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. 2007 Jun;1(2 Suppl):S28–S33. doi: 10.5489/cuaj.65

Current status of cytokine therapy in management of patients with metastatic renal cell carcinoma

Anil K Kapoor *, Sébastien J Hotte †
PMCID: PMC2422946  PMID: 18542782

Abstract

Cytokine therapy with interferon-α and interleukin-2 has arguably been the standard treatment for patients with metastatic renal cell carcinoma for more than 20 years. In this paper, the current evidence for the use of cytokine therapy in this patient population is discussed, including the significant toxicity associated with these agents. A low overall response rate and a marginal survival advantage are observed with interferon-α and interleukin-2; however, these therapies have significant toxicity and impair quality of life. Unlike the current tyrosine-kinase inhibitors, complete tumour responses may be seen with interleukin-2, but again this therapy has significant morbidity and mortality. Newer anti-angiogenesis agents may be combined with current standard cytokine therapy for patients with metastatic renal cell carcinoma.

Before the modern era of anti-angiogenesis in advanced renal cell cancer (RCC) with tyrosine-kinase inhibition, cytokine therapy with interferon and interleukin was used as first-line therapy. RCC is reported to be highly resistant to chemotherapy; no single agent demonstrates significant activity for this disease.1 Although vinblastine has minor activity as a single agent, there are no reports of prolonged survival.2 Hormonal therapy with medroxyprogesterone produces infrequent responses (less than 10%), but again, no reports of prolonged survival exist.3 With observations of rare spontaneous regression after nephrectomy, prolonged stable disease in certain patients and late relapses after nephrectomy, host immune mechanisms are thought to be implicated in regulating tumour growth and form the basis for combating this disease with immunotherapy.4 As a result, more than 80 studies have examined the role of immunotherapy in metastatic RCC, dating back to the 1980s.5

Interferons

Interferons, which are members of a group of regulatory cellular glycoproteins called cytokines, have antiviral activity and also modulate immune response and cell proliferation.6 There are 3 subtypes of interferons: α, β, and γ. Interferon-α and interferon-β, type I interferons, are encoded on chromosome 9.6 Interferon-α upregulates the expression of HLA class I and tumour-associated antigens on tumour cells, theoretically making tumour cells more immunogenic.6 Interferon-γ, a type II interferon, is encoded on chromosome 12.6 This interferon, called immune interferon, is produced by T cells.6

Studies examining the efficacy of immunotherapy have used a variety of end points such as response rate (RR), complete response (CR) or partial response (PR); rate of progression; and progression-free and median survival. However, these studies used different definitions of these end points and none was blinded.5 Further, RR has been reported to be an unreliable surrogate of survival.5

A meta-analysis7 of 1042 patients found that the overall proportion of responses (CR and PR) to interferon-α was 12%. CRs were quite rare. Favourable characteristics of responders included patients with prior nephrectomy and patients with lung metastases. In this particular patient population, the proportion of objective responses was as high as 44%.7 The average time from the start of treatment to an objective response was about 3–4 months. Metastases of the central nervous system tended not to respond to interferon, and soft-tissue disease tended to respond more readily than bony metastases. Results of a review of more than 1500 patients8 suggest that the disease RR is between 12% and 15% for patients receiving interferon-α. CRs occurred in 2%–5% patients, usually in those with pulmonary metastases. The recently published Cochrane collaboration review5 estimated a gain of 3.8 months and a 1-year risk of mortality reduction by 44% for patients randomized to interferon-α2a, compared with patients randomized to control arms. Toxicity with interferon-α includes fever, malaise, flu-like symptoms and night sweats, and is markedly less than that with interleukin-2 (IL2).9

Interferon has also been evaluated with vinblastine and medroxyprogesterone for patients with metastatic RCC. In general, the results have been mixed for trials examining interferon and vinblastine, whereas medroxyprogesterone has not been shown to augment the effect of interferon.10,11

Only 1 study has shown increased patient survival when vinblastine is combined with interferon. The randomized controlled trial of 160patients done by Pyrhonen and others12 compared a combination of interferon-α2a and vinblastine with vinblastine alone, and showed that patients treated with interferon (18 million units 3times/wk) and vinblastine (0.1 mg/kg q3weeks) had a RR of 16%, compared with 2.5% for vinblastine (0.1mg/kg q3weeks) alone. Median survival was also significantly different between the 2 groups (15.8mo v. 8.8 mo). Fossa and others13 randomized 178 patients to receive interferon-α2a or interferon-α2a with vinblastine with the exact same dosages as those used in the study by Pyrhonen and others.12 Like that study, Fossa and others13 found vinblastine increased RR (from 11% to 24%), but unlike that study, they found no difference in survival rate between the 2groups. Differences in the calculation of survival may explain the difference in conclusions: Pyrhonen and others12 calculated survival in months, whereas Fossa and others13 compared the percentage of surviving patients.

