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Keywords:

  • interferon-α;
  • interleukin-2;
  • renal cell carcinoma;
  • therapy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CYTOKINE THERAPY FOR TREATING RCC
  5. TARGETING PATIENTS WITH POTENTIAL TO RESPOND TO CYTOKINE THERAPY
  6. TARGETED THERAPIES
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

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Tribute to Professor Pieter De Mulder, from Martin Gore

Pieter and I were often pitted against each other in debates at international meetings on the role of cytokine therapy. The truth is that there was little disagreement between us, but we both thought such set pieces were a good way to highlight the issues surrounding the use of cytokines. He wanted our true joint view to be put on record, and the result is this article. Pieter himself suffered from kidney cancer for many years and he died in April as we were putting the finishing touches to this manuscript. Pieter was a remarkable man in so many ways. He was a physician of great compassion, immense intellect, utter integrity and unshakeable scientific rigor. These qualities meant that his perspective on many clinical controversies was in great demand internationally. The European oncology community has lost one of its giants and I, a dear friend. This manuscript is dedicated to the memory of Professor Pieter de Mulder.


Abbreviations
IFN

interferon

IL

interleukin

CAIX

carbonic anhydrase IX

MSKCC

Memorial Sloan-Kettering Cancer Center

mTOR

mammalian target of rapamycin

PFS

progression-free survival

HR

hazard ratio

FDA

Food and Drug Administration

NCCN

National Comprehensive Cancer Network.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CYTOKINE THERAPY FOR TREATING RCC
  5. TARGETING PATIENTS WITH POTENTIAL TO RESPOND TO CYTOKINE THERAPY
  6. TARGETED THERAPIES
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

RCC accounts for 3% of all adult malignancies and is the third most frequent urological malignancy after prostate and bladder cancer [1]. In 2004, almost 60 000 individuals in the European Union were diagnosed with RCC, and almost 30 000 individuals died from the disease [2]. Figures for the USA in 2006 are similarly high, with an estimated 38 890 new cases and 12 840 deaths each year [3]. RCC is highly resistant to conventional cytotoxic chemotherapy and the prognosis for patients with advanced disease is poor. Although most patients (70–80%) present with localized RCC, around half of these will go on to develop metastatic disease [1,4]. For patients with metastatic kidney cancer, a 5-year survival rate of just 9.5% has been reported [4].

Spontaneous remissions have been reported with RCC, probably as a result of immune responses [4–6]. Such observations provide the rationale for developing immunotherapeutic approaches to treatment, with the aim of stimulating or augmenting these apparently effective responses. Cytokine therapy is the only immunotherapeutic approach that has so far been integrated into routine clinical practice for RCC, although other strategies have been investigated. The most widely used and extensively studied cytokines for the treatment of RCC are interferon-α (IFN-α) and interleukin-2 (IL-2). Response rates of 10–20% are reported with these therapies and some patients achieve complete long-lasting remission when treated with IL-2 [7]. However, the antitumour activity of cytokine therapy is generally small and many patients derive little or no benefit from these agents [7]. In addition, cytokine therapy can be poorly tolerated, particularly i.v. IL-2, which is sometimes associated with serious, and in some instances life-threatening, toxicity. As such, there remains a clear need for well tolerated and effective treatments to prolong survival of patients with RCC.

In this review we explore the role of cytokine therapy in advanced RCC and investigate whether some patient populations might respond better than others. We also examine whether new molecular targeted agents can offer a feasible alternative to immunotherapy.

CYTOKINE THERAPY FOR TREATING RCC

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CYTOKINE THERAPY FOR TREATING RCC
  5. TARGETING PATIENTS WITH POTENTIAL TO RESPOND TO CYTOKINE THERAPY
  6. TARGETED THERAPIES
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

IFN-α

IFN-α is widely used for treating advanced RCC throughout Europe, but is not approved for this indication in the USA. The first responses to IFN-α in patients with metastatic RCC were reported in 1985 [8]. In this early study, patients were given IFN-α at doses of 1 or 10 MU/day for up to 4 weeks by i.m. or i.v. injection. In all, there were seven responses (six at the higher dose) in 30 patients, yielding an overall response rate of 23%[8]. Subsequent larger studies reported response rates of 6–21% with IFN-α[9–13].

