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Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp. 1997-2005
© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.03.9594
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Impact of Immune Parameters on Long-Term Survival in Metastatic Renal Cell Carcinoma

Frede Donskov, Hans von der Maase

From the Department of Oncology, Aarhus University Hospital, Aarhus, Denmark

Address reprint requests to Frede Donskov, MD, Department of Oncology, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark; e-mail: fd{at}microbiology.au.dk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
PURPOSE: The purpose of this study was to evaluate the impact of immunologic prognostic factors in combination with established clinical prognostic factors in patients with metastatic renal cell carcinoma (mRCC).

PATIENTS AND METHODS: A total of 120 consecutive patients with mRCC received interleukin-2 (IL-2) -based immunotherapy. Baseline tumor biopsies were available from 85 of these patients. Potential prognostic factors were analyzed by univariate and multivariate analyses.

RESULTS: Multivariate analysis (N = 120) identified high lactate dehydrogenase, lymph node metastases, low hemoglobin, low Karnofsky performance status, and bone metastases as independent poor prognostic clinical factors. The impact of these clinical factors has been demonstrated by others. Multivariate analysis (n = 85) also identified a high blood neutrophil count (> 6.0 x 109/L; hazard ratio, 2.0; P = .015), the presence of intratumoral neutrophils (> 0 cells/mm2 tumor tissue; hazard ratio, 2.3; P = .001), and low intratumoral CD57+ natural killer cell count (< 50 cells/mm2 tumor tissue; hazard ratio, 2.1; P = .01) as independent poor prognostic immunologic factors. These three independent immunologic parameters had significant discriminatory power as supplemental risk factors in prognostic models based on the clinical risk factors, identifying subgroups within the favorable clinical group with estimated 5-year survival rates of 60%, 25%, and 0%, respectively. These findings were apparent in both our own prognostic model and in an extended Memorial Sloan-Kettering Cancer Center (New York, NY) prognostic model.

CONCLUSION: This study points on five clinical and three supplemental immunologic independent prognostic factors of survival in patients with mRCC receiving IL-2.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Annually, some 208,000 new cases and 102,000 deaths result each year from renal cancer throughout the world.1 Metastatic disease is present in 30% of patients at initial diagnosis and will, moreover, develop in 30% to 50% of patients relapsing after initial curative-intended nephrectomy. As a result, approximately 50% of patients suffer from metastatic disease.2 Metastatic renal cell carcinoma (mRCC) is a major challenge for oncologists as this disease is highly refractory to therapy, including radiation, hormones, and chemotherapy.3 Untreated, the overall survival rates at 3 and 5 years are less than 10%4,5 and less than 2%,6 respectively. Interleukin-2 (IL-2) and interferon-alfa (IFN-{alpha}) -based immunotherapy is the only modality that has been shown to improve overall survival in mRCC. Durable tumor regression lasting more than 5 and 10 years has consistently been reported in 5% to 10% of treated patients, and this subgroup of patients is probably cured.7-10 However, the majority of patients will die of their disease with no benefit from immunotherapy. Therefore, identification of prognostic factors that can select patients who will benefit or who will not benefit is of utmost importance.

Before the era of immunotherapy, Elson et al5 established the first prognostic model in mRCC. In the course of the subsequent nearly two decades of IL-2-based immunotherapy, a small number of other prognostic models have been proposed.11-17 However, with the exception of the blood neutrophil count and signs of inflammation,13,15,16 only classical clinical prognostic parameters without immune features have been identified as independent prognostic factors,18 despite IL-2 based immunotherapy being a targeted therapy requiring immune cells for tumor lysis.

We have assessed intratumoral immune infiltrates in consecutive patients receiving IL-2-based immunotherapy.19-22 In this analysis, we have examined the impact of immunologic prognostic factors in combination with established clinical prognostic factors with the aim of identifying patients most likely to benefit from immunotherapy.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Patients and Treatments
A total of 120 consecutive single-institution patients with histologically confirmed mRCC were treated on an outpatient basis with IL-2 based immunotherapy from February 1999 to August 2002. The local ethics committee and the Danish Medical Agency approved the studies. Twenty-six patients were enrolled in a multicenter prospective phase II trial of IL-2, IFN-{alpha}, and histamine dihydrochloride.23 An additional 23 patients received the same IL-2/IFN-{alpha} schedule, but without histamine.20 Sixty-three patients were enrolled in a randomized phase II trial of IL-2 with or without histamine dihydrochloride,24 and the final eight patients were treated with the same IL-2 schedule, but without histamine. The IL-2 doses used can be considered to be of low and intermediate levels in the IFN-containing and the non-IFN containing regimens, respectively. Main inclusion criteria were bidimensionally measurable, histologically confirmed mRCC; progressive disease; age 18 to 75 years; Karnofsky performance status (PS) ≥ 70; and no brain metastases. Prestudy, all patients had brain, chest, abdominal, and pelvic computed tomography scans plus a bone scan. Bone lesions on bone scans were verified by computed tomography scans or x-ray. Objective response was defined according to standard WHO criteria.25

