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The association of anxiety and depression with perioperative and oncologic outcomes among patients with clear cell renal cell carcinoma undergoing nephrectomy
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Urologic Oncology: Seminars and Original Investigations 000 (2019) 1−9
Clinical-Kidney cancer
The association of anxiety and depression with perioperative and oncologic outcomes among patients with clear cell renal cell carcinoma undergoing nephrectomy Vignesh T. Packiam, M.D.a, Mark D. Tyson II, M.D.b, Matvey Tsivian, M.D.a, Christine M. Lohse, M.S.c, Stephen A. Boorjian, M.D.a, John C. Cheville, M.D.d, Brian A. Costello, M.D.e, Bradley C. Leibovich, M.D.a, R. Houston Thompson, M.D.a,* a
Mayo Clinic, Department of Urology, Rochester, MN Mayo Clinic, Department of Urology, Scottsdale, AZ c Mayo Clinic, Department of Health Sciences Research, Rochester, MN d Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, MN e Mayo Clinic, Department of Oncology, Rochester, MN b
Received 17 June 2019; received in revised form 25 August 2019; accepted 29 October 2019
Abstract Objectives: Anxiety and depression have been associated with inferior overall survival for several malignancies, including metastatic renal cell carcinoma (RCC). However, there is minimal data evaluating this association for localized RCC. We evaluated the association of anxiety or depression with survival in patients with surgically treated localized clear cell RCC (ccRCC). Patients and methods: We reviewed our institutional nephrectomy registry of 1,990 adults who underwent radical or partial nephrectomy for unilateral, sporadic, nonmetastatic ccRCC between 1995 and 2011. Baseline anxiety and depression were identified using ICD-9 codes. Associations of anxiety or depression with 30-day complications and oncologic outcomes were evaluated using Cox proportional hazards models as well as adjustment for propensity score (PS) quintile and re-weighting by stabilized inverse probability weights. Results: A total of 197 (10%) patients were identified with a diagnosis of anxiety or depression. Median follow-up among survivors was 10.0 (IQR 7.3−13.6) years, during which time 864 patients died, including 363 from RCC. After PS adjustment, clinical and pathologic features were well balanced between groups. Patients with anxiety or depression had increased overall 30-day complications compared to those without (17% vs. 11%, P = 0.011). No significant differences were noted in time to local ipsilateral recurrence (P = 0.54), distant metastases (P = 0.96), or death from RCC (P = 0.42) between patients with vs. without anxiety or depression, while patients with anxiety or depression trended toward worse overall survival (hazard ratio 1.29, 95%CI 0.98−1.69, P = 0.065). Conclusions: Neither anxiety nor depression were significantly associated with oncologic outcomes among patients who underwent surgery for localized ccRCC. The trend toward worse overall survival among patients with anxiety or depression warrants further investigation. Ó 2019 Elsevier Inc. All rights reserved.
Keywords: Kidney cancer; Mortality; Survival; Depression; anxiety
1. Introduction There were an estimated 65,340 new cases and 14,970 deaths from kidney cancer in the United States in 2018 [1]. Funding sources: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. *Corresponding author. E-mail address: [email protected] (R.H. Thompson). https://doi.org/10.1016/j.urolonc.2019.10.017 1078-1439/Ó 2019 Elsevier Inc. All rights reserved.
