) and nine of 29 (31%) nonresponsive patients (P = greater than .5). The median duration of remission among the antibody-positive and antibody-negative patients were 2 and 10 months, respectively (P = .009). The clinical significance of the antibodies to rIFN alpha A remains unclear, but the coincidence between the detection of antibodies and the early relapse of the disease in some responsive patients suggests that these antibodies may abrogate the biologic activity of rIFN alpha A. This effect, however, was not associated with adverse clinical sequelae. Surgery is the main treatment for localised renal cell carcinoma, but use of radical nephrectomy for metastatic disease is highly controversial. We aimed to establish whether radical nephrectomy done before interferon-alfa-based immunotherapy improved time to progression and overall survival (primary endpoints) compared with interferon alfa alone.
                We included 85 patients from June, 1995, to July, 1998: two (one per group) were ineligible. 42 of the 83 participants were randomly assigned combined treatment (study group) and 43 immunotherapy alone (controls). All patients had metastatic renal-cell carcinoma that had been histologically confirmed and was progressive at entry. In study patients, surgery was done within 4 weeks of randomisation, and immunotherapy (5x10(6) IU/m(2) subcutaneously three times per week) started 2-4 weeks later. In controls, immunotherapy was started within 1 working day of randomisation. Follow-up visits were monthly. All analyses were by intention to treat.
                40 (53%) of 75 patients received at least 16 weeks of interferon-alfa treatment, which was also the median duration of treatment. Time to progression (5 vs 3 months, hazard ratio 0.60, 95% CI 0.36-0.97) and median duration of survival were significantly better in study patients than in controls (17 vs 7 months, 0.54, 0.31-0.94). Five patients responded completely to combined treatment, and one to interferon alfa alone. Dose modification was necessary in 32% of patients, most commonly because of non-haematological side-effects.
                Radical nephrectomy before interferon-based immunotherapy might substantially delay time to progression and improve survival of patients with metastatic renal cell carcinoma who present with good performance status. In a randomized study of advanced renal cell carcinoma 60 patients were allocated to treatment with either recombinant interferon alpha-2a or medroxyprogesterone acetate. Correlation between the dose of interferon alpha-2a and plasma-concentration indicated linear kinetics. Survival was similar in the two treatment groups. Only one complete and one partial response were seen in the interferon group and only one complete response in the medroxyprogesterone group, indicating a low therapeutic potential of both interferon and medroxyprogesterone. Interferon influenced the serum liver enzyme levels; increased transaminases were seen in 17 patients treated with interferon but in only four patients in the medroxyprogesterone group. Two patients had very high serum liver-enzyme levels concomitant with intolerable tiredness, in both patients the symptoms disappeared and the enzymes normalized after discontinuation of the interferon treatment. Antibodies to interferon developed frequently in patients receiving high dose oligomeric interferon therapy but rarely in patients receiving low dose monomeric interferon treatment. Conjugation of polyethylene glycol to recombinant human interleukin-2 (IL-2) results in a compound, polyethylene glycol-modified IL-2 (PEG-IL-2) that retains the in vitro and in vivo activity of IL-2, but exhibits a markedly prolonged circulating half-life. In mice, one dose of PEG-IL-2 results in tumor regression comparable to that achieved with multiple bolus doses of IL-2. Based on these preclinical studies, a Phase I study with PEG-IL-2 was undertaken in patients with metastatic renal cell carcinoma (RCC) and melanoma. Then, to exploit the higher peak levels attained with IL-2 and the improved trough levels of PEG-IL-2, a combination regimen beginning with bolus IL-2 followed by low dose maintenance PEG-IL-2 was devised and tested for efficacy.
                Patients with measurable metastatic melanoma or RCC were entered in a Phase I dose escalation trial of PEG-IL-2 given once a week by intravenous bolus. This trial then was repeated using a twice-a-week schedule. After determining the maximum tolerated dose (MTD) and a safe outpatient regimen for PEG-IL-2, a hybrid regimen combining an initial high dose IL-2 cycle followed by chronic maintenance with weekly PEG-IL-2 was devised. This regimen was compared with a standard regimen consisting of two cycles of high dose unconjugated IL-2 in a randomized prospective clinical trial.
                When given by intravenous bolus once a week, the MTD of PEG-IL-2 was 12 million IU/m2, with toxicities similar to those of unconjugated IL-2. A twice-a-week schedule was less well tolerated. Of 28 patients given 32 treatment courses at varied dose levels, there were two partial responses and one minor response. A total of 124 patients with metastatic melanoma or RCC were randomized to either standard unconjugated IL-2 therapy or the hybrid regimen. There was no treatment-related mortality in either arm, and the use of PEG-IL-2 resulted in a significant decrease in the need for intensive-care-unit care. The response rates (partial response and complete response) for patients with RCC and melanoma were 19% and 15%, respectively, for IL-2 alone and 17% and 11%, respectively, for the IL-2 and PEG-IL-2 combination.
