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In Reply

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark

The letter by Fumagalli and Brivio is primarily based on the results from the previous study by Fumagalli et al,¹ identifying circulating lymphocytes as an independent prognostic factor in metastatic renal cell carcinoma (mRCC). Fumagally and Brivio affirm a strange concept of interleukin-2 (IL-2) being able to improve the overall survival of a large part of cancer patients, and therefore, they strongly disagree with our suggestion of patient selection for IL-2 treatment in mRCC.² However, the conclusions by Fumagalli and Brivio are not supported by data.

IL-2 was approved by the Danish Medical Agency in 1989 and by the US Food and Drug Administration in 1992 for the treatment of mRCC. The principal justification for this approval was the ability of IL-2 to induce dramatic and durable responses in a minority of patients in this previously treatment-refractory disease. After 20 years, however, the value of immunotherapy for locally advanced renal cell carcinoma and mRCC is still controversial. Only a few oncologists consider this treatment modality to be effective for a large part of cancers as stated by Fumagalli and Brivio. The variable natural history of mRCC with even spontaneous remissions, the lack of positive randomized phase III trials evaluating IL-2 with a placebo control arm, and, probably, the high level of toxicity related to the drug have nourished skepticism about IL-2.³ In fact, despite a yearly worldwide mortality of approximately 100,000, the large majority of mRCC patients are not offered active treatment, and supportive care alone is considered the standard of care in many centers. The majority of the remaining patients are offered interferon alpha despite its modest activity with a median survival improvement of 2.6 months and a reduction of the 1-year mortality by 27%.³ A minority of patients receive subcutaneous IL-2 and only approximately 100 to 200 patients worldwide per year receive high-dose bolus intravenous IL-2. Moreover, within the last few years, a large number (> 20) of new drugs, targeted biologic therapies, have been assessed in mRCC. Several of these drugs have shown promising results, and US Food and Drug Administration approved sorafenib and sutent (Pfizer Inc, New York, NY) in December 2005 and January 2006, respectively. Thus, the era of IL-2-based immunotherapy in mRCC may extinct. However, in our opinion IL-2 should certainly continue, but it should be restricted to patients more likely to benefit from treatment.

A survival benefit of IL-2 has not been shown in randomized studies with a nonimmunotherapy control group.^4,5 However, all randomized trials have been small. No IL-2 treated group has exceeded 140 patients. This represents statistical power too low to detect the long-term survival benefit actually seen in a small group of IL-2 treated patients. A large number of long-term follow-up reports have consistently been published demonstrating durable responses and long-term survival in a minority of patients (approximately 10%) treated with IL-2.^2,6-8 Thus, the true value of IL-2 lies in the probability that this drug can be curative for a small group of patients with metastatic disease. The important issue is then to identify this subgroup of patients.

IL-2 works entirely through activation of the patient's endogenous immune system by binding to subunits of the IL-2 receptor on T-cells,⁹ natural killer cells,¹⁰ B cells,¹¹ monocytes/macrophages,¹² and neutrophils.¹³ Consequently, our group has focused on the understanding of immune cell orchestration in blood and tumor tissue in relation to IL-2-based immunotherapy and the correlation of these immune cell subsets with objective response and/or survival with the aim of identifying parameters that may help to select patients more likely to benefit from IL-2-based immunotherapy. An understanding of IL-2 based immunotherapy as a targeted therapy requiring lymphocyte subsets—T cells and natural killer cells—for tumor rejection emerged from these analyses.^14-17 In contrast, circulating as well as intratumoral phagocytes—monocytes and neutrophils—were shown to be powerful negative prognostic factors for IL-2-based immunotherapy.^2,15,17 Previously, three large studies of prognostic factors for IL-2-based immunotherapy in mRCC, including a total of 1,422 patients, have all identified baseline elevated blood neutrophils as poor prognostic factors(reviewed in Donskov et al¹⁷). In the study by Fumagalli et al,¹ blood neutrophils were available from the differential WBC automatic counter. The reason why Fumagalli did not include blood neutrophils in the multivariate analysis, but only included blood lymphocytes, is unknown. Our present study² validates and strengthens the impact of neutrophil count as a poor prognostic factor in mRCC by identifying both blood neutrophils and intratumoral neutrophils as independent poor prognostic factors. As we assessed a large number of blood and tumor immune cells, dichotomy by the median value is correct from a statistical point of view.