Over 90% of kidney cancers are renal cell carcinoma (RCC), predominantly of clear cell histology [2]. Growing utilization of cross-sectional imaging has resulted in increased incidental detection of localized RCC, with approximately 70% to 75% newly diagnosed cases staged nonmetastatic [3]. While management for localized disease has evolved to include consideration of active surveillance and ablative techniques, there has been an increasing trend
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towards surgical management for patients with localized RCC [4−6]. Overall survival for RCC has slowly improved over time with advances in surgical and systemic management [7]. Psychological distress impacts patients with cancer throughout the course of their care from time of diagnosis to treatment and post-treatment surveillance [8]. Accumulating evidence from animal and clinical studies suggests that anxiety and depression modulate angiogenesis and immune response that may result in increased mortality [9]. Partly due to these findings, the American Society of Clinical Oncology and Centers for Medicare and Medicaid Services have strengthened recommendations to assess and address psychosocial needs in oncologic care plans, which is now mandated for cancer center hospital accreditation [10−13]. Randomized data have demonstrated that psychologic intervention in cancer patients improves both overall survival and quality of life [14,15]. However, while some reports have corroborated the association between distress and survival for certain malignancies, others have shown conflicting data [16−20]. Anxiety and depression are common among kidney cancer patients [21,22]. Whereas an association between biopsychosocial distress and mortality in patients with metastatic kidney cancer has been reported [23], little is known regarding psychological conditions and mortality for surgically treated localized kidney cancer [24]. In this context, we tested the hypothesis that anxiety and depression are associated with survival in a large institutional cohort of patients with surgically treated localized clear cell RCC. 2. Patients and methods
nephrectomy for unilateral, sporadic, M0, noncystic clear cell RCC between 1995 and 2011. 2.2. Assessment of data Clinical features studied included year of surgery, age at surgery, sex, race, symptoms, constitutional symptoms, smoking status, Eastern Cooperative Oncology Group performance status, Charlson score, body mass index (BMI), preoperative estimated glomerular filtration rate (eGFR) calculated using the Chronic Kidney Disease Epidemiology Collaboration formula and expressed as mL/min/1.73m2, radiographic tumor size, surgical approach, and surgical margin status. The diagnoses of anxiety or depression prior to or at surgery were determined by ICD-9 codes for these diagnoses adapted from previous studies (Table 1) [25]. A medical record chart review was conducted on a random 10% sample of the population which demonstrated 98% accuracy of these diagnoses based on ICD-9 codes. Patients with a palpable flank or abdominal mass, discomfort, gross hematuria, acute onset varicocele, or constitutional symptoms including rash, sweats, weight loss, fatigue, early satiety, and anorexia were considered symptomatic. Pathologic features included pathologic tumor size, 2018 pT and N classifications, WHO/ISUP grade, coagulative tumor necrosis, sarcomatoid differentiation, and the Mayo Clinic SSIGN score [26,27]. To obtain these pathologic features, 1 urologic pathologist (J.C.C.) reviewed all microscopic slides from the surgery over time as the database was prospectively maintained, without knowledge of patient outcome. Outcomes studied included 30-day postoperative complications and local ipsilateral recurrence, distant metastases, death from any cause, and death from RCC.
2.1. Study population 2.3. Statistical analyses After Institutional Review Board approval was obtained, the Mayo Clinic Rochester Nephrectomy Registry was queried to identify 1,990 adults treated with radical or partial
Continuous features were summarized with means and standard deviations when approximately normally distributed
Table 1 Summary of anxiety and depression ICD-9 codes, N = 1,990 Diagnosis
ICD-9 codes
n
Anxiety disorders Acute reaction to stress Adjustment disorder with anxiety or mixed anxiety/depressed mood Post-traumatic stress disorder or other reactions to severe stress Single episode depressive disorders Recurrent depressive disorders Atypical depressive disorder Unspecified episodic mood disorder Dysthymic disorder Affective personality disorder/cyclothymia Depression NEC (not elsewhere classifiable)
293.84, 293.89, 300.0, 300.00, 300.01, 300.02, 300.09, 300.21 308.0, 308.1, 308.2, 308.3, 308.4, 308.9 309.24, 309.28 309.81, 309.82, 309.83, 309.89 296.2, 296.20, 296.21, 296.22, 296.23, 296.24, 296.25, 296.26 296.3, 296.30, 296.31, 296.32, 296.33, 296.34, 296.35, 296.36 296.82 296.90 300.4 301.1, 301.10, 301.12, 301.13 311
91 8 11 6 20 46 1 3 33 1 116
*Some patients had multiple diagnoses. **No patients in this cohort had the following ICD-9 codes: 293.89, 300.0, 300.09, 308.0, 308.1, 308.2, 308.4, 309.82, 309.83, 296.2, 296.22, 296.23, 296.24, 296.3, 298.0, 301.1, 301.10, 301.12, 313.1.
