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Annals of Oncology Advance Access originally published online on October 23, 2006
Annals of Oncology 2007 18(2):249-255; doi:10.1093/annonc/mdl371
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© 2006 European Society for Medical Oncology

urogenital tumors

Prognostic factors associated with long-term survival in previously untreated metastatic renal cell carcinoma

TK Choueiri1,*, BI Rini1, JA Garcia1, RC Baz1, RM Abou-Jawde1, SG Thakkar1, P Elson1, TM Mekhail1, M Zhou2 and RM Bukowski1

1 Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Center
2 Department of Pathology, Cleveland Clinic Foundation, Cleveland, USA

* Correspondence to: Dr T. K. Choueiri, Cleveland Clinic Taussig Cancer Center, 9500, Euclid Avenue, Desk R-35, Cleveland, OH 44195, USA. Tel: +1-216-444-2200; Fax: +1-216-444-9464; E-mail: choueit{at}ccf.org


   Abstract
Top
 Abstract
background
 patients and methods
 results
 discussion
 References
 
Purpose: To identify prognostic factors (PF) for long-term survival in metastatic renal cell carcinoma (RCC) patients.

Methods: We retrospectively reviewed a metastatic RCC database at the Cleveland Clinic Foundation consisting of 358 previously untreated patients who were enrolled in institutional review board-approved clinical trials of immunotherapy and/or chemotherapy at our institution from 1987 to 2002. In order to identify patient characteristics associated with long-term survival, we compared 226 ‘short-term’ survivors [defined as overall survival (OS) <2 years] with 31 ‘long-term’ survivors (OS ≥5 years).

Results: Using logistic regression models, four adverse PF were identified as independent predictors of long-term survival: hemoglobin less than the lower limit of normal, greater than two metastatic sites, involved kidney (left), and Eastern Cooperative Oncology Group (ECOG) performance status (PS). Using the number of poor prognostic features present, three distinct risk groups could be identified. Patients with 0 or 1 adverse prognostic feature present had an observed likelihood of long-term survival of 32% (21/66) compared with 9% (8/91) for patients with two adverse features present and only 1% (1/93) for patients with more than two adverse features.

Conclusions: Independent predictors of long-term survival in previously untreated metastatic RCC include baseline hemoglobin level, number of involved sites, involved kidney, and ECOG PS. Incorporation of these factors into a simple prognostic scoring system enables three distinct groups of patients to be identified.

Key words: Five-year survivors, metastatic renal cell carcinoma, prognostic factors


   background
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 Abstract
 background
patients and methods
 results
 discussion
 References
 
Renal cell carcinoma (RCC) is the most common malignancy of the kidney. It accounts for ~3% of adult tumors [1]. In the year 2006, there will be more than 36 000 cases in the United States with ~12 600 deaths [1]. In all, 30% of newly diagnosed patients with RCC present with metastatic disease [2]. Despite major advances in cancer therapy, treatment options continue to be disappointing with 10% overall 5-year survival [3]. Chemotherapy [4], radiation therapy [5], and hormonal therapy [6] demonstrated a very little therapeutic advantage in this setting. Cytokine therapy including either interleukin 2 (IL-2) and/or interferon-{alpha} (IFN-{alpha}) have been utilized in RCC patients [7]. Overall response rates for metastatic RCC patients treated with IL-2 are 15%–20% similar to those reported for IFN-{alpha} [7, 8]. Since treatment with cytokines is associated with significant side effects [9] and response rates are limited, investigational approaches are commonly utilized in patients with metastatic RCC.