Kriegmair and others14 found a higher RR for patients receiving interferon and vinblastine than that for patients receiving only medroxyprogesterone, but found no difference in survival. There were several important limitations of this study: patients who received medroxyprogesterone rather than interferon in the control arm, a lower dose of interferon (8 million units 3 times weekly) and the small sample size (n = 89 patients). The study was likely too underpowered to be able to detect a difference in survival rates.

A key Medical Research Council study15 compared interferon-α (10 million units, subcutaneously 3 times weekly for 12 weeks) with medroxyprogesterone (300 mg/d for 12 weeks). This study enrolled 335 patients with metastatic RCC and was stopped early because of differences in the 1-year survival rates. Patients treated with interferon-α had a 13.5% RR and those treated with medroxyprogesterone, 7%. The 1-year survival rate was 43% for the interferon-α arm and 31% for the medroxyprogesterone arm (median survival rate 8.5 mo v. 6.0 mo). Quality of life, which was assessed in this study at 4 weeks, 12 weeks and 6 months, was significantly worse in the interferon group. Lack of appetite, fatigue, nausea, shivering, dry mouth and heartburn were reported. Most of these symptoms were not different at 12 weeks and no differences remained at month 6. This landmark study concluded that patients with metastatic RCC treated with interferon-α had significantly improved survival over those treated with medroxyprogesterone.

Across studies, the average dose range of interferon-α administered subcutaneously was between 5 million units and 20 million units per day, usually 3–5 times per week.8,9,12,15–17 Higher doses were associated with significantly higher toxicity.18 The average period of time to any objective response was 3–4 months.7,9,12,15–17 Two studies (Pyrhonen and others12 and Medical Research Council15) suggested a survival benefit with interferon-α; however, response was low, and long-term survival was rare and not without significant toxicity.

In a randomized, double-blind, placebo-controlled phase 4 trial,19 the Canadian Urologic Oncology Group studied interferon-γ given to 180 patients with metastatic RCC. Interferon-γ (60μg/m2 body surface area subcutaneously, once every 7days) was compared with a placebo. All patients required control of their primary tumour with either nephrectomy or angioinfarction. The placebo group had an RR of 6%, compared with 4% for patients receiving interferon-γ. As a result of this trial, interferon-γ is not used for the treatment of advanced RCC.

Interleukin-2

Recombinant human IL-2, a T cell growth-factor protein, affects tumour growth by activating lymphoid cells in vivo, but does not affect tumour proliferation directly.20 IL-2 affects the proliferation and maturation of effector cells, enhancing natural killer Tcell function, generating lymphokine-activated killer (LAK) cells, and stimulating Tcell and Bcell growth, resulting in a reduction in tumour growth.

IL-2 can be administered by 3 routes: in a high-dose IL-2 bolus, by continuous intravenous infusion or by subcutaneous injection. The CRs observed in patients receiving IL-2 are usually in those patients receiving high-dose IL-2.18 In addition, patients with a performance status of 1 or more, a primary tumour in place, or liver or bone metastases have been shown to be less likely to respond.21

An initial study22 by the National Cancer Institute (NCI) used short intravenous infusions of high-dose IL-2 in combination with LAK autologous lymphocytes, and showed objective responses in 30% of patients. Subsequently, it was shown that LAK cells added no therapeutic benefit and could no longer be used in treatment.23 The results of a later NCI randomized trial16 (n = 200 patients) comparing high-dose IL-2 (720 000 IU/kg every 8 h for 15 doses) with a lower-dose bolus (72 000 IU/kg every 8 h for 15 doses) showed a 19% RR in the high-dose IL-2 treatment arm, compared with 10% in the low-dose IL-2 treatment arm. No difference in median survival between the 2 groups was found.

