0022-5347/04/1715-1810/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 171, 1810 –1813, May 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000121440.82581.d3
CACHEXIA-LIKE SYMPTOMS PREDICT A WORSE PROGNOSIS IN LOCALIZED T1 RENAL CELL CARCINOMA HYUNG L. KIM, KEN-RYU HAN, AMNON ZISMAN, ROBERT A. FIGLIN AND ARIE S. BELLDEGRUN* From the Departments of Urology and Medicine (RAF), University of California School of Medicine, Los Angeles, California
ABSTRACT
Purpose: Although cachexia is a common sequela of advanced and metastatic renal cell carcinoma (RCC), cachexia-like symptoms may also represent a paraneoplastic finding. We assessed the prognostic significance of these symptoms in patients with stage T1 RCC. Materials and Methods: Using the kidney cancer database at our institution 250 patients were identified who underwent partial or radical nephrectomy for T1N0M0 RCC between 1989 and 2001. The prognostic significance of the symptoms present at diagnosis and findings on preoperative laboratory evaluation were examined. Results: Mean and median followup was 33 and 43 months, respectively. Malaise, weight loss, anorexia and hypoalbuminemia were cachexia related findings that were significant predictors of worse disease specific survival (DSS). DSS in patients with 1 vs greater than 1 cachexia related symptoms was not significantly different (p ⫽ 0.077). Therefore, any patient with at least 1 cachexia related finding was considered to be positive for cachexia and cachexia occurred in 37 (14.8%). Cachexia was associated with significantly worse recurrence-free survival (HR 3.03, p ⫽ 0.032) and DSS (HR 4.39, p ⫽ 0.011) even after controlling for tumor size, grade and performance status. The 5-year survival rate in patients with low grade (1 or 2) tumors with and without cachexia was 91% and 81%, respectively. The 5-year survival rate in patients with high grade (3 or 4) tumors with and without cachexia was 75% and 55%, respectively. Conclusions: Cachexia-like symptoms independently predict a worse prognosis in patients with T1 RCC. Patients with cachexia (malaise, weight loss, anorexia and hypoalbuminemia), especially when associated with high grade tumors, should be considered for clinical trials of adjuvant therapies. KEY WORDS: kidney; carcinoma, renal cell; prognosis; cachexia
Cachexia related findings have previously been identified as an independent predictor of survival in patients with renal cell carcinoma (RCC).1 Although cachexia is commonly the sequela of advanced and metastatic RCC, it may also represent a paraneoplastic finding. Paraneoplastic findings include a constellation of signs and symptoms that result from the release of tumor associated proteins rather than from local or distant invasion. Proteins responsible for the paraneoplastic effects may be elaborated directly by the tumor cells or by the immune system in response to tumor. Paraneoplastic findings are common in patients with RCC and systemic symptoms in patients with small, localized tumors are often attributed to paraneoplastic effects. We assessed the prognostic significance of cachexia-like findings in patients with localized (N0M0) stage T1 RCC. METHODS
Patients and definitions. Using the kidney cancer database at our institution 250 patients were identified who underwent partial or radical nephrectomy for T1N0M0 RCC between 1989 and 2001. Presenting signs and symptoms were determined at the time of preoperative history and physical examination using a standard patient questionnaire. Hypertension was defined as new hypertension or worsening of existing hypertension, as determined by the primary physi-
cian. Weight loss was defined as an unintended decrease of at least 5 pounds within 3 months. Anorexia, fever, chills, night sweats and malaise were reported by the patient. Anorexia and malaise refer to subjective reports by the patient of a decrease in appetite and energy level, respectively. Patients with incomplete data were included, namely 5 with missing grade, 4 with missing Eastern Cooperative Oncology Group (ECOG) and 5 with missing University of California Integrated Staging System (UISS) data. Preoperative laboratory studies were used to assess presenting signs. Anemia was defined as hematocrit less than 40% in men and less than 36% in women. Polycythemia was defined as hematocrit greater than 50% in men and greater than 44% in women. Thrombocytosis and hypoalbuminemia were defined as platelet count greater than 440 ⫻ 103/l and serum albumin less than 3.6 gm/dl, respectively. Alanine transaminase greater than 50 IU/l, aspartate transaminase greater than 50 IU/l or alkaline phosphatase greater than 105 IU/l was considered evidence of hepatic dysfunction. Calcium levels were adjusted for albumin less than 4 gm/dl according to the formula, measured calcium ⫹ 0.8 ⫻ (4 ⫺ serum albumin). Patients with corrected calcium greater than 10 mg/l were considered hypercalcemic. Cases were staged according to the 1997 TNM criteria proposed by the American Joint Committee on Cancer.2 Performance status was determined using the ECOGPerformance Score (PS) scale.3 Tumor grade was categorized using the Fuhrman grade.4 Cases were also categorized according to the UISS.5 Following surgery patients were evaluated for disease recurrence by physical examination, liver
