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Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1562-1569 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.0274 Pretreatment Levels of Peripheral Neutrophils and Leukocytes As Independent Predictors of Overall Survival in Patients With American Joint Committee on Cancer Stage IV Melanoma: Results of the EORTC 18951 Biochemotherapy Trial
From the Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium; Department of Medical Oncology, University Medical Centre, Nijmegen; Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Royal Marsden Hospital, London; Cancer Research UK Clinical Center, St James' University Hospital, Leeds, United Kingdom; Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland; and Department of Medicine III, Charité, Campus Benjamin Franklin, Berlin, Germany Address reprint requests to Henrik Schmidt, MD, Department of Oncology, Aarhus University Hospital, Norrebrogade 44, 8000 Aarhus C, Denmark; e-mail: hesch{at}as.aaa.dk
Purpose An elevated count of blood neutrophils and monocytes recently was shown independently to predict short survival in patients with stage IV melanoma undergoing interleukin-2–based immunotherapy. In this study, we aimed to validate this finding in a large cohort of stage IV melanoma patients. Patients and Methods For this retrospective prognostic study, the data from the European Organisation for the Research and Treatment of Cancer 18951 study were used. Patients were randomly assigned between treatment with dacarbazine, cisplatin, and interferon alfa with or without interleukin-2. Counts of neutrophils and leukocytes were analyzed together with other known prognostic factors: serum lactate dehydrogenase, performance status, metastatic site, and sex. Two multivariate prognostic factor analyses were carried out in the model: one with leukocyte counts and one with neutrophil counts. Results A total of 363 patients were randomly assigned and baseline blood neutrophil and leukocyte counts were available from 316 and 350 patients, respectively. A high neutrophil count (> 7.5 x 109/L) was an independent prognostic factor for short overall survival (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = 0.02), and a high leukocyte count (> 10 x 109/L) was an independent prognostic factor of both short overall survival (HR, 1.7; 95% CI, 1.3 to 2.4; P = 0.0005) and short progression-free survival (HR, 1.5; 95% CI, 1.1 to 2.1; P = 0.008). Conclusion A high pretreatment count of neutrophils in blood was confirmed as an independent prognostic factor for short overall survival in stage IV melanoma patients undergoing interleukin-2–based immunotherapy. Furthermore, a high count of leukocytes was an independent prognostic factor for short overall survival and progression-free survival. Both parameters should be useful as stratification factors in clinical trials.
The prognosis for patients with metastatic melanoma is poor, with a median survival time between 4 and 12 months.1 Interleukin-2 (IL-2) has resulted in durable responses and cure in 5% to 7% of the patients.2,3 Prognostic factors that may predict response or long-term survival to this treatment have been investigated to select patients suitable for treatment. A number of clinical prognostic factors such as performance status and metastatic sites have been identified and confirmed in previous studies.4-7 Serum lactate dehydrogenase (LDH) currently is the strongest prognostic factor in stage IV melanoma and is used in the American Joint Committee on Cancer (AJCC) stage IV classification in combination with site of metastases.8 Several other biomarkers currently are under investigation, such as circulating melanoma-related mRNA,9 and new serum markers such as TA9010 and YKL-40.11,12 Recently, elevated levels of blood neutrophils and monocytes were identified as independent prognostic factors in a cohort of 321 patients with stage IV melanoma receiving IL-2–based immunotherapy.13 The aim of this study was to confirm, in a large independent cohort of melanoma patients within a multicenter randomized trial using biochemotherapy, that pretreatment neutrophil count has a strong prognostic value, independent from other well-known prognostic factors.
Patients were eligible for this trial if they had stage IV melanoma with measurable disease that could not be controlled by surgery and a Karnofsky performance status of at least 60. Exclusion criteria were as follows: presence of brain metastases on brain computed tomography scan or magnetic resonance imaging; prior therapy with IL-2 or two other components of the regimen; symptomatic cardiac, pulmonary, renal, liver, or thyroid disease; autoimmune diseases; corticosteroid treatment; and significant bone marrow dysfunction. The protocol was approved by the European Organisation for Research and Treatment of Cancer Protocol Review Committee and by the institutional review committees of all participating hospitals; informed consent was obtained from all patients before random assignment.