The effect of IFN-α on survival was explored in several studies [9–13]. IFN-α offers a small but significant advantage in overall survival and is best summarized in the recently published Cochrane analysis of 6117 patients treated in 53 randomized studies [12]. The overall response rate was 12.5%, vs 1.5% for non-immunotherapy controls (pooled odds ratio 7.6, 95% CI 3.0–19.2) with a reduced 1-year mortality (0.56, 0.40–0.77) and a statistically significant improvement in median survival of 3.8 months (11.4 vs 7.6 months, P < 0.001; Fig. 1). Similar findings were reported in a retrospective analysis of 463 patients with advanced RCC treated with IFN-α (as a single agent or in combination) as initial therapy in six studies [14]. In this analysis, the 5-year survival rate was only 10% and the median overall survival was 13 months [14].

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Figure 1. Cochrane meta-analysis: overall survival in patients treated with IFN-α[12]. Copyright Cochrane Collaboration, reproduced with permission. MRCRC, Medical Research Council Renal Cancer Collaborators.

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Over the past 20 years, many studies have attempted to establish the optimum dose, schedule and duration of IFN-α therapy. However, large, high-quality trials are lacking. At low doses, there is a dose–response relationship and the minimum effective dose is considered to be 20–40 MU/week [1]. Higher doses result in greater toxicity with no concomitant improvement in response rates. Unfortunately, dosing schedules vary among studies, making it difficult to reach definitive conclusions on the optimum dosing regimen. In addition, treatment duration varies considerably across the major trials, leaving questions about how to translate study treatment protocols into clinical practice.

Attempts to enhance IFN-α activity by adding various agents, including IL-2, cimetidine, coumarin plus cimetidine and vinblastine, have failed to consistently improve survival compared with IFN-α alone [7,12,15–18]. However, one study showed an improvement in median overall survival, which was of borderline statistical significance, with IFN-α in combination with 13-cis-retinoic acid (17.3 months; 95% CI 13.1–23.1) compared with IFN-α alone (13.2 months; 11.0–17.8; P = 0.048); however, the combination was also associated with increased toxicity [19]. The most effective combination regimen to date was that used by Atzpodien et al.[20], who combined IFN-α with 5-fluorouracil and IL-2. This regimen achieved response rates of 39% in that study, but less impressive response rates when used by other groups [1].

As described later, evidence is accumulating that IFN-α therapy is only beneficial in patients with a favourable prognosis. IFN-α is also contraindicated in certain patients and there are several specific precautions associated with its use, mainly relating to toxicity [21]. This suggests that a large majority of patients will not benefit from, or be eligible to receive, IFN-α therapy.

Toxicities associated with IFN-α can be acute or late [1]; most acute effects tend to abate over a short period. The most commonly encountered acute toxicities are ‘flu-like symptoms comprising fever, fatigue, headache and myalgia. Other less common toxicities include weight loss, nausea, vomiting, altered taste, depression, anaemia, leukopenia and elevated liver function test results (Table 1) [21,22]. Despite the modest clinical activity of IFN-α in metastatic RCC, toxicities are manageable and the ability to administer the drug in an outpatient setting means that IFN-α-based therapies continue to be investigated and used in the clinic for patients with advanced RCC. However, the lack of compelling data on IFN-α and the increasing availability of alternative targeted treatments has led the National Comprehensive Cancer Network (NCCN) to remove its recommendation for use of IFN-α as a first-line treatment option for patients with inoperable stage IV RCC and predominantly clear-cell histology, in their latest guidelines [23]. Likewise, a recent evidence-based review of clinical data on systemic treatments for metastatic RCC, which used the RAND/University of California Los Angeles Appropriateness Method, reported that IFN-α was an inappropriate treatment for both immunotherapy-naive and previously treated patients [24].