Accepted for publication December 19, 2003. * Correspondence: University of California School of Medicine, Department of Urology, CHS 66-188, 10833 Le Conte Ave., Los Angeles, California 90095 (telephone: 310-206-1434; FAX: 310-2065343; e-mail:
[email protected]). 1810
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function tests, chest x-ray and computerized tomography of the abdomen/pelvis every 6 to 12 months. Statistical analysis. The Kaplan-Meier method was used to determine disease specific survival (DSS) and recurrencefree survival (RFS) rates. DSS and recurrence rates between groups with and without cachexia were compared using the log rank test. Patient characteristics in the groups with and without cachexia were compared using the t or chi square test. Multiple predictive parameters were assessed in a Cox proportional hazard model. The Schoenfeld test was used to test the proportional hazard assumption, and p ⬍0.05 was considered significant. All statistical analyses were performed using Stata statistical software (Stata Corp., College Station, Texas). RESULTS
Mean and median followup was 33 and 43 months, respectively. By the last followup 47 patients (19%) had died. Table 1 lists patient characteristics. Table 2 lists the frequency of paraneoplastic findings and their effect on DSS. Malaise, weight loss, anorexia and hypoalbuminemia were cachexia related findings that were significant predictors of worse DSS. DSS for patients with 1 vs greater than 1 cachexia related symptom was not significantly different (p ⫽ 0.077). Therefore, any case with at least 1 cachexia related finding was considered to be positive for cachexia and cachexia occurred in 37 (14.8%) of all T1N0M0 cases. Patients presenting with hypercalcemia or night sweats also had worse survival, although neither finding was an independent predictor of DSS on multivariate analyses that included ECOG and grade. Table 1 also lists the characteristics of patients with and without cachexia. The distribution of histological RCC subtypes in the 2 groups was similar (p ⫽ 0.314). However, the cachexia group had higher tumor grade (p ⫽ 0.017), ECOG (p ⬍0.001) and UISS (p ⫽ 0.005) compared to the group presenting without cachexia. The risk of recurrence was significantly higher in the cachexia group (fig. 1). The increased risk of recurrence associated with cachexia remained significant after controlling for tumor size, grade and ECOG on multivariate analysis (table 3). DSS was also significantly worse in the cachexia group (fig. 2). DSS remained significantly worse in the cachexia group even after controlling for tumor size, grade and ECOG on multivariate analysis (table 3). Table 4 shows 5-year DSS rates by cachexia status and tumor grade. Subset analysis revealed that 15 patients with tumors 3 cm or less presented with cachexia. However, only
TABLE 1. Cachexia at time of presentation Pt Characteristics No. pts Mean age (⫾SD) No. men/women Mean tumor size ⫾ SD (cm) No. tumor greater than 5 cm (%) No. histological pattern (%): Clear cell Papillary Chromophobe Unspecified or mixed No. Fuhrman grade (%): 1 2 3 4 No. ECOG-PS (%): 0 1 2 No. UISS (%): 1 2
Overall
No Cachexia
Cachexia
250 62.5 (12.2) 32 3.8 ⫾ 1.6 53 (21.2)
213 62.0 (12.4) 32 3.8 ⫾ 1.6 43 (20.2)
37 65.7 (10.7) 11 3.9 ⫾ 1.6 10 (27.0)
179 52 12 7
(71.6) (20.8) (4.8) (2.8)
148 47 11 7
(69.5) (22.1) (5.2) (3.3)
31 5 1 0
(83.8) (13.5) (2.7)
72 141 31 1
(29.4) (57.6) (12.7) (0.4)
66 121 21 1
(31.6) (57.9) (10.1) (0.5)
6 20 10 0
(16.7) (55.6) (27.8)
159 83 4
(64.6) (33.7) (1.6)
150 58 1
(71.8) (27.8) (0.5)
9 25 3
(24.3) (67.6) (8.1)
213 32
(86.9) (13.1)
187 22
(89.5) (10.5)
26 10
(72.2) (27.8)
TABLE 2. Paraneoplastic findings and their effect on DSS No. Pts (%)
Univariate HR
Univariate p Value
Anemia 83 (33.2) 3.0 0.137 Hepatic dysfunction 35 (14.0) 2.5 0.290 Malaise 20 (8.0) 3.4 0.031 Weight loss 19 (7.6) 7.9 0.002 Thrombocytosis 12 (4.8) 2.4 0.409 Fever 11 (4.4) 0.0 1.000 Anorexia 8 (3.2) 18.4 <0.001 Hypoalbuminemia 8 (3.2) 12.3 0.042 Hypercalcemia 5 (2.0) 11.2 0.049 Polycythemia 4 (1.6) 0.0 1.000 Night sweats 6 (2.4) 5.9 0.018 Hypertension 6 (2.4) 0.0 1.000 Chills 4 (1.6) 0.0 1.000 Cachexia* 37 (14.8) 4.2 0.004 * Patients with hypoalbuminemia, weight loss, malaise or anorexia were considered positive for cachexia.