In 1992, the Federal Drug Administration approved the use of single-agent IL-2, based on 7 phase 2 studies of 255 patients between 1986 and 1992.17 The treatment schedule consisted of 600 000 IU/kg of IL-2, administered intravenously every 8 hours for 14 doses over 5 days, which was repeated after a 9-day rest period. CRs were observed for 4% patients and PRs for 8% patients,17 with an overall RR of 15%. Median survival for the 255 patients was 16.3 months. The majority of responders were patients with soft-tissue disease (mainly lung and lymph-node disease). In this study, however, patients with a good performance status (Eastern Cooperative Oncology Group performance status [ECOG] 0 or 1) were selected, so caution must be used when these findings are extrapolated to all patients. Further, treatment-related toxicity was significant: 4% (9 patients) had a CR, and an equal proportion (4%, 11 patients) died because of the treatment. When this study was updated in 1997,24 the authors reported a 15% RR (37 patients): 17 (7%) patients with a CR and 20 (8%) with a PR. The increased RR was partly due to the inclusion of patients who had surgical resection of their residual disease after their PR to high-dose IL-2.

Results of a review25 of clinical results for more than 1700 patients suggest that objective responses (CR and PR) in patients receiving high-dose IL-2 are 15%–16%. The most important prognosticator for metastatic patients is performance status (ECOG 0 or 1).17 In addition, nonnephrectomized patients or those with bone or liver metastases are less likely to respond to IL-2.17

Treatment-related morbidity and mortality has declined because of restricted patient selection. Patients with a good performance status are likely to better tolerate treatment. Screening patients with exercise tests or thallium scans and pulmonary function tests has been used to exclude patients with cardiopulmonary disease.18 However, as Negrier26 points out, these results cannot necessarily be extended to all patients. Furthermore, Kammula and others27 reported no treatment-related mortality in a review of 809 patients treated with high-dose IL-2, and another group28 could find no difference in quality of life between patients given high-dose IL-2 and those given low-dose IL2. Nonetheless, the toxicity associated with high-dose IL-2 must be considered in patients with a poor performance status.

The significant toxicity of IL-2 is related to endothelial injury that increases vascular permeability.29 This increased vascular permeability leads to extravasation of intravascular fluid in the interstitial space, causing overall organ edema. The toxicity profile includes cardiovascular, pulmonary, renal, neurologic and metabolic effects, many of which can be severe and may be life-threatening.17 The more common side effects of IL-2 include hypotension (96%); acute myocardial infarction (2%); arrhythmias (14%); respiratory (30%); renal toxicity with oliguria (81%); neurologic, including agitation and confusion (82%); nausea and vomiting (81%); and diarrhea (81%).23 Hypotension often requires vasopressor support with dopamine or phenylephrine. A capillary leak in the lung often mimics an adult respiratory distress syndrome-like picture. Often intensive care monitoring is required when these patients receive high-dose IL-2.

Low-dose subcutaneous IL-2 has significantly less toxicity and may have comparable RR.23 Buter and others30 examined 46 patients treated with subcutaneous IL-2 in a phase 2 trial. IL-2 was administered at 18 million units daily for 5 days; the dose was then reduced to 9 million units every other day, alternating with 18 million units for 4 weeks. Two patients (4%) had a CR, and 7 patients (15%) had a PR, for an overall RR of 20%. Those (10 patients) without cytoreductive nephrectomy did not respond to low-dose IL-2. Toxicities were mild to moderate and included fever, chills, nausea, vomiting, diarrhea and mild hypotension.

Results of systematic reviews conducted by the Cochrane group5 and by the Cancer Care Ontario Program in Evidence-based Care31 demonstrated no survival advantage of regimens containing low-dose IL-2 over those not based on IL-2. In a phase 3 study of low-dose IL-2 conducted by the NCI,32 patients were randomized to 1 of 2 IL-2 treatment arms, either high-dose (720 000 IU/kg) or low-dose (72 000 IU/kg). Of the 60 patients in the low-dose arm, 4 CRs and 5 PRs were observed (15% overall RR); of the 65 patients in the high-dose arm, 2 CRs and 11 PRs were observed (20% overall RR). No difference in overall survival and no difference in response duration were observed. Results of the study were updated in 199733 with a 52-month follow-up period: a 10% RR in the low-dose arm (5 CRs, 6 PRs) and a 19% RR in the high-dose arm (9 CRs, 13 PRs) were found. Although the overall RR was significantly higher in the high-dose arm, no difference in overall survival was observed.