Treatment Plan
Statistical Analysis The actuarial curves were computed using the Kaplan-Meier technique. The Cox proportional hazards model has been used to obtain the estimate and the 95% CI of the hazard ratio (HR) of the instantaneous event rate in one group versus that in the baseline group. The Cox model stratified for treatment arm has been used for multivariate analysis to determine whether several variables were of independent prognostic importance. The Wald test has been used to determine the prognostic importance of each variable included in the model. All analyses were performed according to the intent-to-treat principle. The Spearman rank correlation test (rS) was used to assess the correlation between different ordered categoric variables.
Performance status initially was scored according to the Karnofsky scale but for reasons of comparison, it was converted to the Eastern Cooperative Oncology Group (ECOG) performance status as follows. Karnofsky 100 equals ECOG 0, Karnofsky 80 to 90 equals ECOG 1, and Karnofsky 60 to 70 equals ECOG 2. Given that reference levels were missing for laboratories involved, cutoff levels of 10 x 109/L for leukocytes and 7.5 x 109/L for neutrophils were chosen as representative upper reference levels (upper limit of normal [ULN]). Given that leukocyte counts were available, these were analyzed instead of the missing monocyte counts. The neutrophil and leukocyte counts were analyzed as routine differential counts. The potential prognostic factors used for covariate selection were the following: treatment (chemotherapy + IFN v chemotherapy + IFN + IL-2); LDH (< ULN v
Patient Characteristics A total of 363 patients with a median age of 48 years (range, 20 to 70 years) were included onto this randomized phase III trial: 180 patients were randomly assigned to the cisplatin, DTIC, and IFN-  arm, and 183 patients were randomly assigned to the cisplatin, DTIC, IFN-, and IL-2 arm. The median actuarial follow-up was 4.2 years. A total of 331 patients were observed until death and 349 patients were observed until progression or death. The median overall survival was 9 months and the median progression-free survival was 3.7 months. Patient characteristics are summarized in Table 1. Eighteen percent of patients had neutrophil counts above 7.5 x 109/L and 16% of patients had leukocyte counts above 10 x 109/L. The relationships between initial neutrophil counts and other patient characteristics as well as initial leukocyte counts and other patient characteristics are also listed in Table 1. High neutrophil counts were correlated with a poorer performance status (rS = 0.24; P < .0001), high LDH values (rS = 0.19; P = .0004), and with high leukocyte counts (rS = 0.78; P < .0001). The same was true regarding leukocytes and performance status (rS = 0.22; P < .0001) and LDH (rS = 0.21; P < .0001)
Pretreatment Variables and Overall Survival There was no significant difference in overall or progression-free survival between treatment arms (Table 2). Therefore, for the prognostic factor analysis, all patients were included, regardless of treatment arm.
Patient sex, LDH, performance status, liver metastases, and peripheral-blood neutrophils and leukocytes were correlated significantly with overall survival in univariate analyses (Table 2; Fig 1). Regarding the results on LDH, there was no statistically significant difference in overall survival between patients with an LDH below ULN and an LDH between ULN and below 2x ULN. Therefore, these two groups were pooled together and compared with patients with an LDH  2x ULN for the multivariate analysis. No significant difference in survival was observed between AJCC M stages M1a, M1b, and M1c. In the Cox multivariate model, stratified for treatment arm, the following characteristics seemed to be independently associated with short overall survival: male (HR, 1.4; 95% CI, 1.1 to 1.7; P = .006); liver metastases (HR, 1.6; 95% CI, 1.2 to 2.2; P = .003); LDH 2x ULN (HR, 2.2; 95% CI, 1.6 to 3.1; P < .0001); performance status (P = .02) and a high neutrophil count (HR, 1.5; 95% CI, 1.1 to 2.1; P = .02; Table 3). Given that peripheral leukocyte and neutrophil counts were very closely correlated, a separate multivariate Cox analysis was performed in which neutrophils were substituted with leukocytes. In this analysis, a high count of peripheral leukocytes (HR, 1.7; 95% CI, 1.3 to 2.4; P = .0005) was an independent prognostic factor for short overall survival together with the other factors described (Table 3).