A number of statistical models have been proposed to identify predictors of overall survival (OS) in patients with metastatic RCC [10–17, 18–23]. Median survival for these patients is generally short, 12–18 months, and therefore these models implicitly focus on relatively short-term survival. There is, however, a small proportion of patients, ~10%, who survive beyond 5 years. Little attention has been paid to these ‘long-term’ survivors or to identifying factors that might be predictive of long-term survival. The purpose of the present study was to examine a database of patients with metastatic RCC treated on clinical trials at the Cleveland Clinic Foundation (CCF) to identify predictors of long-term survival and to determine whether these predictors are the same as those previously identified.


   patients and methods
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 Abstract
 background
 patients and methods
results
 discussion
 References
 
patients
Our metastatic RCC database consists of 358 previously untreated patients entered into institutional review board (IRB)-approved clinical trials at CCF from January 1987 to April 2002. The trials were mainly phase I and II studies of IFN-{alpha}, and/or IL-2-based therapies with or without chemotherapy [23] (primarily 5-fluorouracil and capecitabine [24, 25]).

Inclusion criteria were relatively uniform across trials and included histologic confirmation of RCC; clinical or biopsy evidence of metastatic disease; bidimensionally measurable disease; absent or stable central nervous system metastasis; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 and adequate hematological, renal, and hepatic function; and no prior history of cancer (except basal cell carcinoma or carcinoma in situ of the cervix).

At the time of entry into a clinical trial, patients had detailed history and physical examination, complete and differential blood count, creatinine concentration, total bilirubin concentration, calcium, albumin, blood urea nitrogen, lactate dehydrogenase, and alkaline phosphatase. Also, pre-treatment tumor status was evaluated with computed tomography scans of the brain, chest, abdomen, and pelvis. Data collected included standard pre-treatment and disease characteristics, baseline biochemical parameters, first date of treatment, best response to treatment, date of progression, and date of death or last follow-up. Survival was measured from clinical trial enrollment until death or last follow-up.

pathology review
The pathologic data were retrieved from an IRB-approved database and include histological subtype, Fuhrman nuclear grade, tumor size, status of perinephric/renal sinus invasion, vascular invasion, and surgical margin status. The histological classification is based on 2004 World Health Organization of Renal Neoplasms. Pathology slides were reviewed on all patients by pathologists of a single institution (Cleveland Clinic).

statistical analysis
In order to assess prognostic factors (PF) for long-term survival, we arbitrarily defined a cut-off of survival of <2 years from entry on to a clinical trial as representative of ‘typical’ survival and a cut-off of survival >5 years from study entry as representing long-term survival and focused on comparisons of these two groups. The relationship between survival and the factors examined was analyzed using Fisher's exact test, the Wilcoxon rank sum test, and logistic regression. Factors that are by nature categorical, such as gender and PS were individually analyzed using Fisher's exact test, whereas biochemical parameters and other factors that are measured on a continuum, such as age and time from diagnosis to study entry, were analyzed using the Wilcoxon rank sum test. Categorical forms of these variables were also examined using Fisher's exact test. The cut points used for the categorizations were based on cut-offs previously described in the literature and/or recursive partitioning. Logistic regression models were used to simultaneously assess multiple factors. A significance level of 0.05 was used as the criterion for determining variable entry and removal from the models. Both the uncoded and the categorical form of continuous factors were considered in this analysis. Patients with bilateral kidney involvement were excluded from this analysis. The resulting model was validated internally using a bootstrap procedure in which samples of size n = 257 were randomly generated (with replacement) from the original study population, also of size n = 257, and analyzed as described above. One thousand such samples were generated and analyzed, and the frequency of each factor's inclusion in these models was calculated. Factors present in ≥60% of the models were considered to be of prognostic significance and were used to build a final ‘bootstrap-based’ model. This model and the original model were compared.

All tests of statistical significance were two-sided. All data analyses were conducted using SAS version 8 (Statistical Analysis Software, Raleigh, NC).


   results
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 Abstract
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 patients and methods
 results
discussion
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Of the 358 patients initially considered, 257 (72%) were included in the analysis; 31 patients (9%) had survival times >5 years (long-term survivors) and 226 patients (63%) had survival times <2 years (2-year survivors). One hundred patients were excluded because of follow-up <2 years or survival/follow-up between 2 and 5 years. One patient was excluded because histology revealed a neuroendocrine tumor.