The same group recently reported the results of their randomized study18 of high-dose and low-dose IL-2. This 3-arm study compared high-dose (720000U/kg) intravenous IL-2, low-dose (72000U/kg) intravenous IL-2 and low-dose (125000 U/kg) daily subcutaneous IL-2. The RR in the intravenous high-dose arm (21%) was higher than that in the intravenous low-dose IL-2 (13%) and subcutaneous IL-2 (10%) arms. No overall difference in survival was found.

The systematic review conducted by Hotte and others31 identified 6 randomized studies34–38 that compared regimens containing low-dose IL-2 and regimens devoid of IL-2. RRs were higher in patients receiving regimens containing IL-2, but mortality at 1 year was not different. The authors concluded that there was no difference in treatment efficacy between low-dose IL-2 regimens and those devoid of IL-2, and that toxicity in regimens containing IL-2 increased. This finding is in keeping with the results of a recent Cochrane collaboration review5 that concluded no difference in RR or survival.

Interferon and IL-2 combination regimens

Preclinical observations that interferon-α and IL2 may have synergistic antitumour activity led to a number of clinical studies examining this premise. Results of a review39 of more than 1400 patients receiving interferon-α and IL-2 indicated an overall RR of 20% for the combination, and found that 3%–5% of patients had CRs.

Atkins and others,39 in their randomized phase 2 trial of high-dose IL-2 with and without interferon-α, found no difference in response in either group. However, toxicity was higher with the addition of interferon-α.

Quan and others40 examined the addition of famotidine to IL-2 for treatment of 15 patients with metastatic RCC. Famotidine may augment LAK activity against kidney cancer cells. IL-2 was given for 72 hours along with famotidine (20 mg, intravenously, twice per day, in 3-week cycles). One CR and 1 PR were seen. The overall RR was 47% (median duration of response 9 mo; median survival of all patients 20 mo). The authors of this small study suggested that famotidine in combination with IL-2 improves RRs for patients with metastatic RCC; however, no definitive conclusion is possible because of the lack of a control group.

A randomized 3-arm study by Negrier and the French Immunotherapy Intergroup9 studied 425 patients treated with either continuous intravenous infusion of recombinant IL-2 (18 million units per square metre of body surface area [MIU/m2]) alone or human IL-2 (18 MIU/m2 per day) and interferon-α (6 MIU 3 times weekly), or human interferon-α (18 MIU 3 times weekly) alone. The results at week 10 showed that the combination arm had a higher RR (18.6%) than the interferon-α–alone arm (7.5%) or the IL-2–alone arm (6.5%). The toxicity of the combination arm was significant; therapy-related mortality was high. Although the RR was higher in the combination arm, overall survival among the 3 arms was not different (combination arm, 12 mo; interferon-α arm, 13 mo; IL2arm, 17 mo).

This same French Immunotherapy Group recently reported on their PERCY Quattro randomized trial41 for patients with metastatic RCC of intermediate prognosis. This trial compared medroxyprogesterone acetate (MPA arm), interferon (9MIU 3 times/wk) (IFN arm), subcutaneous IL2 (18 MIU 5 d/wk for 2 cycles of 4 weeks) (IL2 arm), and combined subcutaneous IL-2 (18 MIU 5 d/wk for 2 cycles of 4 weeks) and interferon (6MIU 3times/wk) (IFN/IL-2 arm) for patients with an intermediate prognosis. A minimum of 114 patients were required for each arm; a total of 492 patients were enrolled. Comparison of the interferon and noninterferon arms showed no overall survival advantage (15.4 mo v. 15.1 mo). Comparison of the IL-2 and the non–IL-2 arms showed no survival advantage (15.7 mo v. 14.9 mo; p = 0.52). No survival advantage was found among all arms (MPA, 14.9 mo; IFN, 15.2 mo; IL-2, 15.3 mo; IFN/IL-2, 16.8 mo). The RR at 6 months was 1.6% for the MPA arm, 8.7% for the IFN arm, 4.2% for the IL2 arm and 7.1% for the IFN/IL-2 arm. Based on these data, the French Immunotherapy Intergroup concluded that they could no longer recommend the use of cytokines for the treatment of patients with an intermediate prognosis for metastatic RCC.