Pretreatment Variables and Progression-Free Survival The following pretreatment variables were correlated significantly with progression-free survival in univariate analyses: LDH, performance status, sex, liver metastases, and peripheral-blood neutrophils and leukocytes (Table 2; Fig 2). Regarding the results for LDH, there was no statistically significant difference in progression-free survival between patients with an LDH below ULN and an LDH between ULN and below 2x ULN. Therefore, these two groups were pooled together and compared with patients with an LDH 2x ULN for the multivariate analysis. In the multivariate model, the following variables were independent prognostic factors for progression-free survival: liver metastases (HR, 1.5; 95% CI, 1.1 to 2.0; P = .008), LDH 2 x ULN (HR, 1.6; 95% CI, 1.1 to 2.2; P = .01), and a high leukocyte count (HR, 1.5; 95% CI, 1.1 to 2.1; P = .008; Table 4). Because of the strong correlation between neutrophils and leukocytes, a second multivariate model with neutrophils instead of leukocytes was performed. In this model a high neutrophil count was not an independent prognostic factor for progression-free survival (P = .29). It was notable that all patients with high counts of neutrophils and leukocytes experienced progression of their disease within the first 2 years after random assignment; all but one patient experienced disease progression during the first year (Fig 2; Table 2).
Prognostic Model In our previous article on neutrophils as an independent prognostic factor, we presented a prognostic model based on LDH (normal v elevated), neutrophils (normal v elevated), and WHO performance status (0 to 1 v 2).13 We applied the current data to possibly confirm this prognostic model in an independent analysis. A significant separation in survival (P < .0001) was observed among patients with no elevated variables (low risk), one to two elevated variables (intermediate risk), and three elevated variables (high risk; Fig 3A; Table 5). An additional analysis of the stratification in 0, 1, 2, or 3 elevated variables showed an overall significant separation in survival (P < .0001). Patients with zero and one elevated variable did not have significant differences in survival (HR, 1.2; 95% CI, 0.9 to 1.5; P = .19), but the risk of early death increased drastically when patients had two (HR, 2.6; 95% CI, 1.8 to 3.7; P < .0001) or three elevated variables (HR, 6.1; 95% CI, 2.6 to 14.01; P < .0001; Table 5).
The primary aim of this retrospective study was to validate in a large, randomized, multicenter study database the observation from a previous analysis that a high pretreatment count of neutrophils in peripheral blood was an independent prognostic factor for short survival in patients with AJCC stage IV melanoma.13 Three hundred twenty-one patients treated in several phase II trials with IL-2–containing regimens were included in that study, which also showed that blood monocytes counts had an independent prognostic impact similar to that of neutrophils. In our study, 363 patients were treated within a randomized phase III trial.14 Counts of monocytes were not available in the database. Thus, the analyses were carried out to confirm the prognostic role of pretreatment neutrophil counts, and because data on monocytes were not available, we investigated the prognostic role of pretreatment leukocyte counts. LDH was analyzed with three categorizations in the univariate analyses, but because there was no significant difference between patients with a normal LDH and patients with an LDH between the ULN and 2x ULN, we pooled these two categories into one and compared these data with the category of patients with a LDH above 2x ULN. With this categorization, LDH had an independent prognostic impact, which was not the case if using the original three categorizations or the categorization of normal versus elevated. In this way, we strengthened the challenge of the prognostic importance of neutrophils and leukocytes. Counts of neutrophils were highly correlated with counts of leukocytes. This was expected, given that neutrophils comprise the majority of leukocytes. In this study, we did not have data on the ULN of leukocytes and neutrophils from the involved laboratories. Instead, we have applied cutoff values that were representative of the ULN used in the initial study.13 These cutoff values were validated in the original patient material with identical results as for the original use of ULN in the multivariate analyses (data not shown). In univariate analysis, both neutrophils and leukocytes were of significant prognostic