Table 1.  Common toxicities associated with IFN-α and IL-2
IFN-α[21]IL-2 [22]
AnaemiaAnaemia
Altered tasteCNS effects
DepressionDiarrhoea
Elevated liver function testsHypotension
Flu-like symptomsIncreased serum creatinine
LeukopeniaNausea
NauseaOliguria
VomitingThrombocytopenia
Weight lossVomiting

Il-2

The activity of IL-2 in metastatic RCC was first reported by Rosenberg et al. in 1985 [25] and various dosing schedules have since been developed. The inpatient, high-dose, bolus IL-2 regimen appears to provide the most durable responses [26,27], and low-dose IL-2 is no longer recommended as first-line therapy in new treatment guidelines [23,24].

Response rates of 14–23%, lasting for 14–16 months, were reported for the high-dose regimen [28–30]. As observed in the registration phase II studies [28,29], some patients treated with high-dose IL-2 can achieve durable complete responses. However, evidence from a randomized dataset that such durable complete remissions are possible was not obtained until 2003; even then, only a very small subset of patients benefited. In two separate randomized, phase III studies, durable (>3 years) complete responses were only achieved in nine of 156 [31] and seven of 95 patients [30] receiving high-dose IL-2. Similarly, in a case series of 227 patients, only 14 of 21 patients who achieved a complete response were relapse-free for ≥5 years [32]. Considering the relative homogeneity of clinical trial populations, this benefit is likely to occur in an even smaller proportion of patients in a general RCC clinic. Nonetheless, the value that patients place on achieving a potential cure cannot be overestimated.

Although high-dose IL-2 is considered to be the most effective IL-2 regimen, long-term survival is only achieved in a small minority of patients and no randomized studies to date have reported an overall survival benefit over placebo or other therapies. In a study by Yang et al.[31], there was no difference in terms of overall survival compared with a low-dose regimen, even though patients in the high-dose arm achieved a higher response rate. Similarly, McDermott et al.[30] reported better response rates in patients randomized to high-dose IL-2 (23%) than in those randomized to combined IL-2 and IFN-α (10%), but there was only an insignificant trend in favour of high-dose IL-2 in terms of overall survival (Fig. 2).

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Figure 2. Overall survival in patients treated with high-dose (HD) IL-2 or IL-2 and IFN [30]. P = 0.211 by log-rank test. Reprinted with permission from the American Society of Clinical Oncology.

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IL-2 is often highly toxic, expensive and not universally available, because specialist facilities are required for its administration, and intensive patient monitoring is needed [1,26,33]. The toxicity profile of IL-2 is similar to that of IFN-α (Table 1), but IL-2 is also associated with capillary leak syndrome, oliguria, hypotension and an increase in serum creatinine levels [1]. Cardiopulmonary toxicity (rhythm disturbances and myocardial infarctions) sometimes occur and haematological toxicity is common [1]. Toxicity is dose- and schedule-dependent, with less toxicity reported for the low-dose and s.c. regimens. In most cases, these toxicities are rapidly reversed when treatment is stopped. The potential for severe toxicity with high-dose IL-2 must be balanced against the possibility of long-term survival benefit or potential cure in the few patients who respond completely to treatment.

TARGETING PATIENTS WITH POTENTIAL TO RESPOND TO CYTOKINE THERAPY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CYTOKINE THERAPY FOR TREATING RCC
  5. TARGETING PATIENTS WITH POTENTIAL TO RESPOND TO CYTOKINE THERAPY
  6. TARGETED THERAPIES
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

It is clear that cytokines can induce durable responses in a small subset of patients with advanced RCC. The important issue is whether these individuals can be selected more accurately to avoid unnecessary exposure of patients who are unlikely to respond to these toxic drugs.