In a randomized phase 3 trial, McDermott and others21 compared a combination of IL-2 (5MIU/m2, subcutaneously every 8 hours for 3doses on day1, then daily 5 d/wk for 4 weeks) and interferon-α (5MIU/m2, subcutaneously, 3times per week for 4 weeks) every 6 weeks with high-dose IL-2 (600000 U/kg per dose, intravenously, every 8 hours on days 1 through 5 and days 15 through 19) every 12 weeks. Unlike other reports, patients were stratified within treatment, based on ECOG status (0 or 1), liver or bone metastases, and prior nephrectomy. The study recruited 192 patients. RR was 23% for the high-dose IL2 group and 9.9% for the subcutaneous IL-2 and interferon group. Overall median survival was not significantly different, 17.5 months and 13 months, respectively (p = 0.24). However, in patients without nephrectomy and with liver or bone metastases, high-dose IL-2 did result in a longer median survival rate (14.7% v. 8.0% and 12.4% and 8.2%, respectively). This study concluded that a combination of subcutaneous IL-2 and interferon was inferior to high-dose IL-2 therapy when all patients were compared.

To date, no sufficiently powered phase 3 study has demonstrated a survival benefit for combination therapy over a single agent alone for the treatment of patients with metastatic RCC.

Cytokine and new agent combination regimens

Recent studies with tyrosine-kinase inhibitors and other new agents often use interferon-α for the comparative treatment arm, arguably the current standard of care. These studies are discussed elsewhere in this supplement. Studies comparing combination therapy with these new agents, including sunitinib, sorafenib and bevacizumab with interferon-α therapy, are ongoing. Recent results from a 3-arm randomized trial42 comparing interferonα, intravenous temsirolimus, and combination temsirolimus and interferon-α suggest no additional benefit with interferon. Single-agent temsirolimus (n = 209), compared with interferon-α (n = 207), has been shown to significantly increase the overall survival (10.9 mo v. 7.3 mo; p = 0.0069) of patients with metastatic RCC and poor risk factors. Overall survival by treatment arm was 7.3 months (interferon), 10.9 months (temsirolimus) and 8.4 months (temsirolimus + interferon). Median progression-free survival was 1.9 months, 3.7 months and 3.7 months, respectively. Objective response (CR + PR) was 7%, 9% and 11%, respectively. Compared with interferon, single-agent temsirolimus (25 mg, intravenously, weekly) used as a first-line therapy significantly increased the overall survival of poor-risk patients with advanced RCC and has an acceptable safety profile. Interferon offered no advantage in combination therapy, and the toxicity found in results for this arm was largely attributable to interferon-α.

Conclusions

Metastatic RCC remains a disease highly resistant to conventional systemic therapy. Cytokine therapy has been the mainstay of treatment in this patient population for many years. However, only small numbers of patients (about 15%–20%) respond to cytokine therapy. CRs, although rare, are more often seen with high-dose IL-2 than with interferon-α, but high-dose IL-2 is associated with significant toxicity and should be offered with caution.

New treatments that specifically target angiogenesis have profoundly affected the way we treat advanced RCC and have rapidly become the standard of care. The role of cytokine therapy, especially interferon and non–high-dose IL-2, is likely to be relegated to the treatment patients who have progressed through these treatments and have exhausted their therapeutic options. High-dose IL2 may occasionally be considered for curative attempts, but because of toxicity must be used with caution. Combination studies with anti-angiogenesis inhibitors are ongoing and may show more promise than existing cytokine therapies.

Footnotes

This article has been peer reviewed.

Competing interests: None declared.