FIG. 1. RFS in patients with T1N0M0 RCC stratified by presence or absence of cachexia related finding, namely hypoalbuminemia, weight loss, anorexia or malaise.
TABLE 3. RFS and DSS after nephrectomy Univariate
RFS: Cachexia Tumor size Grade ECOG-PS DSS: Cachexia Tumor size Grade ECOG-PS
Multivariate
HR
p Value
HR
p Value
2.81 1.50 2.57 2.26
0.020 0.001 0.003 0.022
3.03 1.37 2.36 1.72
0.032 0.022 0.011 0.205
4.19 1.36 2.47 2.69
0.004 0.033 0.010 0.020
4.39 1.17 2.42 1.77
0.011 0.325 0.015 0.249
1 of the 15 patients had died at the last followup and, therefore, DSS analysis in this subgroup was not possible. DISCUSSION
In patients with metastatic RCC it is generally accepted that poor performance status and constitutional symptoms portend a poor prognosis.5–9 Signs and symptoms in patients with localized RCC are more likely to reflect paraneoplastic effects rather than overall tumor burden. Therefore, to assess the prognostic significance of paraneoplastic effects we limited our current analysis to patients with the lowest stage RCC. To our knowledge this is the first report to assess the prognostic significance of specific symptoms in localized
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CACHEXIA-LIKE SYMPTOMS AND RENAL CELL CANCER PROGNOSIS
been previously documented in the absence of metastatic disease and they resolved following nephrectomy.13, 14 It has been suggested that cachexia may be due to the secretion of tumor necrosis-␣, interleukin-1 or interleukin-6 by the tumor or infiltrating immune cells.12, 15–17 Other studies suggest that the tumor may secrete substances responsible for cachexia.18 –20 While other studies have compared survival in patients with and without symptoms, no attempt was made to separate patients based on presenting symptoms. Two previous reports showed no difference in prognosis in patients with RCC presenting with symptoms or without symptoms.21, 22 However, others reported that symptomatic presentation portends a worse prognosis.6, 8 The current study suggests that specific signs and symptoms, ie cachexia-like findings, and not simply the presence or absence of symptoms in general have a prognostic significance that is independent of established clinical predictors such as stage, grade and ECOG-PS. FIG. 2. DSS in patients with T1N0M0 RCC stratified by presence or absence of cachexia related finding, namely hypoalbuminemia, weight loss, anorexia or malaise.
TABLE 4. Five-year DSS % Pts No cachexia (RCC grade): 1–2 3–4 Cachexia (RCC grade): 1–2 3–4
91 75 81 55
RCC. We observed that malaise, weight loss, anorexia, hypoalbuminemia, hypercalcemia and night sweats are significant predictors of a poor prognosis. In a previous study that included patients with localized as well as metastatic RCC we identified hypoalbuminemia, weight loss, anorexia and malaise as independent predictors of a poor prognosis and termed them cachexia related findings.1 There was no difference in survival based on the number of cachexia related findings and, therefore, any patient with at least 1 of these findings was considered positive for cachexia. The correlation between prognosis and the number of cachexia related findings approached statistical significance. Therefore, with a larger patient population and more precise outcomes tools for identifying some of the more subjective findings the number cachexia related findings may directly reflect the prognosis. In the current study we noted that the incidence of cachexia in patients with T1N0M0 RCC was 14.8%. Cachexia was associated with lower RFS and DSS rates. The poor prognosis associated with cachexia was independent of tumor size, grade and ECOG. On multivariate analysis cachexia, tumor size and grade remained significant predictors of RFS and cachexia was associated with the largest HR (2.81). Similarly on multivariate analysis assessing DSS cachexia and grade were significant predictors of survival and cachexia was associated with an HR of 4.19. Patients with cachexia and grade 3– 4 tumors had a 5-year DSS rate of only 55%. Presenting signs and symptoms at diagnosis in patients with stage T1 localized RCC reflect tumor biology rather than simply local tumor extent. Many presenting symptoms and signs in RCC represent paraneoplastic effects that result from the elaboration of various proteins by the tumor. A parathyroid hormone-like peptide has been implicated as the cause of hypercalcemia.10, 11 Polycythemia is thought to result from the production of erythropoietin by RCC.12 Hepatic dysfunction (Stauffer’s syndrome) and hypertension have
CONCLUSIONS
Cachexia-like findings, defined as hypoalbuminemia, weight loss, anorexia and malaise, predict a worse prognosis after controlling for Fuhrman grade and PS. Patients with cachexia-like findings, especially when associated with high grade tumors, should be considered for clinical trials of adjuvant therapies. REFERENCES
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