Several studies have shown that clinical prognosis might be associated with response to IFN-α. In a retrospective study of 463 patients receiving IFN-α, the median overall survival for all patients was 13 months [14]. When patients were grouped according to clinical risk factors, the median overall survival was significantly longer in the ‘favourable’ prognosis subgroup (30 months) than in the ‘intermediate’ (14 months) and ‘poor’ (5 months) prognosis subgroups (Fig. 3) [14]. Consistent with these data, the recent PERCY Quattro study of 492 patients with intermediate prognosis found no survival benefit for IFN-α therapy (median overall survival 15.2 months; 95% CI 12.8–19.9) compared with the medroxyprogesterone acetate control (median overall survival 14.9 months; 95% CI 11.7–19.2) [34].

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Figure 3. Survival of patients receiving IFN-α stratified according to risk group [14]. P < 0.001 for between-groups comparison. Reprinted with permission from the American Society of Clinical Oncology.

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Prognostic factors might also influence response to IL-2. A median overall survival of 30.9 months was reported after high-dose IL-2 therapy in a subgroup of patients with advanced RCC and ‘good’ prognostic characteristics according to Memorial Sloan-Kettering Cancer Center (MSKCC) criteria [30]. This compared with a median survival of 16.8, 3.0 and 1.6 months for patients in the same study with intermediate, intermediate/poor or poor prognostic characteristics [30]. Moreover, as reported in the recent PERCY Quattro study for IFN-α, there was no apparent survival advantage for IL-2-based therapy (median overall survival 15.3 months; 95% CI 12.8–19.9) compared with medroxyprogesterone acetate control (median overall survival 14.9 months; 95% CI 11.7–19.2) [34].

Many clinical features have been identified that might influence survival in patients receiving cytokine therapy [30,35–38]. Performance status and the number of metastatic sites might be the most relevant [1]. Analysis of outcome by prognostic factors is complicated by the lack of a common system for prospectively identifying and stratifying patients, and analysing the findings. Moreover, differences in the findings of studies conducted to date (nearly all of which have been retrospective) suggest that large, prospective studies are required to usefully define prognostic clinical features.

By contrast with clinical features, histological, immunological and molecular markers might prove to be more accurate prognostic indicators, particularly for predicting the response to IL-2. For example, the presence of papillary or significant granular histological features appear to be predictors of poor response to IL-2 therapy. In a recent study of 163 patients with RCC, clear-cell histology was associated with a 21% response rate, compared with 6% for patients whose tumours had other than clear-cell histology [39]. Prognosis also influenced the response in this study, with patients in the ‘best’ prognosis group (with >50% alveolar histological features and no granular or papillary histological features) achieving a response rate of 39%[39]. These results led the authors to suggest that patients with tumours that have papillary, >50% granular or no alveolar features should be excluded from IL-2 therapy. Other studies have also highlighted the poor responsiveness of tumours with other than clear-cell histology to current treatments [40].

Carbonic anhydrase IX (CAIX) is also emerging as a strong candidate for predicting response, progression and survival in patients with metastatic RCC treated with IL-2. CAIX is a transmembrane protein that is thought to play a role in the regulation of cell proliferation under hypoxic conditions. CAIX is present in 94% of clear cell RCCs and low CAIX levels are associated with poor prognosis in patients with metastatic disease [41]. More recently, tumour histology and CAIX expression were combined in a new predictive model, where tissue specimens from patients with good pathological prognosis alone or intermediate pathological prognosis with high CAIX expression were found to include 96% of responders to IL-2 treatment [42]. A recent report also suggests that patients who lack the mammalian target of rapamycin (mTOR) pathway and, in particular, those who have increased expression of phosphorylated Akt, might not respond well to cytokine therapy [43].