Overall, 76% of the patients analyzed were male, the median age at study entry was 56 (range 24–76), 38% were PS 0, 80% had prior nephrectomy, and 18% had received prior radiotherapy. The lungs were the most common sites of metastatic disease (73%); 33% of patients had more than two sites of disease involvement at on-study. The median tumor size was 8.8 cm for right-side tumors and 9.0 cm for the left-side tumors (P = 0.92). There were no statistical differences between right- and left-side tumors regarding all clinical variables examined except for tumor grades: 64/89 (72%) of ‘short-’ survival patients who had right-sided tumors and grade information had high-grade tumors (grades III and IV) as did 7/12 (58%) of patients of long-term survivors (P = 0.02).

Grade was available for 208 patients (81%). Twenty percentage of patients who survived <2 years had Grade I/II tumors compared with 53% of long-term survivors (P = 0.003). There was no clear evidence of effect related to the type of treatment received: 183/219 (84%) of patients who died within 2 years of study entry and 21/23 (91%) of long-term survivors were treated with IL-2 and/or IFN-based therapy (P = 0.55). Regarding response to treatment, 7/23 (30%) long-term survivors had a partial response or complete response compared with 11/195 (6%) 2-year survivors (P < 0.001).

Table 1 gives a detailed listing of the clinical and pathological characteristics of the 31 long-term survivors.


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  		Table 1. Characteristics of long-term survivors

 
Table 2 lists the potential PF examined and summarizes the results of the univariable analyses.


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  		Table 2. Univariable analyses

 
As can be seen from Table 2, a large number of factors appear to be associated with long-term survival. These include, ECOG PS at study entry, time from diagnosis to entry on-study, nuclear grade, histology, prior nephrectomy, prior radiotherapy, the location and number of metastatic disease sites at on-study, baseline serum albumin, serum calcium and corrected calcium, hemoglobin, and the kidney involved.

Because a large number of factors appear to be related to survival, logistic regression models were used to determine which factors are independent predictors of long-term survival. All factors listed in Table 2, with the exception of prior nephrectomy, histology, nuclear grade, and neutrophil count were considered in these models. Prior nephrectomy was not included in this analysis because it is highly associated with time from diagnosis to study entry (P < 0.001). In addition, cytoreductive nephrectomy is considered standard of care, and most recent trials require prior nephrectomy before trial entry. Histology, nuclear grade, and neutrophil count were not included because of the large number of 2- and/or 5-year survivors for whom data were missing and the limited number of non-clear-cell histologies.

The results of this analysis are summarized in Table 3. Although a large number of factors are individually associated with long-term survival, only four were found to be independent predictors of prognosis on multivariate analysis. Listing the less favorable feature first, the factors identified were, hemoglobin [≤LLN (lower limit of normal) versus >LLN], the number of involved sites (greater than two versus lesser than or equal to two), the involved kidney (left versus right sided), and ECOG PS (1 versus 0). Based on the magnitude of the parameter estimates and the fact that their variances were similar, it is convenient to combine these factors into a simple scoring system. Three distinct prognostic groups can be identified based on number of adverse risk factors (Table 4). Patients with no or one poor PF present had an observed 32% (21/66) likelihood of long-term survival, compared with 9% (8/91) for patients with two PF and only 1% (1/93) for patients three or more poor PF.


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  		Table 3. Logistic regression model for long-term and short-term survivorsa

 

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  		Table 4. Risk groups stratifications and probability of long-term survivala

 
During the bootstrap validation step, hemoglobin, the involved kidney, the number of metastatic sites, and ECOG PS were the only factors found to be included in 60% or more of the generated models, thus confirming their importance (hemoglobin, 95%; involved kidney, 81%; number of involved sites, 86%; and ECOG PS, 62%).