value: the higher the hematologic values, the worse the prognosis. Multivariate Cox analyses showed leukocyte and neutrophil counts to be independent prognostic factors for overall survival, and leukocyte counts were an additional independent prognostic factor for progression-free survival. Both parameters may be useful as stratification factors in future studies, in addition to performance status and LDH, for instance. The overall leukocyte count seemed to be the stronger of the two parameters. To rule out whether the difference was related to the fewer patients with known neutrophil counts compared with patients with known leukocyte counts, we analyzed a second model in which we only entered the patients with available neutrophil counts (n = 314). However, the leukocyte count was still of stronger prognostic importance than neutrophil count, even after adjustment for other prognostic factors (data not shown). In our previous study, we presented a prognostic model based on normal versus elevated levels of LDH and blood neutrophils together with performance status (0 to 1 v 2).13 This model showed a highly significant separation in survival between patients with no elevated variables (low-risk group), one to two elevated variables (intermediate-risk group), and three elevated variables (high-risk group). We applied the patient data from the current study to this model and were able to confirm the results. The categorization of neutrophils was slightly different in these two materials, as discussed. A superior model was observed when analyzing each individual layer (zero, one, two, or three elevated variables). It was observed that the risk of early death increased steeply in patients with more than one elevated variable. Few studies exist on the prognostic role of peripheral leukocytes and differential counts of neutrophils and monocytes. One study concluded that a high count of neutrophils was correlated with a poor prognosis in 589 patients with a variety of cancers, such as breast cancer, female genital cancer, head and neck cancer, and sarcoma.15 More recent studies in stage IV renal cell carcinoma have shown that a high count of peripheral neutrophils was an independent prognostic factor for short survival in three studies of immunotherapy.16-18 The prognostic role of the overall leukocyte count was not addressed in these studies. A different approach has been to examine the prognostic role of tumor-associated macrophages and neutrophils in primary tumors and metastases. It is known that the tumor microenvironment can actually attract, educate, and control invading leukocytes to promote angiogenesis, viability, motility, and invasion.19-21 Tumor-associated macrophages seem to play a crucial role in this interaction and have been correlated to short survival in the majority of studies.22 However, the opposite has also been observed in a small number of studies in cancers of the lung, prostate, and stomach.22 One explanation for this discrepancy may be that macrophages can differentiate into functionally polar subtypes that are defined as either proinflammatory or anti-inflammatory. The former subtype is also termed alternatively activated macrophages, and is believed to promote tumor progression through stimulation of angiogenesis and invasion.23,24 None of the referenced studies have differentiated between these subtypes. The differentiation of tumor-associated macrophages into functionally different subtypes is governed by cytokines encountered in the tumor microenvironment, and in vitro it has been possible to switch between these polar subtypes by use of different cytokines.25 Modulation of these cells may constitute a therapeutic option in the future.26 The explanation for the association between high counts of blood neutrophils and leukocytes and a poor prognosis is not clarified, but these parameters might represent surrogate markers of a high degree of inflammatory cell infiltration in metastases. The stroma around the periphery of solid cancers have several similarities with granulation tissue such as that found in wound healing or inflammation. Thus, cancer has been compared with a wound that will not heal.27 In conclusion, the pretreatment count of neutrophils as well as overall leukocytes independently predicted overall survival and, in the case of overall leukocyte count, also progression-free survival. Thus, both parameters may serve as stratification factors in randomized trials, depending on confirmation of the results in a prospective study. The overall leukocyte count potentially is superior to the neutrophil count.
