Japanese Journal of Clinical Oncology 31:13-17 (2001)
© 2001 Foundation for Promotion of Cancer Research
Serum Immunosuppressive Acidic Protein as a Potent Prognostic Factor for Patients with Metastatic Renal Cell Carcinoma
1Department of Urology, Chiba University School of Medicine and 2Department of Urology, Asahi General Hospital, 3Department of Urology, Teikyo University School of Medicine, Ichihara Hospital, Chiba, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Estimation of survival probability of individual patients with metastatic renal cell carcinoma was difficult owing to diverse prognostic factors. We analyzed serum immunosuppressive acidic protein (IAP) levels and the cutoff value, then tested its validity for assessing patients’ prognoses.
Methods: Serum IAP was measured longitudinally in 84 patients with metastatic disease. Before therapy, cutoff levels of IAP were tested every 20 µg/ml between 600 and 1200 µg/ml. The prognostic importance of IAP and its cutoff level was estimated.
Results: The cutoff level of IAP was set at 800 µg/ml for 40 patients who had metastatic disease with the primary tumor in situ and for 44 patients with recurrent disease. IAP was found to be a significant prognostic factor for both patient groups.
Conclusions: Serum IAP is an important prognostic factor for patients with metastatic renal cell carcinoma. Stratification of patients according to prognosis is feasible using the cutoff level.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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By the time patients are diagnosed with renal cell carcinoma, in more than half of the patients the disease has already reached a metastatic stage or has the potential to metastasize. The survival of patients with metastatic renal cell carcinoma is reportedly affected by various factors including performance status (1–4), number of metastatic sites (2), a long disease-free interval (5), history of nephrectomy (1), type of organs involved (1,4,6) and the malignant potential of the primary tumor (1,6). However, estimation of survival probability in each patient is difficult because of diverse prognostic factors. Monitoring disease status using a serum tumor marker would be beneficial for the assessment of individual patients’ prognoses, which, in turn, may help determining the therapeutic strategy through their clinical courses.
Immunosuppressive acidic protein (IAP), a type of 
1-acid glycoprotein (7), reportedly correlates with tumor size and stage of disease (8,9) in renal cell carcinoma. Moreover, IAP can be used to detect lymph node metastasis and distant metastasis (10,11). This is considered to be useful in monitoring the clinical course of patients who are in a metastatic stage of the disease (12). The present study was undertaken to estimate prognoses in patients with metastatic disease by analyzing levels of serum IAP and determining the cutoff level.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We analyzed serum IAP levels in 84 of 98 patients treated between March 1988 and July 1997 at our institutions. Serum IAP levels were measured every 3 months at routine checkups. Among the 84 patients, 40 had concomitant disease at the time of diagnosis of the primary tumor and 44 experienced recurrences after nephrectomy. Of the patients with concomitant disease, five underwent nephrectomy followed by interferon therapy and resection of metastatic lesions. Twenty patients underwent nephrectomy and interferon therapy. Eleven patients underwent interferon therapy only. Four patients underwent nephrectomy only. In patients who had recurrent disease, four underwent resection of metastatic lesion followed by interferon therapy and 40 underwent interferon therapy only. Patients receiving interferon therapy received human lymphoblastoid interferon, recombinant interferon-
at a dose of 3–6 MU or recombinant interferon-
at a dose of 1–3 MJRU. Serum IAP levels were determined by nephelometric immunoassay (SRL, Tokyo). Survival time was counted from the date of nephrectomy for the patients who had concomitant metastasis with primary tumor in situ and from the date of interferon therapy or resection of the metastatic site for those who developed recurrent disease after nephrectomy and for those who had not received nephrectomy. The patients were followed up for 1–87 months (median, 12 months).
Survival rates were calculated using the Kaplan–Meier procedure. The log-rank test was used to compute differences in survival time between the two groups. The Cox proportional hazards model was used to determine the relative importance of prognostic factors to overall survival. All statistical calculations were performed using JMP version 3 software (SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Characteristics such as male to female ratio, age, histopathology of the primary lesion and the site of metastatic organs are listed in Table 1. Serum IAP levels did not show significant relationships among age, gender, site and number of metastatic organs and histopathology. First, we tested pretreatment IAP levels every 20 µg/ml between 600 and 1200 µg/ml to obtain the cutoff level of IAP in patients with concomitant disease with primary tumor in situ and recurrent disease after nephrectomy. Differences in the survival time of patients stratified according to tested levels of IAP are listed in Table 2. The difference in survival time became maximum when the IAP cutoff level was set between 740 and 820 µg/ml for those who had concomitant disease with primary tumor in situ and between 800 and 820 µg/ml for those with recurrent disease. Thus we set 800 µg/ml as a cutoff level of IAP in patients with metastatic renal cell carcinoma. Fig. 1 shows the survival curves of patients with concomitant disease with primary tumor in situ and those with recurrent disease according to this cutoff level. In patients with concomitant disease with the primary tumor in situ, 1- and 3-year survival rates were 62 and 25% for those whose IAP levels were below 800 µg/ml and 27 and 8% for those whose IAP levels were over 801 µg/ml. In patients with recurrent disease, 1- and 3-year survival rates were 77 and 42% for those whose IAP levels were below 800 µg/ml and 40 and 0% for those whose IAP levels were over 801 µg/ml. A significant difference was observed between the survival times of patients divided according to the cutoff level of IAP in patients with the primary tumor in situ (p = 0.016) and in patients with recurrent disease (p < 0.0001).