A secondary analysis was undertaken where we excluded kidney site. Hemoglobin and the number of metastatic sites remained as important factors but ECOG PS was replaced by time from diagnosis to study entry. A comparison of both models (with and without kidney site), however, shows a superiority for the model that takes kidney site into consideration (area under receptor operating curve of 83% versus 79%).


   discussion
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 Abstract
 background
 patients and methods
 results
 discussion
References
 
Most studies of PF for survival in patients with metastatic RCC have addressed OS. In the present study we considered the survival ‘extremes’ in an effort to identify PF for long-term survival. That is, one group is considered as having a short-survival time typical of metastatic RCC (<2 years survivors). This group comprised 63% of our 358 patient database and is representative of the typical metastatic RCC patient entered into clinical trials. The other group represents long-time survivors (>5 years) and included 31 patients (9%) of the original database. Using logistic regression models, four independent predictors of long-term prognosis were found. Counting the number of poor PF present, i.e. hemoglobin <LLN, more than two metastatic sites, left-sided tumor, and ECOG PS 1, a simple scoring system can be created that divides patients into three distinct prognostic subgroups. Only 66 (26%) patients analyzed had no or only one poor PF present; however, they had an observed 5-year survival of 32% (95% confidence interval, 21% to 44%).

Three factors identified in the current study (hemoglobin, the number of involved sites, and ECOG PS) have been previously reported as prognostic in metastatic RCC [10–12, 14–18, 20–23]). The involved kidney, however, has not been previously identified. It was tested in few previous studies [12, 23] and was not found to influence survival. In a study by Wronski et al. [26], however, the kidney site was cited as an important PF in patients with primary RCC and brain metastases, before craniotomy. In these patients, median survival from craniotomy was longer for left-sided kidney tumors versus right-sided ones; 21.3 versus 7.4 months (P < 0.014) [26]. In our study, right-sided kidney tumors, rather than left-sided ones were found to have a better long-term prognosis. One might postulate that tumor size could be larger on the left side in our patients, thus more difficult to be resected, and as a result, a suboptimal nephrectomy was employed. The difference in size, however, was not significant in the two groups (P = 0.92). Also, it does not appear that there is an anatomical reason to explain why right-sided tumors have longer survival than the left-sides ones. Tumor grade was a significant PF on univariate analysis and correlated with kidney site with right-sided tumors having lower grades (P = 0.02). Nevertheless, it was not included in the final model because of missing data in a large proportion of patients, notably among long-term survivors, contributing to a study limitation. Overall, this is an interesting finding and should be looked at in further prognostication studies in RCC. In an attempt to clarify all the concerns about the validity of tumor site, we run an analysis where we excluded kidney site. Although there is not a good explanation right now for why right versus left kidney involvement should matter, that model which includes kidney site seems to be superior to the one that ignores it (area under ROC curve of 83% versus 79%).

Another limitation of our study is the absence of external validation by another set of patients at this time. Future analysis should include external validation from a different set of patients to add more validity to our current proposed model.

Biologic and molecular characteristics of the tumors of long-term survivors also require examination to gain insight into the more indolent behavior of tumor subsets. Recently, expression of lecithin:retinol acetyltransferase [27], the receptor tyrosine kinase EphA2 [28], carbonic anhydrase IX [29], phosphatase and tensin homologue deleted on chromosome 10 [30], and others [31] were shown to be independently associated with survival in patients with metastatic RCC and may provide additional insight to the clinical behavior of the disease.

Recently, von Hippel–Lindau (VHL) gene silencing/inactivation has been observed as a key factor resulting in increased expression of vascular endothelial growth factor and platelet-derived growth factor-beta in clear-cell RCC. Agents inhibiting these pathways have anti-tumor activity. Recently, agents such as bevacizumab [32], sunitinib [33, 34], and sorafenib [35] that inhibit these pathways were found to have significant clinical activity in RCC. We are currently examining potential clinical PF in patients treated with these agents in addition to looking at VHL gene alterations in order to assess additional factors that may be associated with outcomes in patients with this malignancy.

Received for publication July 18, 2006. Revision received September 2, 2006. Accepted for publication September 8, 2006.


   References
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 Abstract
 background
 patients and methods
 results
 discussion
 References
 
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