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and with medians and interquartile ranges (IQRs) otherwise. Categorical features were summarized with frequency counts and percentages. Clinical and pathologic features were compared between patients with and without anxiety or depression using 2-sample t, Wilcoxon rank sum, and chi-square tests. Observed local ipsilateral recurrence-free, distant metastases-free, overall, and cancer-specific survival rates were obtained using the Kaplan-Meier method. The duration of follow-up was calculated from the date of surgery to the date of the outcome of interest or the date of last clinical follow-up. Propensity scores (PS) for being diagnosed with anxiety or depression were obtained using a logistic regression model with anxiety or depression as the outcome and the clinical and pathologic features listed above, except for race and radiographic tumor size, as covariates. These 2 features were not included in the model because of the amount of missing data. The pattern of missing data for the remaining features was assumed to be arbitrary, and all analyses were conducted using a complete case approach. Associations of anxiety or depression with 30-day postoperative complications were evaluated using chi-square tests in the pseudo cohort after re-weighting by stabilized IPWs. Associations of anxiety or depression with time to ipsilateral local recurrence, distant metastases, death from RCC, and death from any cause were evaluated using Cox proportional hazards regression models and summarized with hazard ratios (HRs) and 95% confidence intervals (CIs). Two PS techniques were used to evaluate these associations: adjustment for PS quintile and re-weighting by stabilized inverse probability weights (IPWs). Predicted local ipsilateral recurrence-free, distant metastases-free, cancer-specific, and overall survival rates were obtained for the pseudo cohort using Cox proportional hazards regression models after re-weighting by stabilized IPWs. Statistical analyses were performed using SAS version 9.4 (SAS Institute; Cary, NC). All tests were 2-sided, and P values <0.05 were considered statistically significant. 3. Results 3.1. Patient characteristics Among the 1,990 patients included, 57 were diagnosed with anxiety alone, 107 diagnosed with depression alone, and 33 diagnosed with both anxiety and depression (Table 1). Comparisons of clinical and pathologic features between the 1,793 (90%) patients without anxiety or depression and the 197 (10%) patients with anxiety or depression are shown in Table 2. The most significant differences between groups were for the variables age, year of surgery, gender, Eastern Cooperative Oncology Group performance status, and surgical approach (all P < 0.001), while there were also differences in BMI, preoperative eGFR, pathologic tumor size and T stage, SSIGN score, symptomatic presentation, and pathologic grade.
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Fifty-eight patients without anxiety or depression and 5 patients with anxiety or depression had missing data for 1 or more of the clinical and pathologic features included in the PS model. In addition, 26 patients without anxiety or depression and 1 patient with anxiety or depression had PS that did not fall within the common range for the 2 groups and were excluded. As such, a total of 1,900 patients formed the cohort for the PS analyses, including 1,709 (90%) without anxiety or depression and 191 (10%) with anxiety or depression. After PS adjustment, the clinical and pathologic features were wellbalanced between the 2 groups. Specifically, no clinical or pathologic feature was statistically significantly different between patients with and without anxiety or depression after adjusting for PS quintile (data not shown) or in the pseudo cohort after re-weighting by stabilized IPWs (Table 3). 3.2. Complications Among the 1,900 included in the PS analyses, there were 215 (11%) who experienced at least 1 complication, including 96 (5%) who experienced a Clavien grade 3/4/5 complication. Comparisons of 30-day postoperative complications between patients with and without anxiety or depression in the pseudo cohort are also shown in Table 4. Patients with anxiety or depression had higher rates of any 30-day postoperative complication (17% vs. 11%, P = 0.011), 30-day myocardial infarction (4% vs. 1%, P = 0.001), and 30-day urine leak (4% vs. 1%, P = 0.004) compared to those neither diagnosis. 