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Interferons
Interferons are a heterogeneous group of glycoproteins produced by mammalian cells in response to viral infections or other inducers. Three major types have been identified – interferon-a, interferon-β (class I) and inter-feron-8 (class II).
As well as helping to fight viruses, interferons have anti-tumour properties. These may be mediated through a direct cytotoxic effect on tumour cells or through augmentation of the immunogenicity of tumours by upregulation of histocompatibility and tumour-associated antigens, and/ or activation of macrophages, T lymphocytes and natural killer cells [14]. It is also thought that interferons possess anti-angiogenic properties.
The anti-neoplastic activity of IFN-a was first shown in hairy cell leukaemia and Kaposi’s sarcoma. Subsequent studies have documented its activity in chronic mylogenous leukaemia, B and T cell lymphomas and melanoma. IFN-a is the most extensively tested IFN in clinical studies of patients with mRCC.
The use of IFN-a in Renal cell carcinoma first began in the 1980s. It is now widely accepted in the UK as first-line treatment for metastatic renal cancer. A series of phase I and II studies have shown overall objective response rates for single-agent IFN-a in the region of 15%, with CRs in approximately 1%. The best responses have been achieved in patients with a good performance status and limited metastatic disease. Prognostic factors that help to predict response include prior nephrectomy, performance status, sites of metastatic disease and interval from presentation to the development of metastases. However, the modest increases in survival can be offset by treatment-related side-effects and the fact that responses are often not durable. Two large randomized phase III trials have been published demonstrating a clear survival advantage with the use of IFN-a.
Pyrohnen et al. prospectively randomized 160 patients with either locally advanced Renal cell carcinoma or mRCC to receive either Vinblastine alone or IFN-a plus Vinblastine for 12 months or until disease progression. At the time, many considered Vinblastine to be standard treatment. In both groups, intravenous Vinblastine was given at 0.1 mg/ kg every 3 weeks, and in the combination arm IFN-a was administered subcutaneously (s.c.) at 3 mega units three times a week for 1 week and 18 mega units three times a week thereafter. The median survival was 67.6 weeks in the combination arm and 37.8 weeks in the Vinblastine arm (p < 0.0049). Overall response rates were 16.5% in the combination arm and 2.5% in the Vinblastine arm (p < 0.0025). Survival rates for patients treated with the combination or with Vinblastine alone were 55.7% and 38.3%, respectively, after 1 year, and 11.7% and 5.1%, respectively, after 3 years. Survival was prolonged in the overall patient population, even in the subset of patients who did not have objective tumour responses, and was not decreased in patients who required a reduction of their IFN-a dose from 18 to 9 mega units to improve tolerability.
A subsequent multicentre randomized trial by the Medical Research Council Renal Cancer Collaborators (Medical Research Council RE01) randomized 335 patients with mRCC to receive either s.c. IFN-a (three doses – 5, 5, 10 mega units – for week 1, then 10 mega units three times per week for a further 11 weeks) or MPA 300 mg once a day for 12 weeks. A survival advantage of IFN-a over MPA was demonstrated, with an absolute improvement in 1-year survival of 12% (43% vs 31%). The median survival time was 8.5 months for patients treated with IFN and 6 months for patients treated with MPA. The time to relapse, however, was short, and progression-free survival at 2 years was 5% or less for both groups. Side-effects were also more marked in the IFN-a group, notably tiredness, anorexia, loss of energy and nausea. The difference was most significant at 4 weeks, persistent at 12 weeks but had resolved by 6 months
Treatment-related toxicity can be marked and, whilst rarely life-threatening, does affect quality of life. Acutely, patients suffer from flu-like symptoms, namely fevers, rigors and myalgia that can be largely alleviated by coadministration of paracetamol. These symptoms usually resolve within approximately 2 weeks of treatment. Lethargy is common and tends to accumulate with repeated injections. In addition, anorexia, weight loss, depression and loss of libido can occur. At higher doses, hepatotoxicity and myelosuppression may be seen.
Several dose schedules have been investigated. Overall, the differences in terms of response rates have been modest. The most commonly used regimen in the UK is 9-10 mega units s.c, three times per week. Patients typically self-administer their interferon on an outpatient basis. Injecting at night means that patients can sleep through the worst of the acute side-effects.
Single-agent IFN-a produces a small but consistent response in renal cancer. Efforts to increase the proportion of patients who respond and to make responses more durable have largely focused around using interferon in combination with other active agents.
Interleukin-2
IL-2 is a 15000-Da glycoprotein secreted predominantly by T helper-1 (Thl) lymphocytes. It is a potent growth factor that causes activation and proliferation of cytotoxic T lymphocytes, natural killer cells and macro-phages. The first clinical trials with IL-2 were carried out in 1984. Promising early results were reported by Rosenberg et <xl., who used high-dose, intravenous bolus IL-2. A 22% overall RR was reported in 54 patients with mRCC treated with IL-2 .
A subsequent multicentre study by Fyfe et <xl. reported an overall RR of 14%. Two hundred fifty-five patients were treated with high-dose bolus IL-2, 600 000-720 000 IU/kg, administered intravenously for 14 consecutive doses over 5 days, and repeated after a 5- to 9-day rest period. A long-term follow-up showed that 15% of patients achieved a CR or a PR. Of those patients achieving a CR, the median duration of response exceeded 80 months and 60% remained in CR at 10-year follow-up. The associated toxicity was severe and treatment-related death was 4%. This was despite the study population consisting of a relatively young group of patients (median age 52 years) with a good performance status.