References

  • 1.Motzer RJ, Vogelzang NJ. Chemotherapy for renal cell carcinoma. In: Raghaven D, editor. Principles and practice of genitourinary oncology Philadelphia: Lippincott-Raven; 1997. p. 885-96. [Google Scholar]
  • 2.Yagoda A. Chemotherapy of renal cell carcinoma. Semin Urol 1989;7:199-206. [PubMed] [Google Scholar]
  • 3.Harris DT. Hormonal and chemotherapy of renal cell carcinoma. Semin Oncol 1983; 10: 422-30. [PubMed] [Google Scholar]
  • 4.de Riese W, Goldenberg K, Allhoff E, et al. Metastatic renal cell carcinoma (RCC): spontaneous regression, long-term survival and late recurrence. Int Urol Nephrol 1991;23: 1325. [DOI] [PubMed] [Google Scholar]
  • 5.Coppin C, Porzsolt F, Kumpf J, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev 2005; (3):CD001425. [DOI] [PubMed] [Google Scholar]
  • 6.Kurzrock R, Talpaz M, Gutterman JU. Interferons: basic principles and preclinical studies. In: DeVita VT, Hellman S, Rosenberg SA, editors. Biologic therapy of cancer Philadelphia: J.B. Lippincott; 1991. p. 247-74. [Google Scholar]
  • 7.Wirth MP. Immunotherapy for metastatic renal cell carcinoma. Urol Clin North Am 1993; 20: 283-95. [PubMed] [Google Scholar]
  • 8.Bukowski RM, Novick AC. Clinical practice guidelines: renal cell carcinoma. Cleve Clin J Med 1997;64(Supp 1):SI1-48. [DOI] [PubMed] [Google Scholar]
  • 9.Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant interferon alpha-2A, or both in metastatic renal cell carcinoma. N Engl J Med 1998; 338: 1272-8. [DOI] [PubMed] [Google Scholar]
  • 10.Steineck G, Strander H, Carbin BE, et al. Recombinant leukocyte interferon alpha-2a and medroxyprogesterone in advanced renal cell carcinoma. A randomized trial. Acta Oncol 1990;29:155-62. [DOI] [PubMed] [Google Scholar]
  • 11.Porzsolt F, Messerer D, Hautmann R, et al. Treatment of advanced renal cell cancer with recombinant interferon alpha as a single agent and in combination with medroxyprogesterone acetate. A randomized multicenter trial. J Cancer Res Clin Oncol 1988; 114: 95-100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Pyrhonen S, Salminen E, Ruutu M, et al. Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 1999;17:2859-67. [DOI] [PubMed] [Google Scholar]
  • 13.Fossa SD, Martinelli G, Otto U. Recombinant interferon alpha-2A with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Ann Oncol 1992;3:301-5. [DOI] [PubMed] [Google Scholar]
  • 14.Kriegmair M, Oberneder R, Hofstetter A. Interferon alfa and vinblastine versus medroxyprogesterone acetate in the treatment of metastatic renal cell carcinoma. Urology 1995; 45:758-62. [DOI] [PubMed] [Google Scholar]
  • 15.Medical Research Council Renal Cancer Collaborators. Interferon alpha and survival in metastatic renal carcinoma: early results of a randomized controlled trial. Lancet 1999; 353: 14-7. [PubMed] [Google Scholar]
  • 16.Yang JC, Rosenberg SA. An ongoing prospective randomized comparison of interleukin-2 regimens for the treatment of metastatic renal cell cancer. Cancer J Sci Am 1997; 3(Suppl 1): S79-84. [PubMed] [Google Scholar]
  • 17.Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. JClin Oncol 1995;13:688-96. [DOI] [PubMed] [Google Scholar]
  • 18.Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003;21:312732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Gleave ME, Elhilali M, Fradet Y, et al. Interferon gamma-1b compared with placebo in metastatic renal cell carcinoma. N Engl J Med 1998;338:1265-71. [DOI] [PubMed] [Google Scholar]
  • 20.Motzer RJ, Bander NH, Nanus DM. Renal cell carcinoma — medical progress. NEngl J Med 1996;335:865-75. [DOI] [PubMed] [Google Scholar]
  • 21.McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005;23:133-41. [DOI] [PubMed] [Google Scholar]
  • 22.Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987;316:889-97. [DOI] [PubMed] [Google Scholar]
  • 23.Law TM, Motzer RJ, Mazumdar M, et al. Phase III randomized trial of interleukin-2 with or without lymphokine lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer 1995;76:824-32. [DOI] [PubMed] [Google Scholar]