Additional pathological markers that might add to the ability to evaluate prognosis in patients with RCC include factors that indicate immune status, e.g. the number of CD4+CD25+ regulatory T cells after cytokine treatment [44]. Findings of a recent study show that adding three independent immunological variables (blood neutrophil count, presence of intratumoral neutrophils and intratumoral CD57+ natural killer cell count) to prognostic models based on clinical risk factors, could identify subgroups of patients amongst those with favourable clinical features [45]. Estimated 5-year survival rates for the subgroups based on the number of immunological risk factors identified within a combined immunological and clinical model were 60%, 25% and 0%, for patients with zero, one, and two to three immunological risk factors, respectively (Fig. 4).

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Figure 4. Prognostic models based on clinical factors (A) supplemented with immunological factors (B) in patients with metastatic RCC receiving IL-2-based immunotherapy [45]. Reprinted with permission from the American Society of Clinical Oncology.

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However, even in individuals with a favourable prognosis according to the above criteria, cytokine therapy is contraindicated in certain patients. For example, IFN-α is contraindicated in patients with autoimmune hepatitis and hepatic decompensation (Child–Pugh class A and B) [21,46]. IFN-α might also cause (or aggravate) life-threatening neuropsychiatric, autoimmune, ischaemic or infectious disorders. However, IL-2 is contraindicated in patients with an abnormal thallium stress test, abnormal pulmonary function tests or organ allografts, and in patients who have experienced prior drug-related toxicities while receiving IL-2 [22]. In addition, IL-2 is contraindicated in patients with clinically significant cardiac, respiratory, renal, hepatic or CNS impairment. IL-2 might also exacerbate autoimmune and inflammatory disorders.

TARGETED THERAPIES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CYTOKINE THERAPY FOR TREATING RCC
  5. TARGETING PATIENTS WITH POTENTIAL TO RESPOND TO CYTOKINE THERAPY
  6. TARGETED THERAPIES
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

Several agents are being developed that specifically target molecular signalling pathways implicated in RCC growth, proliferation and angiogenesis. Agents that have shown evidence of activity in phase III trials in advanced RCC include sorafenib [47], sunitinib [48], temsirolimus [49] and bevacizumab [50]. Sorafenib is approved for treating advanced RCC in the USA, and patients with advanced RCC who have failed previous IFN-α- or IL-2-based therapy or are considered unsuitable for such therapy in the European Union; sunitinib is approved for the treatment of advanced and/or metastatic RCC in the USA and the European Union. The toxicities of immunotherapy have been replaced by those of the targeted agents that are different in many respects, perhaps with the exception of fatigue. Other agents under investigation in this setting include cetuximab, ABX-EGF and gefitinib.

Sorafenib, an oral multikinase inhibitor, has been investigated in the Treatment Approaches in Renal Cancer Global Evaluation Trial, the largest randomized, double-blind, placebo-controlled, phase III study in metastatic RCC conducted to date [47]. In this study, 903 patients in whom one previous systemic therapy had failed were randomized to receive either sorafenib (400 mg orally, twice daily) or placebo. In a planned analysis, sorafenib significantly prolonged progression-free survival (PFS) compared with placebo (5.5 vs 2.8 months, respectively; hazard ratio, HR 0.44; 95% CI 0.35–0.55; P < 0.001), with benefit across all patient subgroups analysed, regardless of age, performance status, prognostic category (according to MSKCC criteria) or previous therapy. Given this striking benefit to PFS, the protocol was amended to allow patients in the placebo arm to cross over to active treatment. Compared with placebo, sorafenib showed a trend towards improved overall survival both at the time of crossover (HR 0.72; 95% CI 0.54–0.94; P = 0.02) and 6 months after crossover (0.77, 0.63–0.95; P = 0.02), although the pre-specified O’Brian–Fleming stopping boundary for statistical significance (P < 0.001 and P = 0.009, respectively) was not reached in either analysis. Clinical benefit (defined as the proportion of patients with stable disease or better at 12 weeks) was 84% with sorafenib and 55% with placebo. Sorafenib was well tolerated, with a manageable side-effect profile. The most frequent adverse events among patients treated with sorafenib included diarrhoea, rash, alopecia and hand–foot skin reaction. Importantly, sorafenib treatment did not impair overall health-related quality of life [51]. A randomized phase II trial comparing first-line sorafenib with IFN in patients with advanced disease failed to show any advantage for PFS with sorafenib [52], although the progression-free survival reported for patients treated with sorafenib in this study was lower than that in several other studies with this agent in the first-line setting [53,54].