3.3. Survival outcomes 3.3.1. Overall survival outcomes At last follow-up, 160 of the 1,900 patients included in the PS analyses experienced a local ipsilateral recurrence at a median of 1.6 (IQR 0.6−4.6) years following surgery. The observed local ipsilateral recurrence-free survival rate (95% CI; number still at risk) at 10 years was 90% (89−92; 670). There were 494 patients who experienced distant metastases at a median of 1.6 (IQR 0.5−4.5) years following surgery. The observed metastases-free survival rate at 10 years was 73% (70−75; 622). A total of 864 patients died at a median of 5.1 (IQR 2.0−9.2) years following surgery, including 363 who died from RCC at a median of 3.0 (IQR 1.3−6.8) years. Seventy-three patients who died from unknown causes were excluded from the analyses of cancer-specific survival. The median duration of follow-up for the 1,036 patients who were still alive at last follow-up was 10.0 (IQR 7.3−13.6) years. The observed overall and cancer-specific survival rates at 10 years following surgery were 60% (58−63; 702) and 79% (77−81; 662), respectively. 3.3.2. Survival outcomes stratified by presence of anxiety and depression We found no statistically significant associations of anxiety or depression with time to ipsilateral local
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Table 2 Comparisons of clinical and pathologic features by anxiety or depression Mean (SD) All N = 1,990
Neither N = 1,793
Feature Age at surgery in years BMI in kg/m2 (N = 1,988) Preoperative eGFR (N = 1,961) Radiographic tumor size in cm (N = 1,784) Pathologic tumor size in cm (N = 1,985)
62.0 (12.0) 30.3 (6.2) 66.1 (20.2) 5.6 (3.4) 5.9 (3.7)
Charlson score SSIGN score (N = 1,985) Year of surgery 1995−1999 2000−2004 2005−2011 Sex Female Male Race (N = 1,807) All others White Symptoms (N = 1,988) Constitutional symptoms (N = 1,988) Smoking status (N = 1,966) Never Current Former ECOG performance status 0 1 2 3 4 BMI ≥30 kg/m2 (N = 1,988) Preoperative eGFR (N = 1,961) ≥90 60 to <90 45 to <60 30 to <45 15 to <30 <15 Surgical approach Open radical Open partial Laparoscopic radical Laparoscopic partial Positive surgical margins (N = 1,988) 2018 pT (N = 1,986) pT1a pT1b pT2a pT2b pT3a pT3b pT3c pT4 2018 pN pNx pN0
1 (0−2) 2 (0−5) 398 (20) 601 (30) 991 (50)
62.4 (11.9) 30.1 (6.2) 65.6 (19.9) 5.6 (3.4) 5.9 (3.8) Median (IQR) 1 (0−2) 2 (0−5) n (%) 382 (21) 567 (32) 844 (47)
Anxiety or depression N = 197
P value
58.8 (12.1) 31.3 (6.8) 70.4 (21.9) 5.3 (3.2) 5.4 (3.4)
<0.001 0.011 0.002 0.25 0.047
1 (0−2) 1 (0−4)
0.86 0.019
16 (8) 34 (17) 147 (75)
<0.001
701 (35) 1,289 (65)
598 (33) 1,195 (67)
103 (52) 94 (48)
<0.001
64 (4) 1,743 (96) 932 (47) 323 (16)
55 (3) 1,564 (97) 862 (48) 295 (16)
9 (5) 179 (95) 70 (36) 28 (14)
0.33
808 (41) 349 (18) 809 (41)
737 (42) 306 (17) 726 (41)
71 (36) 43 (22) 83 (42)
0.18
1,708 (86) 197 (10) 52 (3) 30 (2) 3 (<1) 900 (45)
1,555 (87) 169 (9) 45 (3) 22 (1) 2 (<1) 794 (44)
153 (78) 28 (14) 7 (4) 8 (4) 1 (1) 106 (54)
<0.001
248 (13) 969 (49) 469 (24) 200 (10) 56 (3) 19 (1)
209 (12) 870 (49) 438 (25) 181 (10) 53 (3) 16 (1)
39 (20) 99 (51) 31 (16) 19 (10) 3 (2) 3 (2)
0.001
943 (47) 726 (36) 201 (10) 120 (6) 59 (3)
879 (49) 630 (35) 177 (10) 107 (6) 54 (3)
64 (32) 96 (49) 24 (12) 13 (7) 5 (3)
<0.001
777 (39) 461 (23) 165 (8) 69 (3) 373 (19) 107 (5) 13 (1) 21 (1)
688 (38) 418 (23) 144 (8) 65 (4) 344 (19) 97 (5) 13 (1) 21 (1)
89 (45) 43 (22) 21 (11) 4 (2) 29 (15) 10 (5) 0 0
0.027
1,509 (76) 402 (20)
1,352 (75) 368 (21)
157 (80) 34 (17)
0.40
0.001 0.43
0.011
0.71
(continued)
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Table 2 (Continued) Mean (SD) All N = 1,990
Neither N = 1,793
Feature pN1 Grade 1 2 3 4 Coagulative Necrosis Sarcomatoid features
Anxiety or depression N = 197
79 (4)
73 (4)
6 (3)
155 (8) 887 (45) 773 (39) 175 (9) 440 (22) 45 (2)
132 (7) 790 (44) 713 (40) 158 (9) 402 (22) 42 (2)
23 (12) 97 (49) 60 (30) 17 (9) 38 (19) 3 (2)
P value
0.010
0.31 0.46
*Sample sizes for features with missing data are indicated in italics in parentheses.