Collection of Samples
Core needle biopsies (18G cutting needle) were collected by standard ultrasound-guided procedures at baseline. The local ethics committee approved the biopsy study. Of the 120 consecutive patients, written informed consent and baseline biopsies were obtained from 101 patients. Four patients did not complete one course of therapy because of toxicity and were not assessable for objective response. Two patients had only fine needle biopsies performed. These six patients were excluded from the tumor analysis. Thus, 95 patients had assessable tumor biopsies. Three patients had biopsies containing necrotic tissue only, six patients had biopsies with insufficient tumor tissue, and in one patient intratumoral CD57+ lymphocytes could not be assessed as the neoplastic cells also stained positively for this marker. Thus at baseline, 85 patients had a complete set of tumor immunologic data.

Biopsies were performed from accessible tumor locations: kidney (n = 68); abdominal soft tissue (n = 16); liver (n = 17); pleura/chest wall (n = 10); lymph node (n = 9); muscle (n = 5); kidney bed (n = 4); subcutis (n = 5); and lung (n = 3). Some patients had biopsies from more than one location. No complete responding patients had a baseline tumor accessible for core needle biopsies.

Immunohistochemistry
Standard procedures were used for immunohistochemistry as previously described.19,20 Paraffin sections were stained with monoclonal antibodies from: CD8 (M7103 1:100) and CD20 (M0755 1:500; Dako, Glostrup); CD4 (NCL-CD4-1F6 1:50) and CD56 (NCL-CD56-1B6 1:40; NovoCastra, Newcastle, United Kingdom); MACRO (NCL-MACRO 1:80; NovaCastra); and CD57 (33251A 1:500) and CD66b (Neutrophils, 33731A 1:100; BD Pharmingen, San Diego, CA). Primary antibodies were detected using the Envision-peroxidase system (K4000, Dako). All staining was performed in a TechMate automatic immunohistochemistry staining machine (Dako).

Immunohistochemical Evaluation
Intratumoral immune cells were counted by an objective and reproducible stereologic method.26 A computer-generated unbiased counting frame was used to perform measurements. The first field of vision was chosen at random, after which the computer systematically sampled the subsequent fields of vision within the entire tumor biopsy. Necrosis, artifacts, and fibrous areas were omitted. Using a 40 x objective, a total number of 40 fields (4,951 µm2 each) were counted, if the size of the tumor biopsy allowed for it. Only cells showing specific staining, a visible nucleus, and location within the counting frame were counted as positive. The mean number of cells/mm2 tumor tissue was assessed for each patient. Staining was analyzed blinded by one observer. Selected sections were counted blinded by a second observer and a high level of reproducibility was demonstrated.19

Blood Samples
Differential blood cell counts were determined by standard Coulter counter technique (Coulter STKS; Beckman Coulter, Fullerton, CA).