A phase III study evaluated sunitinib (a multitargeted tyrosine kinase inhibitor) compared with IFN-α in treatment-naive patients with clear-cell metastatic RCC. The PFS was 11 months for 375 sunitinib-treated patients and 5 months for 375 receiving IFN-α, a difference that was highly statistically significant (HR 0.42, 0.32–0.54; P < 0.001) [48]. A statistically significant improvement in objective response rate was also reported for sunitinib compared with IFN-α (31% vs 6%; P < 0.001) [48]. In addition, there was a trend to better overall survival for sunitinib than IFN-α (0.65, 0.45–0.94; P = 0.02), although the pre-specified level of significance was not met. The most frequently observed adverse events overall included fatigue, diarrhoea, nausea and pyrexia. Grade 3–4 diarrhoea, hypertension and hand–foot syndrome were reported with greater frequency in the sunitinib than the IFN-α group, and grade 3–4 fatigue was reported with greater frequency in patients receiving IFN-α than in those receiving sunitinib (P < 0.05 for all comparisons).

Recently, results of a randomized trial involving patients receiving first-line treatment were presented at the American Society of Clinical Oncology Annual Meeting in Chicago [50]. In the AVOREN study, 649 patients with a good and intermediate prognosis were randomized into two treatment arms, bevacizumab plus IFN-α or IFN-α alone. Intravenous bevacizumab 10 mg/kg was given every 2 weeks and IFN-α was given s.c. three times a week at 9 MIU. Bevacizumab plus IFN-α was better than IFN-α alone, both in terms of overall response rate (30.6% vs 12.4%, P < 0.001) and median PFS (10.2 vs 5.4 months; HR 0.63; P < 0.001). These results suggest that the standard of care for patients with metastatic disease requiring first-line systemic therapy is either sunitinib monotherapy or bevacizumab plus IFN-α, with sorafenib as the standard of care in the second-line setting, and for those intolerant to or unsuitable for cytokines or targeted first-line options. For those patients receiving first-line bevacizumab plus IFN-α, sunitinib remains an important treatment option for subsequent lines of therapy.

The first analysis of a study designed to evaluate overall survival after treatment with temsirolimus (a specific inhibitor of mTOR, 209 patients), IFN-α (207) or combined temsirolimus and IFN-α (210) in patients with advanced RCC who had received no previous systemic therapy and had ‘poor’ risk disease, was reported recently [49]. Temsirolimus was associated with a statistically significant median (95% CI) overall survival benefit of 10.9 (8.6–12.7) months, compared with 7.3 (6.1–8.9) months for IFN-α alone (P = 0.007). An overall survival of 8.4 (6.6–10.2) months was achieved with the combination of temsirolimus and IFN-α, although this was not significantly greater than that achieved with IFN-α alone (P = 0.691) [49]. Temsirolimus was generally well tolerated, with the most frequent grade 3–4 adverse events being asthenia, anaemia and dyspnoea [49].

Although the long-term benefits of these treatments still need to be established, the pace of recent progress has been very exciting. Sorafenib and sunitinib have been approved for use in advanced RCC by several regulatory authorities (including the European Agency for the Evaluation of Medicinal Products and the USA Food and Drug Administration, FDA) and are recommended by the NCCN as first-line treatment options for patients with metastatic, recurrent or unresectable clear cell RCC [23]. Recently, temsirolimus was also approved by the FDA for treating advanced RCC. Furthermore, as these treatments are less toxic than cytokine therapy they might be of practical use in a greater proportion of patients. However, there is a real need to develop predictive models to help define which patients are most likely to benefit from targeted therapies.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CYTOKINE THERAPY FOR TREATING RCC
  5. TARGETING PATIENTS WITH POTENTIAL TO RESPOND TO CYTOKINE THERAPY
  6. TARGETED THERAPIES
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