Our current study² suggests a prognostic model based on clinical factors supplemented with independent immunological prognostic factors. Patients in the good prognostic groups had 5-year survival rates of 60% and 25%. In contrast, all patients in the poor prognostic group died within 3 years. We suggest IL-2-based immunotherapy restricted to patients who most likely will benefit, while referring other patients to alternative investigational modalities. We also are clinicians treating patients and patients in the poor prognostic group do not seem to benefit from IL-2-based immunotherapy, but all suffer from treatment-related toxicity. This view is in line with the conclusion in a recent Cochrane review,³ that for the large majority of patients with mRCC, the disease parameters are more powerful determinants of outcome than any treatment modality. Finally, validation of our prognostic model,² based on clinical factors supplemented with immunological factors, is of high priority as validation of these features may help to select patients more likely to benefit from IL-2-based immunotherapy.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Fumagalli LA, Vinke J, Hoff W, et al: Lymphocyte counts independently predict overall survival in advanced cancer patients: A biomarker for IL-2 immunotherapy. J Immunother 26:394-402, 2003[Medline]

2. Donskov F, von der Maase H: Impact of immune parameters on long-term survival in metastatic renal cell carcinoma. J Clin Oncol 24:1997-2005, 2006[Abstract/Free Full Text]

3. Coppin C, Porzsolt F, Awa A, et al: Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev CD001425, 2005

4. 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 77:1311-1317, 1998[Medline]

5. 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. J Clin Oncol 23:1093s, 2005 (abstr 4511)

6. Fisher RI, Rosenberg SA, Fyfe G: Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 6:S55-S57, 2000 (suppl 1)[Medline]

7. Negrier S, Maral J, Drevon M, et al: Long-term follow-up of patients with metastatic renal cell carcinoma treated with intravenous recombinant interleukin-2 in Europe. Cancer J Sci Am 6:S93-S98, 2000 (suppl 1)[Medline]

8. Atzpodien J, Hoffmann R, Franzke M, et al: Thirteen-year, long-term efficacy of interferon 2alpha and interleukin 2-based home therapy in patients with advanced renal cell carcinoma. Cancer 95:1045-1050, 2002[CrossRef][Medline]

9. Smith KA: Interleukin-2: inception, impact, and implications. Science 240:1169-1176, 1988[Abstract/Free Full Text]

10. Farag SS, Caligiuri MA: Human natural killer cell development and biology. Blood Rev 20:123-137, 2006[CrossRef][Medline]

11. Mingari MC, Gerosa F, Carra G, et al: Human interleukin-2 promotes proliferation of activated B cells via surface receptors similar to those of activated T cells. Nature 312:641-643, 1984[CrossRef][Medline]

12. Espinoza-Delgado I, Bosco MC, Musso T, et al: Interleukin-2 and human monocyte activation. J Leukoc Biol 57:13-19, 1995[Abstract]

13. Ferrante A: Activation of neutrophils by interleukins-1 and -2 and tumor necrosis factors. Immunol Ser 57:417-436, 1992[Medline]

14. Donskov F, Bennedsgaard KM, von der Maase H, et al: Intratumoural and peripheral blood lymphocyte subsets in patients with metastatic renal cell carcinoma undergoing interleukin-2 based immunotherapy: Association to objective response and survival. Br J Cancer 87:194-201, 2002[CrossRef][Medline]

15. Donskov F, Bennedsgaard KM, Hokland M, et al: Leukocyte orchestration in blood and tumour tissue following interleukin-2 based immunotherapy in metastatic renal cell carcinoma. Cancer Immunol Immunother 53:729-739, 2004[Medline]

16. Donskov F, von der Maase H, Marcussen N, et al: Fas ligand expression in metastatic renal cell carcinoma during interleukin-2 based immunotherapy: No in vivo effect of Fas ligand tumor counterattack. Clin Cancer Res 10:7911-7916, 2004[Abstract/Free Full Text]

17. Donskov F, Hokland M, Marcussen N, et al: Monocytes and neutrophils as "bad guys" for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma: Results from a randomised phase II trial. Br J Cancer 94:218-226, 2006[CrossRef][Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Donskov, F. Articles by von der Maase, H. Search for Related Content PubMed Articles by Donskov, F. Articles by von der Maase, H. Social Bookmarking                            What's this?