Table 3 Comparisons of clinical and pathologic features by anxiety or depression in the pseudo cohort after re-weighting by stabilized IPWs
Table 3 (Continued) Mean (SD)
Mean (SD) Neither N = 1,707
P value
61.9 (11.9)
62.4 (12.3)
0.63
30.3 (6.3) 66.1 (20.2) 5.6 (3.4)
30.3 (6.1) 65.5 (20.2) 5.6 (3.3)
0.96 0.70 0.86
5.9 (3.7)
5.6 (3.4)
0.45
Feature Age at surgery in years BMI in kg/m2 Preoperative eGFR Radiographic tumor size in cm (N = 1,712) Pathologic tumor size in cm Charlson score SSIGN score Year of surgery 1995−1999 2000−2004 2005−2011 Sex Female Male Race (N = 1,729) All others White Symptoms Constitutional symptoms Smoking status Never Current Former ECOG performance status 0 1 2 3
Neither N = 1,707
Anxiety or depression N = 192
Median (IQR) 1 (0−2) 0 (0−2) 2 (0−5) 2 (0−4) n (%) 327 (19) 34 (18) 509 (30) 62 (32) 871 (51) 96 (50)
Feature
0.33 0.86 0.99
606 (36) 1,101 (64)
70 (36) 122 (64)
0.83
55 (4) 1,496 (96) 793 (46) 275 (16)
5 (3) 173 (97) 93 (48) 26 (13)
0.54
693 (41) 306 (18) 708 (41)
89 (46) 39 (20) 64 (34)
0.10
1,467 (86) 166 (10) 49 (3) 24 (1)
159 (83) 25 (13) 4 (2) 4 (2)
0.39
0.59 0.34
(continued)
4 BMI ≥30 kg/m2 Preoperative eGFR ≥90 60 to <90 45 to <60 30 to <45 15 to <30 <15 Surgical approach Open radical Open partial Laparoscopic radical Laparoscopic partial Positive surgical margins 2018 pT pT1a pT1b pT2a pT2b pT3a pT3b pT3c pT4 2018 pN pNx pN0 pN1 Grade 1 2 3 4 Necrosis Sarcomatoid
Anxiety or depression N = 192
P value
1 (<1) 774 (45)
0 95 (49)
215 (13) 846 (50) 408 (24) 170 (10) 51 (3) 17 (1)
24 (12) 104 (54) 37 (19) 23 (12) 1 (1) 3 (2)
0.55
803 (47) 627 (37) 174 (10)
90 (47) 76 (40) 18 (9)
0.76
103 (6)
8 (4)
52 (3)
5 (3)
0.81
678 (40) 401 (23) 136 (8) 55 (3) 322 (19) 88 (5) 11 (1) 16 (1)
77 (40) 42 (22) 19 (10) 4 (2) 34 (18) 16 (8) 0 0
0.91
1,294 (76) 346 (20) 67 (4)
138 (72) 47 (24) 7 (4)
0.34
135 (8) 766 (45) 660 (39) 146 (9) 372 (22) 35 (2)
21 (11) 76 (39) 80 (42) 15 (8) 37 (19) 4 (2)
0.82
0.28
0.39 0.96
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Table 4 Comparisons of 30-day postoperative complications by anxiety or depression in the pseudo cohort after re-weighting by stabilized IPWs n (%) Neither N = 1,707 Feature 30-day postoperative complications Death Hemorrhage Deep vein thrombosis Pulmonary embolism Myocardial infarction Wound infection or dehiscence Abscess Urine leak Sepsis Acute renal failure Dialysis Pneumothorax Other Any of the above Any of the above Clavien grade ≥3
8 (<1) 46 (3) 14 (1) 12 (1) 9 (1) 36 (2) 11 (1) 25 (1) 13 (1) 61 (4) 12 (1) 10 (1) 12 (1) 181 (11) 79 (5)
Anxiety or depression N = 192
P value
1 (1) 6 (3) 1 (<1) 2 (1) 7 (4) 8 (4) 2 (1) 8 (4) 3 (1) 8 (4) 1 (1) 1 (1) 2 (1) 32 (17) 13 (7)
0.85 0.85 0.44 0.75 <0.001 0.046 0.38 0.004 0.32 0.67 0.83 0.88 0.91 0.011 0.24
recurrence, distant metastases, death from RCC, and death from any cause. Of note, we did identify a trend toward an association between anxiety or depression and death from any cause (HR in pseudo cohort after re-weighting 1.29; 95% CI 0.98−1.69, P = 0.065; Table 5). Predicted local ipsilateral recurrence-free, distant metastases-free, cancerspecific, and overall survival rates in the pseudo cohort after re-weighting by stabilized IPWs are illustrated in Fig. 1(A−D), respectively. 4. Discussion Our study suggests that compared to patients without anxiety or depression, patients with anxiety or depression: (1) are more likely female with more recent operations, (2) have higher overall 30-day rates of complications, (3) have Table 5 Associations of anxiety or depression with survival outcomes Local ipsilateral recurrence