Statistics
Overall survival time was measured from the first day of treatment until death or last follow-up evaluation. Survival distributions were estimated using the Kaplan-Meier method and the relationship between survival and each parameter was analyzed with the log-rank test. Multivariate analyses were performed using Cox proportional hazards models. Included variables were time interval between diagnosis of renal tumor and occurrence of metastases (≤ 12 months v > 12 months), Karnofsky PS (70/80 v 90/100), primary kidney tumor in situ (yes v no), lung metastases (yes v no), lymph node metastases (yes v no), liver metastases (yes v no), bone metastasis (yes v no), number of disease sites (> 3 v ≤ 3) and hemoglobin (< normal v normal). Three variables had predefined cutoff levels: lactate dehydrogenase (> 1.5 upper limit of normal v normal),14 the number of circulating neutrophils (> 6.0 x 109/L v ≤ 6.0),13 and the number of intratumoral CD57+ natural killer (NK) cells (< 50 cells/mm2 tumor tissue v ≥ 50).19 For all other variables, dichotomy was done at the median value: circulating lymphocytes (1.59 x 109/L), circulating monocytes (0.7 x 109/L), intratumoral neutrophils (0 cells/mm2), CD4+ cells (27.6 cells/mm2), CD8+ cells (91 cells/mm2), CD20+ cells (5 cells/mm2) and CD56+ cells (0 cells/mm2). For simplicity, high numbers of cells indicates cell numbers higher than the cutoff levels; low numbers of cells indicates cell numbers lower than the cutoff levels. The survival data were updated April 2005. Statistical analyses were performed using SPSS version 11.0 (SPSS Inc, Chicago, IL) statistical software.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Patient Characteristics
The distribution of pretreatment characteristics for the 120 patients is presented in Table 1. Median age was 57 years (range, 19 to 74 years), and 71% were male. Half of the patients had their primary kidney tumor in situ. About two thirds of patients had ≥ 3 disease sites and 3% had lung metastases only. Based on an intention-to-treat analysis, the overall response rate was 13%, which included six complete responses and nine partial responses; 35% had stable disease and 47% had disease progression. The median overall survival time was 15.1 months (95% CI, 11.5 to 18.7 months), Figure 1. At the time of analysis, 21 of 120 patients (18%) were alive and 14 of 85 patients with a full tumor immunologic data set (16%) were alive. The median follow-up time was 57 months (range, 32 to 73 months). The estimated 1-year, 2-year, 3-year and 5-year survival rates were 60%, 31%, 21%, and 16%, respectively (Fig 1).


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  		Table 1. Baseline Patient Characteristics (N = 120)

 

Figure 1
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  		Fig 1. Overall survival of 120 patients with metastatic renal cell carcinoma receiving interleukin 2-based immunotherapy. Median survival, 15.1 months. Estimated 5-year survival, 16%. Vertical and horizontal axes, the survival probability and months of follow-up, respectively. Tick marks (|) indicate last date of follow-up.

 
Univariate Survival Analysis of Clinical Variables
Clinical factors significantly associated with short survival time (Table 2) were time interval between diagnosis of renal tumor and occurrence of metastases (< 12 months), Karnofsky PS (70/80), LDH (>1.5 upper limit of normal), hemoglobin (< normal), lymph node metastases, bone metastases, and number of disease sites (> 3). Presence of the primary kidney in situ, local recurrence, lung metastases, liver metastases, and histologic subtype had no significant prognostic impact by univariate analyses.


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  		Table 2. Pretreatment Clinical Factors in an Univariate Analyses (N = 120)

 
Multivariate Survival Analysis of Clinical Variables
Eight clinical factors demonstrating an effect on overall survival with a P value of < .10 were included in the multivariate analysis. Five prognostic clinical factors were identified to be of independent significance. Thus, increased LDH, lymph node metastases, low hemoglobin, low Karnofsky PS, and bone metastases were all associated with short survival (Table 3).


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  		Table 3. Multivariate Analysis of Clinical Risk Factors* (N = 120)

 
Univariate Survival Analysis of Immunologic Variables
Pretreatment immune parameters significantly associated with short survival time (Table 4) were high number of circulating neutrophils, high number of circulating monocytes, low number of circulating lymphocytes, low number of intratumoral CD57+ NK cells, and the presence of intratumoral neutrophils. Absence of intratumoral CD56+ NK cells was also associated with short survival time, although this was only of borderline significance (P = .07). Intratumoral macrophages and intratumoral CD4+, CD8+, CD20+ lymphocyte subsets had no significant prognostic impact by univariate analyses.


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  		Table 4. Pretreatment Immunologic Factors in Univariate Analyses (N = 120)

 
Multivariate Survival Analysis of Clinical and Immunologic Variables
As the objective of this study was to examine the impact of immunologic prognostic factors in combination with established clinical prognostic factors, a new multivariate analysis was performed, entering the eight clinical variables together with the six immunologic variables (blood neutrophils, monocytes, lymphocytes, intratumoral CD56+ cells, intratumoral CD57+ cells, and intratumoral neutrophils). The modeling was based on 85 patients with a complete set of data. The independent clinical variables (ie, LDH, lymph node metastases, hemoglobin, Karnofsky PS and bone metastases) were again identified as independent prognostic factors (Table 5). Karnofsky PS hazard ratio remained at the same level, although it was only of borderline significance. Furthermore, three immunologic variables were identified to be significant independent risk factors of short survival (ie, a low intratumoral CD57+ NK cell count, a high blood neutrophil count, and the presence of intratumoral neutrophils; Table 5).