                The combination of high dose IL-2 followed by PEG-IL-2 is a well tolerated regimen with significant activity against RCC and melanoma, but it shows no significant increase in antitumor activity compared with high dose IL-2 alone. nan Since 1985, multiple centers have demonstrated that interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells produce durable anticancer responses in patients with metastatic renal cell carcinoma. High-dose recombinant IL-2 (rIL-2) has been administered by intravenous bolus injection (Rosenberg SA, et al: N Engl J Med 313:1485-1492, 1985) and by continuous intravenous infusion (West WH, et al: N Engl J Med 316:898-905, 1987) combined with lymphokine-activated killer (LAK) cells, with both methods producing responses in patients with advanced renal cell carcinoma. The Extramural IL-2/LAK Working Group has conducted a randomized phase II trial of two intravenous high-dose rIL-2 regimens (bolus three times daily or 24-hour continuous infusion) to determine if either one manifests greater anticancer activity or a more acceptable toxicity profile.
                Ninety-four patients with measurable advanced renal cell carcinoma were enrolled on this study: 46 to the bolus injection arm and 48 to the continuous infusion arm. On both arms, patients underwent a priming phase of rIL-2 administration, four daily lymphocytaphereses to harvest mononuclear cells that were placed in 3- to 4-day culture for generation of LAK cells, and an rIL-2/LAK coadministration phase. Patients were then observed monthly for evidence of response to this therapy and were offered up to two additional courses of treatment every 3 months if evidence of response was detected.
                Twenty percent of patients on the bolus injection arm experienced objective responses (three complete responses and six partial responses); 15% of patients on the continuous infusion arm responded (two complete responses and five partial responses). Complete responses were durable, persisting for 310+ to 700+ days. The incidence of severe life-threatening toxicities typical of high-dose rIL-2 therapy was similar in both arms (eg, patients with hypotension requiring pressors: bolus 71%, continuous 63%; oliguria less than or equal to 200 mL/8 hours: bolus 65%, continuous 71%). More episodes of fever, infection, and serum alkaline phosphatase elevation were associated with the continuous infusion arm, while more thrombocytopenia occurred on the bolus injection arm. Four patients (three bolus injection, one continuous infusion) died of respiratory and circulatory failure while under treatment. No clinical or laboratory parameter accompanying treatment on either arm was, by univariate or multivariate analysis, associated with an increased likelihood of response.
                Both methods of high-dose rIL-2/LAK cell administration produce nearly equivalent anticancer activity and toxicity in the treatment of renal cell carcinoma. The ability to predict responding patients based on patient or treatment characteristics is not possible. A total of 178 patients with metastatic renal cell cancer were randomized to receive interferon alfa-2a (rIFN alfa-2a) or interferon alfa-2a+vinblastine (VLB). IFN alfa-2a was injected intramuscularly at a dose of 18 MIU 3 times a week and VLB was given intravenously at a dose of 0.1 mg/kg once every 3 weeks. The response rate was 11% for patients on monotherapy and 24% for those on combination treatment. The 5-year survival for 145 eligible patients was 9%, independently from the treatment arm. The performance status was significantly related to long-term prognosis, and 13% of the patients with performance status 0 were alive at 5 years, as compared to 6% and 0% for patients with a WHO grade of 1 and 2, respectively. The most frequent adverse events in both treatment arms were flu-like symptoms (95%), fatigue (70%) and gastrointestinal disturbances (68%). Leukopenia was observed more frequently with combination treatment (53%) than with IFN alfa-2a alone (30%). In conclusion, rIFN alfa-2a monotherapy at this dose and schedule has modest antitumor activity in metastatic renal cell cancer. The combination of rIFN alfa-2a+VLB results in a doubling of the response rate, but this does not translate into prolonged survival. Toxicity (except leukopenia) and tolerance were similar in both treatment arms. To assess the value of autolymphocyte therapy (ALT) in the treatment of metastatic renal-cell carcinoma, 90 patients were randomised to receive every month for six months oral cimetidine plus an infusion of autologous peripheral blood lymphocytes activated in vitro by a previously generated autologous lymphokine mixture, or cimetidine alone. The median follow-up was 15 months. Survival time for the autolymphocyte group was approximately 2.5 times that for the cimetidine group (p = 0.008). Patients who had greater than 500 pg interleukin-1 (IL-1) per ml autologous lymphokine mixture had a six-fold survival advantage over those with less than 500 pg/ml (p less than 0.00005). Men treated with ALT had a four-fold survival advantage (p = 0.001) over men who received cimetidine only. Infusion of the cultured autolymphocytes was accompanied by mild, self-limited fever in 11 of the 45 ALT patients, and by only one instance in which fever was accompanied by tachypnoea and hypotension. The purpose of the present study was to investigate the therapeutic effectiveness of interleukin-2 (IL-2) and interferon (IFN), either alone or in combination, in comparable groups of patients affected by advanced renal cell carcinoma (RCC).