The available evidence suggests that a few patients might benefit from cytokine therapy; patients who can potentially benefit should be given the opportunity to do so. There is the possibility of durable complete remission with high-dose IL-2 therapy, and IFN-α can offer survival benefits for patients with a good prognosis. However, the toxicity associated with cytokine therapy can be considerable, so exposure to these toxic drugs should be avoided in the vast majority of patients who are unlikely to gain benefit (Table 2). It is essential to define prognostic features to improve the accuracy of patient selection. Based on recent data, we can already conclude that cytokine therapy is not suitable for patients with poor or intermediate prognostic features. Other risk factors that indicate that patients are unlikely to respond to treatment include low CAIX expression and other than clear-cell histology. Further research to identify additional prognostic factors, including pathological features and immune status, and efforts to combine these into workable clinical models, are urgently required to aid more accurate selection of patients for cytokine therapy.

Table 2.  Cytokine therapy for metastatic RCC
Patients likely to benefitPatients unlikely to benefit
‘Good’ prognosis‘Intermediate’ or ‘poor’ prognosis
Nephrectomy
Positive histologyNegative histology
 Clear cell with alveolar features Not clear cell
 Lack of granular or papillary features Granular or papillary features
Immunological markers Immunological markers
 Low neutrophil count High neutrophil count
 Lack of intratumoral neutrophils Presence of intratumoral neutrophils
 High intratumoral CD57+ T-cells Low intratumoral CD57+ T-cells
 Low regulatory T-cell count after treatment High regulatory T-cell count after treatment
Pathological markersPathological markers
 High CAIX expression Low CAIX expression

Targeted therapies, such as sorafenib, sunitinib and temsirolimus, have shown great promise and are increasingly becoming integrated into clinical practice. Sorafenib, sunitinib and temsirolimus are already approved for treating advanced RCC. Furthermore, studies are underway to evaluate the potential of combining cytokines with targeted therapies. However, we already know from the recent results of the AVOREN trial that the combination of bevacizumab plus IFN-α is better than IFN-α alone as first-line therapy for a mixed population of patients with intermediate and good prognostic features. By contrast with cytokine therapy, targeted therapies have rarely resulted in complete and lasting remission; they require continuous administration and have not been reported to induce periods of indolent growth without continuing administration of the drug.

The future role of cytokines for treating RCC will be ultimately determined by the results of large, randomized clinical trials comparing cytokines with targeted agents in good-prognosis patients. Further research is required to more precisely determine how cytokines can add to the efficacy of targeted therapies, either in combination or as sequential therapy.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CYTOKINE THERAPY FOR TREATING RCC
  5. TARGETING PATIENTS WITH POTENTIAL TO RESPOND TO CYTOKINE THERAPY
  6. TARGETED THERAPIES
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

The author kindly acknowledges the contribution of Kate Unsworth (GeoMed) and Mark Richardson (contract writer) for professional medical writing support and Karen Middleton (GeoMed) for editorial assistance, with funding for professional writing services from Bayer HealthCare Pharmaceuticals.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CYTOKINE THERAPY FOR TREATING RCC
  5. TARGETING PATIENTS WITH POTENTIAL TO RESPOND TO CYTOKINE THERAPY
  6. TARGETED THERAPIES
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

Martin E. Gore is a Principle Investigator for a study part supported by Chiron and Schering Plough, and is on the Advisory Boards of Schering Plough, Pfizer, Wyeth, Bayer and Centocor, and received research funding from Bayer, Pfizer and Centocor.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CYTOKINE THERAPY FOR TREATING RCC
  5. TARGETING PATIENTS WITH POTENTIAL TO RESPOND TO CYTOKINE THERAPY
  6. TARGETED THERAPIES
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES
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