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  		Table 5. Multivariate Analysis of Clinical and Immunologic Risk Factors* (N = 85)

 
Extension of a Clinical Prognostic Model With Immune Parameters
The survival distributions for patients with zero to five independent clinical risk factors are shown in Figure 2. Each of the 120 patients was assigned to one of two clinical risk groups: those with zero, one, or two clinical risk factors (group A) and those with three to five clinical risk factors (group B; Fig 3A). For the 89 patients in group A, the median survival was 19 months with an estimated 5-year survival rate of 21%. For the 31 patients in group B, median survival was 7 months and all patients died within 2 years.


Figure 2
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  		Fig 2. Clinical factors only. Overall survival for patients stratified for zero to five clinical risk factors. Vertical and horizontal axes, the survival probability and months of follow-up, respectively. Tick marks (|) indicate last date of follow-up.

 

Figure 3
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  		Fig 3. Prognostic models based on clinical factors (A) supplemented with immunologic factors (B) in patients with metastatic renal cell carcinoma receiving interleukin 2-based immunotherapy.

 
The 89 patients in group A (0 to 2 clinical risk factors) were then analyzed by adding the three independent immunologic risk factors (ie, a low intratumoral CD57+ NK cell count, a high blood neutrophil count, and the presence of intratumoral neutrophils; Fig 3B). In patients with no immunologic risk factors, the median survival was not reached and the estimated 5-year survival rate was 60%. In patients with one immunologic risk factor, the median survival was 19 months and the estimated 5-year survival rate was 25%. In contrast, patients with two to three immunologic risk factors had a median survival of 13 months and all patients died within 3 years (Fig 3B).

Extension of the Memorial Sloan-Kettering Cancer Center Prognostic Model With Immune Parameters
We applied the three immunologic risk factors to the Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY) prognostic model,14 instead of using the clinical variables from our own patient material, with almost identical results (Fig 4A and Fig 4B). According to the model defined by Motzer et al,14 19 patients (16%), 66 patients (55%), and 35 patients (29%) were in the favorable, the intermediate, and the poor prognostic groups, respectively. Median survival times for these groups were 24, 18, and 7 months, respectively (Fig 4A). These figures are similar to those reported by Motzer et al.14 The 85 patients in the MSKCC favorable and intermediate prognostic group were subsequently analyzed by adding the three independent immunologic risk factors (Fig 4B). In patients with no immunologic risk factor, the median survival was not reached and the estimated 5-year survival rate was 60%. In patients with one immunologic risk factor, the median survival was 19 months and the estimated 5-year survival rate was 21%. In contrast, patients with two to three immunologic risk factors had a median survival of 13 months and all patients died within 3 years (Fig 4B).


Figure 4
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  		Fig 4. Prognostic models based on Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY)14 clinical factors (A) supplemented with immunologic factors (B) in patients with metastatic renal cell carcinoma receiving IL-2 based immunotherapy. Fav, favorable risk; Int, intermediate risk.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
To our knowledge, this is the first study to identify tumor immunology-related factors of independent prognostic significance for the outcome of IL-2-based immunotherapy in mRCC. We found that immunologic variables derived from blood and tumor analyses significantly added to prognostic models based on clinical risk factors only. Clearly, the three independent immunologic risk factors had good discriminatory power as supplemental risk factors, identifying subgroups with estimated 5-year survival rates of 60%, 25%, and 0%, respectively. These findings were also apparent in the extended MSKCC prognostic model. Thus, investigations into new prognostic models based on clinical factors supplemented with immunologic factors are encouraged. However, the sample size is small and our results need to be confirmed in a larger group of patients receiving IL-2.

The influence of cytokine treatment in prolonging survival for patients with mRCC is controversial,27 and therefore, it is unclear whether the observed survival differences in the present study are due to the treatment or due to the disease by itself. In two large retrospective studies, patients receiving cytokine therapy experienced longer survival compared with patients receiving chemotherapy.12,28 In both studies, however, survival for patients with poor-risk features was short with a median survival time of less than 6 months, regardless of type of treatment.12,28 Thus, poor-risk patients do not derive therapeutic benefit from cytokine treatment. Two randomized phase III trials have demonstrated a statistically significant but modest survival benefit of IFN-{alpha} in mRCC.29,30 A survival benefit of IL-2 has not been demonstrated in randomized studies compared with a group of patients not receiving immunotherapy.27,31,32 However, 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 treated with IL-2.7-10 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.33 The important issue is then to identify this subgroup of patients.