                In order to limit selection biases, treatment was allocated on a random basis. Patients randomized to IL-2 alone were scheduled to receive eight rlL-2 24-hour i.v. infusion cycles, days 1 to 4, at a daily dose of 18 x 10(6) lU/m2 for a total of 25 weeks. Patients randomized to IFN alone were scheduled to receive rIFN-alpha at a daily dose of 6 x 10(6) IU/m2, days 1, 3 and 5, every week for a total of 52 weeks. Patients randomized to the combination of IFN and IL-2 were given the same drugs at the same daily doses for a total of 24 weeks. Drug dose was modified according to toxicity.
                Twenty-three percent (95% CI:+/-17.5) of patients treated with IL-2 alone showed an objective response to treatment (9% CR). The corresponding figures in patients treated with IFN alone or IFN plus IL-2 were 9% (95% CI:+/-11.9) and 9% (95% CI:+/-11.9), respectively. Complete responses were observed only in patients treated with IL-2. The median duration of response in the IL-2 arm was 18 months (range, 9.5-24). The duration of the two responses achieved by IFN alone was seven and nine months, respectively. The corresponding figures in the two patients responding to the combination of IFN with IL-2 were 19 and 27 months, respectively. Total IL-2 dose appeared to be a major predictor of response. Only a minority of patients experienced grade 3-4 toxicity, the incidence being higher in those treated with IL-2 or IL-2 plus IFN.
                Neither IFN nor IL-2 or the combination of the two appear to be very active in patients with advanced RCC, even when trial entry was restricted to patients with relatively indolent disease. This stresses the need for the development of new approaches. To evaluate the role of cytoreductive nephrectomy (CRN) in improving survival in patients with renal cell cancer.
                The case-notes of 268 consecutive patients who presented to our specialized renal cancer clinic between 1998 and 2001 were reviewed. All patients with metastatic disease were assessed for CRN. If their primary tumour was considered operable, they were assessed further using the European Cooperative Oncology Group performance score; only patients with a performance score of 0 or 1 were considered for surgery.
                In all, 168 patients underwent nephrectomy with curative intent for M0 disease and 11 were treated conservatively. Ninety-four patients with M+ disease (mean age 65 years, range 38-80) were considered for CRN. Thirty-eight patients had an inoperable primary. Of the remaining 56 patients, 20 had a performance status of 0 or 1 and were offered CRN.
                Metastatic disease at presentation occurred in 34% of all patients referred; 40% patients had an inoperable primary and 38% had a performance score of > or =2. With an active policy of considering all patients for CRN, only 7% of those with renal cancer were suitable for this procedure. CRN is unlikely to have a significant effect on overall survival within a population of patients with renal cancer. We performed a prospective, controlled trial of recombinant leukocyte A interferon (IFN-alpha 2A) with or without aspirin (ASA) in 176 patients with assessable advanced renal cell cancer in light of a 34% response rate (10 of 29 patients) from the two-agent regimen in an earlier nonrandomized trial. This encouraging result was substantially higher than the 15% response rate typically achieved with IFN therapy alone. Eighty-seven patients received IFN-alpha 2A 20 x 10(6) U/m2 intramuscularly three times a week, and 89 received the same IFN therapy with ASA 600 mg orally four times each day. Each group was balanced as to relevant prognostic discriminants. Response rates were 8% for the group receiving ASA in addition to IFN, and 13% for the group receiving IFN alone (P = .30). The median times to progression were 1.9 months for the group receiving IFN with ASA and 2.7 months for the group receiving IFN alone (log-rank P = .36). The median survival durations were 8.8 months for the IFN and ASA group and 8.0 months for the IFN-only group (log-rank P = .60). These figures are also inferior to those typically reported from other studies. Our findings reemphasize the crucial role of randomized trials, admittedly cumbersome and time-consuming, to determine accurately the value of apparently promising therapies. Although some patients may derive benefit from IFN therapy, our findings raise disturbing questions regarding the potential IFN-alpha 2A according to the dose and schedule used in this trial to have any substantive impact on the ultimate outcome of disseminated renal cell cancer. The outcome of treatment of advanced renal cell carcinoma is disappointing. In interferon (IFN)-treated patients, the high incidence of adverse effects causes many patients to withdraw from treatment. This 12-week randomized