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The significance of prognostic factors such as age, gender, size of primary tumor, site and number of metastatic organs, ratio of spindle cell carcinoma to other type of carcinoma and serum IAP level before therapy was tested by univariate analysis (Table 3). Univariate analysis revealed that gender, histopathology, number of metastatic organs and IAP levels were important prognostic factors for patients with concomitant disease with primary tumor in situ and histopathology and IAP levels were significant prognostic factors for those with recurrent disease. These factors were then tested by the Cox proportional hazards model (Table 4). Only the serum IAP level was found to be a significant prognostic factor for both patient groups.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Recent reports have indicated that some therapeutic modalities, such as cytoreductive surgery (5,13) and immunotherapy using interferon-
(4,14) and interleukin-2 (15), have achieved success in improving the survival rates in a limited number of patients with metastatic renal cell carcinoma. Thus, stratification of patients according to their prognosis is intended not only to assess the efficacy of therapeutic modalities but also to determine a therapeutic strategy for each patient. In this study, we used IAP as a tumor-related marker of metastatic renal cell carcinoma and found that IAP levels had prognostic value for patients with this disease status. Further, we obtained a cutoff level of IAP of 800 µg/ml for patients with concomitant disease with the primary tumor in situ and for those with recurrent disease, which was adequate for stratifying patients into fair and poor prognostic groups. Previously, Masuda et al. reported a 600 µg/ml cutoff level of serum IAP in renal cell carcinoma for the detection of lymph node and distant metastasis (16). In contrast, the present study set the cutoff level as a prognostic indicator for patients with metastatic disease. The difference in the patient population and the purpose of setting the cutoff level could explain the difference between our results and those of Masuda et al. Cutoff levels of serum IAP have been determined for other types of cancer. The cutoff level for ovarian cancer is 1100 µg/ml (17) and for gastric cancer 580 µg/ml (18). Although different types of cancer have different biological characteristics, which could account for the differences in cutoff levels, IAP seems to have prognostic value for patients with various types of cancer.
Although neither the function of serum IAP nor the mechanisms involved in changing its level has been fully elucidated, recent reports have stated that IAP showed a reciprocal relationship with serum soluble interleukin-1 receptor antagonist to interleukin-6 ratio (19) in colorectal cancer and showed a positive relationship with serum soluble interleukin-2 receptor and soluble CD30 in lung cancer (20). Thus, an elevated serum level of IAP is associated with the inflammatory reaction in a tumor-bearing host and this may correspond to the increase in serum interleukin-6 or C-reactive protein level in patients with advanced renal cell carcinoma (21). The observation of elevation of serum IAP levels with a relationship with clinical stage of disease and diameter of the primary tumor (9) corresponds to the systemic tumor burden. Elevation of IAP above the cutoff level might indicate that the burden was becoming a serious threat to the patient’s life.
A recent report indicated that interleukin-6 could be regarded as a cumulative prognostic parameter for renal cell carcinoma (22). Serum C-reactive protein, which shows a positive relationship with interleukin-6 (21), is a prognostic factor for patients with metastatic renal cell carcinoma after cytoreductive surgery (13). Since IAP is a type of 1-acid glycoprotein, which is one of the acute-phase proteins, its elevation is considered to be associated with CRP and interleukin-6 (data not shown). However, interleukin-6 and CRP are not suitable for calculation of the cutoff levels, because of inadequate sensitivity with interleukin-6 (23) and CRP (13). We therefore used IAP as a surrogate of interleukin-6 and CRP.
Interleukin-6 has immunosuppressive effects and has been reported to impair natural killer function in ductal breast carcinoma cells (24). IAP also has its own immunosuppressive character in that it induced unresponsiveness of spleen cells to concanavalin A (25) and modulates the expression of CD4 antigen on the surface of lymphocytes (26). Elevation of IAP in the sera of patients with metastatic renal cell carcinoma could be attributed to the advanced immunosuppressive status of the patients. Increased tumor burden and immunosuppressive status are related to their poor prognosis.
In conclusion, our results indicate that serum IAP is a significant prognostic factor for patients with metastatic renal cell carcinoma. Assessment of their survival probability is possible using the cutoff levels.
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FOOTNOTES |
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+ For reprints and all correspondence: Tatsuo Igarashi, Department of Urology, 1–8–1, Inohana, Chuo-ku, Chiba 260-8670, Japan E-mail: tigaras@med.m.chiba-u.ac.jp
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Received July 27, 2000; accepted October 27, 2000.
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