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. Employment: N/A Leadership: N/A Consultant: Martin Gore, Schering-Plough; Poulam Patel, Chiron, Schering-Plough; Ulrich Keilholz, Schering-Plough, Chiron Stock: N/A Honoraria: Martin Gore, Schering-Plough, Chiron; Poulam Patel, Schering-Plough, Chiron; Alexander M.M. Eggermont, Schering-Plough Research Funds: Martin Gore, Schering-Plough, Chiron; Ulrich Keilholz, Schering-Plough, Chiron Testimony: N/A Other: N/A
Conception and design: Henrik Schmidt, Stefan Suciu Provision of study materials or patients: Cornelis J.A. Punt, Martin Gore, Wim Kruit, Poulam Patel, Danielle Lienard, Ulrich Keilholz Collection and assembly of data: Cornelis J.A. Punt, Martin Gore, Wim Kruit, Poulam Patel, Danielle Lienard, Ulrich Keilholz Data analysis and interpretation: Henrik Schmidt, Stefan Suciu, Ulrich Keilholz Manuscript writing: Henrik Schmidt, Stefan Suciu, Hans von der Maase, Alexander M.M. Eggermont, Ulrich Keilholz Final approval of manuscript: Henrik Schmidt, Stefan Suciu, Cornelis J.A. Punt, Martin Gore, Wim Kruit, Poulam Patel, Danielle Lienard, Hans von der Maase, Alexander M.M. Eggermont, Ulrich Keilholz
The following members of the EORTC Melanoma Group participated in this study: Dr Lehmann (Institut Bordet, Brussels), Dr Velu (Hopital Universitaire Erasme, Brussels), Drs Thomas and van Oosterom (UZ Antwerpen, Edegem), Dr Schwuerzer-Voit (Universitaetsklinikum-Charité, Berlin), Dr Aubin (CHR Besançon, Besançon), Dr Khayat (CHU Pitié-Salpetrière, Paris), Dr Negrier (Centre Leon Berard, Lyon), Dr Punt (St. Radboud University Nijmegen Medical Center, Nijmegen), Dr Dummer (University Hospital, Zurich), Egerer (Ruprecht Karls Universitaet, Heidelberg), Dr Enk (Johanned Gutenberg Universitaetskliniken, Mainz), Dr Gore (Royal Marsden Hospital, London), Drs Selby and Patel (St James University Hospital, Leeds), Dr Hamblin (The Royal Bournemouth Hospital, Bournemouth), Dr Lamont (Southend Hospital, Westcliff-on-Sea), Dr Peter (Universitaetsklinik, Ulm), Dr Reichardt (Robert-Roessle Klinik, Berlin), Dr Koller (St. Johanns-Spital, Salzbourg), Drs Kruit and Eggermont (Daniel den Hoed Cancer Center, Erasmus Medical Center Rotterdam), Dr Proebstle (University of Ulm, currently University of Mainz), Drs Keilholz and Schmittel (Hospital La Charité, Free University Berlin), Dr Schadendorf (University of Heidelberg, Heidelberg), Dr Kleeberg (HOPA, Hamburg), Dr Lienard (Centre Hospitalier Universitaire Vaudois, Lausanne), and Dr Testori (Istituto Europeo di Oncologia, Milano).
We acknowledge the tremendous efforts of the staff in all participating hospitals and the superb work by the melanoma-team of the EORTC Data Center: Henriette Bartolomei, Anne Kirkpatrick, Claudia De Clippeleir, Katleen Van Hoefs, Christine Molabu, and Izabella Jagiello.
Supported by Educational grants from Chiron BV, Amsterdam, the Netherlands; Schering-Plough, Kenilworth, NJ; and Grants No. 2U10 CA11488-25 through 5U10 CA11488-36 from the National Cancer Institute, Bethesda, MD. The contents of this study are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. H.S. and S.S. contributed equally to this work. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Keilholz U, Punt CJ, Gore M, et al: Dacarbazine, cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic melanoma: A randomized phase III trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group. J Clin Oncol 23:6747-6755, 2005 15. Riesco A: Five-year cancer cure: Relation to total amount of peripheral lymphocytes and neutrophils. Cancer 25:135-140, 1970[CrossRef][Medline] 16. Atzpodien J, Royston P, Wandert T, et al: Metastatic renal carcinoma comprehensive prognostic system. Br J Cancer 88:348-353, 2003[CrossRef][Medline] 17. Negrier S, Escudier B, Gomez F, et al: Prognostic factors of survival and rapid progression in 782 patients with metastatic renal carcinomas treated by cytokines: A report from the Groupe Francais d'Immunotherapie. Ann Oncol 13:1460-1468, 2002 18. 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 19. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