study compared the incidence of toxicity associated with high-dose IFN monotherapy (15 x 10(6) U thrice weekly) and treatment with the combination of low-dose IFN (5 x 10(6) U thrice weekly) and 6 mg/m2 vinblastine (VBL) every 14 days in 100 consecutive patients. There was no significant difference in response rate between treatment arms (42% IFN vs. 34% IFN + VBL) or between subgroups (by tumor location). Combined treatment was associated with a significantly lower incidence of fever, fatigue, and weight loss but with a higher incidence of leukopenia. There was no significant difference in the incidence of other events. More patients treated with IFN monotherapy required bed rest, and overall treatment costs were 60% higher than for combined treatment. It is concluded that combined treatment with low-dose IFN and VBL, without loss of short-term efficacy, is better tolerated and less expensive than high-dose IFN monotherapy. To prospectively evaluate in a multicenter randomized trial the antitumor activity of CD8(+) tumor-infiltrating lymphocytes (TILs) in combination with low-dose recombinant interleukin-2 (rIL-2), compared with rIL-2 alone, after radical nephrectomy in metastatic renal cell carcinoma patients.
                Between December 1994 and March 1997, 178 patients with resectable primary tumors were enrolled at 29 centers in the United States and Europe. Patients underwent total nephrectomy, recovered, and were randomized to receive either CD8(+) TILs (5 x 10(7) to 3 x 10(10) cells intravenously, day 1) plus rIL-2 (one to four cycles: 5 x 10(6) IU/m(2) by continuous infusion daily for 4 days per week for 4 weeks) (TIL/rIL-2 group) or placebo cell infusion plus rIL-2 (identical regimen) (rIL-2 control group). Primary tumor specimens were cultured at a central cell-processing center in serum-free medium containing rIL-2 to generate TILs.
                Of 178 enrolled patients, 160 were randomized (TIL/rIL-2 group, n = 81; rIL-2 control group, n = 79). Twenty randomized patients received no treatment after nephrectomy because of surgical complications (four patients), operative mortality (two patients), or ineligibility for rIL-2 therapy (14 patients). Among 72 patients eligible for TIL/rIL-2 therapy, 33 (41%) received no TIL therapy because of an insufficient number of viable cells. Intent-to-treat analysis demonstrated objective response rates of 9.9% v 11.4% and 1-year survival rates of 55% v 47% in the TIL/rIL-2 and rIL-2 control groups, respectively. The study was terminated early for lack of efficacy as determined by the Data Safety Monitoring Board.
                Treatment with CD8(+) TILs did not improve response rate or survival in patients treated with low-dose rIL-2 after nephrectomy. Despite the efficacy of IL-2 in the treatment of metastatic renal cell carcinoma (RCC), the prognosis of patients with synchronous metastases still remains poor. Nephrectomy itself, as well as other surgical operations, may further suppress the antitumor immune response. Previous studies suggested that the preoperative injection of IL-2 may neutralize surgery-induced lymphocytopenia in advanced colon cancer. On this basis, a pilot randomized study was performed in an attempt to evaluate the effects of a preoperative administration of IL-2 on postoperative lymphocyte numbers and on the survival in advanced RVV patients with more than 3 synchronous metastases. The study included 20 consecutive patients, who were randomized to receive nephrectomy alone or nephrectomy plus preoperative subcutaneous immunotherapy with IL-2 (18 million IU/day for 3 days). Then, all patients underwent postoperative immunotherapy with IL-2 (6 million IU/day for 5 days/week for 6 weeks). Surgery-induced lymphocytopenia was completely abolished by IL-2 preoperative injection. The frequency of postoperative complications was significantly higher in controls than in patients preoperatively treated with IL-2. On the contrary, significant differences between control and patients preoperatively treated with IL-2 were observed neither in the clinical response to IL-2 immunotherapy, nor in the percent of 1-year survival. The results of this preliminary pilot study would suggest that IL-2 preoperative immunotherapy may neutralize surgery-induced lymphocytopenia and reduce the postoperative complications in RCC patients with synchronous metastases, without, however, influencing their prognosis in terms of survival time. Recombinant human interleukin-2 (IL-2) has a well-documented anti-tumor activity against RCC and has demonstrated a synergistic anti-tumor activity between doxorubicin and IL-2, thus providing better survival. This study investigated the toxicity and efficacy of the association between doxorubicin and IL-2, and interferon-alpha, and the immuno-chemotherapeutic association with IL-2 and 4-Epirubicin.
