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 Fumagalli, L. A. Articles by Brivio, F. Search for Related Content PubMed Articles by Fumagalli, L. A. Articles by Brivio, F. Social Bookmarking                            What's this?

Immunotherapy and Prognostic Factors

Department of General Surgery, 3rd Unit of Surgery, San Gerardo Hospital, Monza, Italy

To the Editor:

In their article "Impact of Immune Parameters on Long-Term Survival in Metastatic Renal Cell Carcinoma," Donskov and von der Maase¹ focused their research on immune parameters within the tumor and in circulating blood, in combination with established clinical prognostic factors, to identify the patients more likely to benefit from interleukin-2 (IL-2) with interferon alpha-based treatment.

At univariate analysis, values of circulating blood lymphocyte count below the median number (1.590/mmc) found in 120 patients were significantly associated with shorter survival, whereas values of blood lymphocyte higher than median were associated with longer survival (18 months v 12 months).

In the subsequent multivariate analyisis, this dicotomic value was found not to be prognostic, after including other parameters, such as neutrophil count in blood and in tumor and CD57+ cells in tumor.

On the contrary, in a previous study,² we found that lymphocyte count at baseline is a prognostic factor for overall survival in metastatic renal cancer patients, not depending on major prognostic clinical characteristics, such as performance status, time to metastatization, and the number of metastatic sites (Elson-based prognostic model³). The relevance of lymphocyte count in blood was previously demonstrated in 1980 by Stanley⁴ in the milestone study on more than 5,000 non–small-cell lung cancer patients, in which approximately 70 different prognostic variables were evaluated. Baseline lymphocyte count was found to be an independent prognostic parameter for overall survival, after performance status, disease extent, and weight loss, whereas all other were excluded.

Moreover, with the aim to assess whether host response to IL-2 administration—measured as blood lymphocyte peak—could have clinical relevance as prognostic marker, we included in our model also tumor response and blood lymphocyte peak observed during treatment. In our series of 266 metastatic cancer patients, both lymphocyte peak and tumor response after IL-2 based treatment were independently predictive of overall survival.²

It is relevant, in our opinion, to point out why the results of Donskov and von der Maase differ from those we observed, for the following reason. Donskov and von der Maase¹ reaffirm that 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." That is, IL-2 is intended to be effective as a potent cytotoxic drug achieving strong tumor response only in a few selected patients.

In our view, IL-2 is a treatment able to improve the overall survival of a large number of cancer patients, despite the fact that tumor disappearing is not achieved by its administration. Why we affirm such a strange concept? Because IL-2 restores, in approximately one half of patients, the severe immune impairment (measurable as lymphocytopenia), having deep influence on overall survival of the of cancer patient. Indeed, patients in whom IL-2 administration induces the higher lymphocyte response (IL-2 is in fact the growth factor for T cells) measurable in blood, live longer independently on tumor response, as we found in our study.²

The fundamental difference between these two studies, in our opinion, consists in the fact that we evaluated lymphocyte count as a continous variable, whereas Donskov and von der Maase evaluated it as a discrete, dicotomic value. As the biologic production of IL-2 and its response by T cells is a continuous phenomenon, the median value of lymphocyte count at baseline as a possible prognostic marker will be easily confounded by more clearly dicotomic variables, such as lactate dehydrogenase or neutrophil count, especially in a series of patients quite homogeneous, such as in Donskov and von der Maase study, mainly in intermediate-risk group (ie, equal to median lymphocyte count). The study of Donskov and van der Maase is of high interest concerning the mechanisms by which immune treatment acts on the tumor.

However, we strongly disagree concerning the statement in the discussion, according to which patients with poor immunologic features, as found by the authors, should not receive IL-2 treatment, as they will die within 36 months. Clinicians treating patients know that those who will not benefit by treatment usually have a life expectation of 3 months to 6 months, not those with 36 months life expectation. We should remember that, in the early prognostic models (ie, Elson) in the era before immunotherapy, metastatic patients median survival ranged from 2 months to 13 months. Motzer et al⁵ in a well-designed retrospective analysis on 600 metastatic renal cancer patients found an increase of overall survival by cytokine treatment (IL-2/interferon alpha) with respect to chemotherapy, from 15 months to 27 months in favorable risk, from 7 months to 12 months in intermediate risk, from 3 months to 6 months in poor-risk group patients. Immunotherapy resulted to be an independent predictor for longer survival.⁶

It is dangerous for potentially treatable patients that some authors state in a such relevant journal that patients with 36 months life expectancy should not receive cytokine treatment.

Immunotherapy, aimed at survival improvement, still waits for being understood and fully applied in cancer cure. The introduction of cheap and feasible biomarker will help the evolution.

Authors' Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Luca A. Fumagalli Chiron Italy (N/R) Chiron Italy (A) Fernando Brivio Chiron Italy (A)

Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

REFERENCES

1. 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]

2. 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]

3. Elson PJ, Witte RS, Trump DL: Prognostic factors for survival in patients with recurrent or metastatic renal cell carcinoma. Cancer Res 48:7310-7313, 1988[Abstract/Free Full Text]

4. Stanley KE: Prognostic factors for survival in patients with inoperable lung cancer. J Natl Cancer Inst 65:25-32, 1980[Medline]

5. Motzer R, Mazumdar M, Bacik, et al: Renal cell carcinoma recurrence after nephrectomy for localized disease: Predicting survival from time of recurrence. J Clin Oncol 18:1928-1935, 2000[Abstract/Free Full Text]

6. Zisman A, Pantuck AJ, Dorey F, et al: Mathematical model to predict individual survival for patients with renal cell carcinoma. J Clin Oncol 20:1368-1374, 2002[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

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 Fumagalli, L. A. Articles by Brivio, F. Search for Related Content PubMed Articles by Fumagalli, L. A. Articles by Brivio, F. Social Bookmarking                            What's this?