  • 24.Fisher RI, Rosenberg SA, Sznol M, et al. High dose aldesleukin in renal cell carcinoma: long term survival update. Cancer J Sci Am 1997;3:S70-2. [PubMed] [Google Scholar]
  • 25.Bukowski RM. Natural history and therapy of metastatic renal cell carcinoma: role of interleukin-2. Cancer 1997;80:1198-220. [DOI] [PubMed] [Google Scholar]
  • 26.Negrier S. Better survival with interleukin-2-based regimens? Possibly only in highly selected patients. J Clin Oncol 2004;22:1174-6. [DOI] [PubMed] [Google Scholar]
  • 27.Kammula US, White DE, Rosenberg SA. Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer. Cancer 1998;83:797805. [PubMed] [Google Scholar]
  • 28.Phan GQ, Morton KE, Liewehr DJ, et al. Quality of life in patients with metastatic renal cell cancer receiving different regimens of interleukin-2. [abstract]. Proc Am Soc Clin Oncol 2002;21:25a. [Google Scholar]
  • 29.Gallagher DC, Bhatt RS, Parikh SM, et al. Angiopoietin 2 is a potential mediator of high-dose interleukin 2-induced vascular leak. Clin Cancer Res 2007;13:2115-20. [DOI] [PubMed] [Google Scholar]
  • 30.Buter J, Sleifer DT, Vander Graaf WT, et al. A progress report on the outpatient treatment of patients with advanced renal cell carcinoma using subcutaneous recombinant interleukin-2. Semin Oncol 1993;20:16-21. [PubMed] [Google Scholar]
  • 31.Hotte S, Waldron T, Canil C, et al. Interleukin-2 in the treatment of unresectable or metastatic renal cancer: a systematic review and practice guideline. CUAJ 2007;1:2738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Yang JC, Topalian SL, Parkinson D. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol 1994;12:1572-6. [DOI] [PubMed] [Google Scholar]
  • 33.Yang JC, Rosenberg RA. An ongoing prospective randomized comparison of interleukin-2 regimens for the treatment of metastatic renal cell cancer. Cancer J Sci Am 1997; 3(Suppl 1):S79-84. [PubMed] [Google Scholar]
  • 34.Atzpodien J, Kirchner H, Jonas U, et al. 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). J Clin Oncol 2004;22:1188-94. [DOI] [PubMed] [Google Scholar]
  • 35.Atzpodien J, Kirchner H, Illiger HJ, et al. IL-2 in combination with IFN-a and 5-FU versus tamoxifen in metastatic renal cell carcinoma: long term results of a controlled clinical trial. Br J Cancer 2001;85:1130-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Boccardo F, Rubagotti A, Canobbio L, et al. Interleukin-2, interferon-α and interleukin-2 plus interferon-a in renal cell carcinoma. A randomized phase II trial. Tumori 1998;84:534-9. [DOI] [PubMed] [Google Scholar]
  • 37.Henriksson R, Nilsson S, Colleen S, et al. Survival in renal cell carcinoma - a randomized evaluation of tamoxifen vs. interleukin-2, alpha-interferon (leucocyte) and tamoxifen. Br J Cancer 1998;77:1311-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Lummen G, Goepel M, Mollhoff S, et al. Phase II study of interferon-gamma versus interleukin-2 plus interferon-alpha2b in metastatic renal cell carcinoma. J Urol 1996; 155: 455-8. [PubMed] [Google Scholar]
  • 39.Atkins MB, Sparano J, Fisher RI, et al. Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alpha-2b in advanced renal cell carcinoma. J Clin Oncol 1993;11:661-70. [DOI] [PubMed] [Google Scholar]
  • 40.Quan WD Jr, Vinogradov M, Quan FM, et al. Continuous infusion interleukin-2 and famotidine in metastatic kidney cancer. Cancer Biother Radiopharm 2006;21:515-9. [DOI] [PubMed] [Google Scholar]
  • 41.Negrier S, Perol D, Ravaud A, et al. Do cytokines improve survival in patients with metastatic renal cell carcinoma (MRCC) of intermediate prognosis? Results of the prospective randomized PERCY Quattro trial [abstract]. [Ann Meet Proc]. J Clin Oncol 2005; 23(16S Suppl Pt 1):4511. [Google Scholar]
  • 42.Hudes G, Carducci M, Tomczak P, et al. A phase 3, randomized 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma (adv RCC) [abstract]. [Ann Meet Proc]. J Clin Oncol 2006;24(Suppl 18):LBA4. [Google Scholar]

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