It is unclear why only a small proportion of patients with mRCC benefit from cytokine treatment and the majority remain refractory. However, the status of the immune system may exert a fundamental role in the response to immunotherapy34 as IL-2 based immunotherapy is a targeted therapy requiring immune cells for tumor lysis.20 Identification of immune parameters correlating with the outcome of IL-2 based immunotherapy allows the establishment of a reliable set of prognostic factors in patients with mRCC. This makes it possible to target a subpopulation of patients to receive immunotherapy while referring other patients to alternative investigational modalities. Table 6 outlines available published prognostic factors of IL-2 based immunotherapy in mRCC including the data from this study. As seen in Table 6, presence of intratumoral neutrophils and low numbers of intratumoral CD57+ NK cells are new independent prognostic markers of poor survival, whereas the other variables found in this study have been reported by others. These variables may, thus, be considered as validated independent prognostic factors.


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  		Table 6. Prognostic Factors In Prognostic Models of IL-2 based Immunotherapy in mRCC

 
Patients with several poor prognostic features, based on clinical risk factors only or clinical risk factors supplemented with immunologic risk factors, should not receive IL-2-based immunotherapy. Almost all patients in the poor prognostic group died within 3 years, the benefit of cytokine treatment for these patients being negligible, with survival rates similar to untreated patients or to patients receiving chemotherapy.4-6 This is in line with the conclusion in a recent Cochrane review,27 that for the large majority of patients with mRCC, the disease parameters are more powerful determinants of outcome than any treatment modality. In contrast, patients in the good prognostic groups had 5-year survival rates of 60% and 25%.

The identification of neutrophils in blood and in tumor tissue as independent poor prognostic factors supports the oxidative stress hypothesis formulated by Hellstrand.35 The CD57 molecule is present on a subpopulation of the total NK cells.36,37 A high number of tumor-infiltrated CD57+ NK cells is associated with a favorable outcome in patients with colorectal,38,39 gastric,40 and lung cancers.41,42 Our study suggests that a delicate balance between members of the innate immune system (ie, neutrophils and NK cells) plays an important role for the outcome of IL-2-based immunotherapy. However, it should be emphasized that a cause and effect relationship between these immune parameters and the mechanisms of IL-2 has not been proven.

An international kidney cancer working group has been established to identify independent, validated predictors of survival and ultimately to develop a single validated prognostic model.43 The variables examined are primarily clinical and biochemical. However, investigations into new prognostic factors based on tumor-immunologic factors or tumor-biologic factors are of high priority. The International Society of Biologic Therapy of Cancer recently recommended investigators to coordinate with academic pathology groups in order to make assessment of intratumoral immune cells (T, NK, dendritic cells, B, neutrophils, eosinophils, and mast cells) in tumor biopsies standard of practice.44 Our results support this recommendation and should prompt additional research focused in particular on tumor tissue derived prognostic factors. Thus, as sample size is small, validation of our results in a larger number of IL-2-treated patients is warranted. We recognize that the use of tumor biopsy analyses may be cumbersome, as assessment of intratumoral immune cells requires a considerable workload.

In conclusion, this study points to five clinical and three supplemental immunologic independent prognostic factors of survival in patients with mRCC receiving IL-2.


   Authors’ Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
Author Contributions
 REFERENCES
 
The authors indicated no potential conflicts of interest.


   Author Contributions
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
REFERENCES
 

Conception and design: Frede Donskov, Hans von der Maase

Administrative support: Hans von der Maase

Provision of study materials or patients: Hans von der Maase

Collection and assembly of data: Frede Donskov, Hans von der Maase

Data analysis and interpretation: Frede Donskov, Hans von der Maase

Manuscript writing: Frede Donskov, Hans von der Maase

Final approval of manuscript: Frede Donskov, Hans von der Maase

 


   NOTES
 
Supported by the Danish Research Council, the foundations of Max and Inger Woerzner, Gerda and Aage Haench, Kristian Kjaer, Beckett, Preben and Anna Simonsen, Agnes Niebuhr Andersson, Johannes Fogh-Nielsen, Agnes and Poul Friis, Erland Richard Frederiksen, Hans and Nora Burchard, and Aarhus Radium Center Research Foundation.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
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Submitted August 19, 2005; accepted February 21, 2006.


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