The side-effects of IL-2 therapy are dose-dependent and at high dose can be formidable. Toxicity is manifest by a vascular leak syndrome as a result of increased capillary permeability. This leads to fluid retention, pulmonary oedema, decreased peripheral vascular resistance, hypotension, tachycardia and oliguria. These in turn can lead to respiratory failure, cardiovascular collapse and renal impairment. Patients often require inotropic support to maintain adequate blood pressure, and occasionally may need transfer to the intensive care unit. As experience with the use of high-dose IL-2 has increased, treatment-related mortality has reduced considerably and is now less than 1%. Careful patient selection is important and all patients should have an adequate assessment of their cardiac, respiratory, renal and hepatic function before commencing treatment.
Since many patients are unsuitable for high-dose treatment, alternative lower-dose regimens have been developed. Continuous infusional IL-2 has been shown to have efficacy comparable to bolus regimens and, by avoiding high peak levels, carries less toxicity.
The use of daily, self-administered subcutaneous IL-2 in patients with mRCC has been widely tested. The convenience and reduced toxicity of this regimen has made it an attractive alternative; it is the commonest route of administration in use in Europe today.
Many phase II studies have been published using subcutaneous IL-2. Essentially these studies show that subcutaneous IL-2 monotherapy produces response rates of 15-20%, similar to those achieved with high-dose therapy. In addition, it is well tolerated. Typical side-effects include fever, malaise, nausea, vomiting and diarrhoea. Rises in serum creatinine, especially in those with pre-existing renal impairment, and thyroid dysfunction may also occur. These toxicities are generally not severe and do not require hospitalization.
It remains uncertain whether high-dose IL-2 confers any benefit over lower-dose regimens in terms of clinical outcome. Whilst response rates appear to be similar, it is not known whether response duration and overall survival are increased using high-dose treatments. IL-2 has been approved by the US Food and Drug Administration for use in patients with mRCC on the strength of studies showing that, in small numbers of patients, IL-2 can induce complete, durable responses, sometimes lasting more than 10 years. The challenge of identifying which patients will respond and of defining the optimal dose and route of administration remains.
Combined immunotherapy
After establishing the individual activity of IFN-a and IL-2 in mRCC, investigators have looked at using them in combination. Studies in in vitro and in vivo animal models were encouraging and showed synergism between the two cytokines. Clinical trials have been disappointing however. A series of small randomized studies have suggested no advantage to combination therapy over IL-2 alone.
However, in a large phase III trial, Negrier et al. randomized 425 patients to receive high-dose intravenous IL-2 alone, subcutaneous IFN-a alone or a combination of both agents. The RR was better for the combination arm (IFN-a 7.5%; IL-2 6.5%; combination 18.6%; p < 0.01) and event-free survival at 1 year also improved (IFN-a 12%; IL-2 15%; combination 20%; p = 0.01). This did not however translate into a significant increase in overall survival.
Biochemotherapy
The concept of combining immunotherapy with standard chemotherapy agents is one that has generated much interest over recent years. The theoretical rationale behind such a combination is that chemotherapy may enhance immunogenicity by causing cellular damage and release of tumour cell antigens that are processed by IFN-a-stimulated antigen-presenting cells and, in turn, activate IL-2-stimulated cellular effectors. This theory, however, has yet to be proven.
One of the more promising regimens in mRCC was first used by Atzpo-dien. Patients with mRCC were treated with a combination of IFN-a, IL-2 and 5-Fluorouracil. Treatment was given in an outpatient setting with 8 weeks of IFN-a (6-9MU/m2 s.c, 1-3 times/week), IL-2 for 4 weeks (5-20 mega units/m2 s.c, 3 times/week, weeks 1—4) and intravenous 5-Fluorouracil 750 mg/m2 weekly for weeks 5-8. The regimen was well tolerated. For the first 35 patients treated, an overall RR of 48.6% was reported.
Since 1993, there have been several phase II trials using this triple-therapy regime with response rates in the range of 15-45%.
In a randomized trial comparing the triple-agent regimen against single-agent tamoxifen, enrolling a total of 78 patients, those patients receiving triple therapy were shown to have an overall RR of 39% compared with 0% in the tamoxifen-only arm. The overall survival (24 vs 13 months) was significantly increased in the triple-therapy arm.
However, one phase III study has been published showing no advantage for triple therapy over interferon plus IL-2 alone. The study used different drug schedules, which may explain the difference.
RE04 is an Medical Research Council randomized controlled phase III clinical trial that is aimed at addressing these issues. The study, currently recruiting, will randomize 670 patients with mRCC to either triple therapy or standard single-agent IFN-a.
Medroxyprogesterone acetate
Medroxyprogesterone acetate (Provera) is a 17-OH progesterone derivative. The rationale for its use in mRCC is derived from the fact that a proportion of renal cancers express oestrogen and progesterone receptors. The exact mechanism of its anti-tumour effect is unclear.
At the time of its introduction there were few alternatives and hence Provera became widely used for patients with mRCC. The reality is that overall response rates with Provera are low (-2%) and short in duration.
At the standard dose of 300 mg daily, Provera is a well-tolerated drug. Its main side-effect is appetite stimulation, which may be beneficial in patients with tumour cachexia or anorexia. Nausea can be a problem early on but tends to improve with continued use. Fluid retention can occur but rarely requires intervention.
Today, Provera can be considered for use in those patients who have either progressed on, or are unsuitable for, first-line immunotherapy. For these patients it may provide a modest palliative benefit.
Posted in: Urological Oncology