                Patients with histologic evidence of metastatic or advanced RCC were randomized to receive either IL-2 + IFN-alpha (Arm A) or IL-2 + 4-Epi (Arm B). Arm A patients received IFN-alpha subcutaneously at doses of 3 million UI on days 1, 3 and 5 for 6 weeks. Arm B patients received 4-EPI at doses of 25 mg/m2 on days 1, 8, 15, 22, 29 and 36. Treatment cycles were repeated at 10 week intervals.
                Of 38 evaluable patients, we observed 2 complete responses, 2 partial responses, 1 minimal response, 1 mixed response, 21 stationary disease and 11 disease progressions. There was no significant difference in overall survival between the two groups. However in arm B, the median overall survival for responding patients was better than that of patients who experienced a disease progression. Performance status was the only predictive prognostic factor.
                Our analysis confirms the low response rate associated with IL-2 treatments but seems to indicate a role of anthracycline in improving the survival of responding patients with an acceptable toxicity. Early results of a prospective, randomized trial of active, specific immunotherapy adjunctive to nephrectomy in all stages of RCC are presented. Forty-three patients with median followup of 30 m, who were randomly allocated to either immuno-hormonotherapy arm (IMT), or hormonotherapy alone (HT), are evaluated in terms of progression-free interval (PFI) and overall survival by life table method. Immunotherapy consisted of autologous irradiated tumor cells (AITC), admixed with bacillus Calmette-Guérin (Glaxo) administered by the intradermal and endolymphatic route. Clinical results of this study show only a trend for advantage of the experimental (IMT) arm over the control (HT) arm, this trend did not reach statistical significance level: prolongation of disease free period in stages I-III with localized disease (p less than 0.1) and prolongation of survival in patients with metastatic disease (p less than 0.07). A correlation was established between induction of cutaneous delayed hypersensitivity (DTH) to AITC and prolonged PFI and survival: patients with positive DTH had a significantly better course of disease than those who could not be converted to positivity after repeated immunizations. Positive in vitro leukocyte migration inhibition against autologous tumor preparations correlates well with positive in vivo cutaneous DTH. Some immunological aspects of active immunization with autologous tumor cells are discussed. Treatment with interleukin-2 (IL-2) and lymphokine-activated killer cells (LAK) resulted in responses in some patients with advanced renal cell carcinoma (RCC). However, the relative therapeutic benefit of the addition of LAK to IL-2 was unknown.
                A randomized Phase III trial was conducted in patients with RCC comparing continuous intravenous infusion (CI) IL-2 alone with CI IL-2 plus LAK. Interleukin-2 was administered at 3 x 10(6) U/m2/day on days 1-5, 13-17, 21-24, and 28-31. Patients on the LAK treatment arm underwent leukapheresis on days 8-10 and LAK cell reinfusion on days 13-15. The results are reported with long-term follow-up. The published experience with IL-2 alone or with the addition of LAK was investigated in a quantitative literature survey. The response proportions were studied by schedule (high dose bolus, moderate dose, low dose) and by concomitant administration of LAK.
                Seventy-one patients were treated, 36 on the IL-2 arm and 35 on the IL-2 plus LAK arm. Four patients (6%) had major responses (two complete, two partial). The median survival of all patients was 13 months (95% confidence interval [CI], 9-18 months). There were no differences between treatment arms with regard to response (P = 0.61) and survival (P = 0.67). More patients on the LAK arm experienced pulmonary toxicity (P = 0.008). The overall weighted response proportion was 16% (95% CI, 8%-24%) for the 39 published series of 1291 patients treated with IL-2. The 95% confidence intervals for response proportion overlapped when compared by schedule and by administration of LAK.
                The dose and schedule of IL-2 used in this study resulted in a low level of antitumor activity and the addition of LAK did not improve the response rate against RCC. Given the infrequent, but reproducible, responses with IL-2 and interferon-based regimens, continued investigation of these agents is warranted as is the study of new cytokines. Alternative treatment strategies should be studied in RCC and new agents and treatment regimens that appear promising in Phase II studies must be studied in randomized trials.
Interferon-alfa provides a modest survival benefit compared to other commonly used treatments. In fit patients with metastases at diagnosis and minimal symptoms, nephrectomy followed by interferon-alfa gives the best survival strategy for fully validated therapies. The need for more effective specific therapy for this condition is apparent.