HR (95% CI)a
P value
Adjusted for PS quintiles In pseudo cohort after re-weighting Distant metastases Adjusted for PS quintile In pseudo cohort after re-weighting Death from RCC Adjusted for PS quintile In pseudo cohort after re-weighting Death from any cause Adjusted for PS quintile In pseudo cohort after re-weighting
1.12 (0.66−1.91) 1.26 (0.60−2.63)
0.68 0.54
1.04 (0.73−1.47) 0.99 (0.64−1.52)
0.84 0.96
1.12 (0.75−1.69) 1.23 (0.75−2.02)
0.58 0.42
1.20 (0.94−1.54) 1.29 (0.98−1.69)
0.15 0.065
a
HR represents the association of anxiety or depression with outcome.
comparable local ipsilateral recurrence-free, distant metastases-free, and cancer-specific survival, and (4) have a trend to worse overall survival. To our knowledge, this report is the first to assess the association between anxiety or depression and oncologic outcomes in a nonmetastatic RCC cohort. This study adds to the emerging literature characterizing distress for other urologic malignancies such as prostate and bladder cancer [25,28−32]. Importantly, psychological distress is increasingly recognized as a crucial component of oncologic care, reflected by the consideration of distress as the “sixth vital sign” in NCCN recommendations [33]. The influence of baseline psychiatric distress on other baseline characteristics, tumor characteristics, and postoperative complications has previously been unexplored for nonmetastatic RCC. Our study found statistically significant but clinically minor differences in several baseline and tumor characteristics between patients with and without anxiety or depression; those with anxiety or depression had lower age, higher BMI, higher eGFR, smaller pathologic tumor size, lower SSIGN score, and less symptomatic disease compared to those without anxiety or depression. Larger differences were seen with respect to more recent surgery year and higher rate of female gender among patients with anxiety or depression. These findings are concordant with previous studies demonstrating that psychological distress is increasingly prevalent over time and almost twice as common in women than men [34−36]. Notably, our study did not identify a significant association between anxiety or depression and high grade postoperative complications. This is in contrast to a report by Sharma et al. that found an association with poor patient-reported mental health metrics and high grade complications after radical cystectomy [37]. This discordance may be secondary to the much lower event rate for high grade complications for kidney cancer in this study vs. for bladder cancer in Sharma et al.’s (5% vs. 16.8%, respectively) [37]. There are many mechanisms by which anxiety and depression may influence oncologic outcomes, including altered angiogenesis and immune dysregulation [9]. Our study found that after PS adjustment for baseline clinical and tumor characteristics, there was no statistically significant association between anxiety or depression and any survival measures. However, there was a nonsignificant reduction in overall survival (P = 0.065) in patients with anxiety or depression after re-weighting by stabilized IPWs. The implications of this finding are unclear, especially in light of no previously existing data assessing this association. Interestingly, Bergerot et al. identified a similar nonstatistically significant trend between biopsychosocial distress and poorer overall survival in 102 patients with metastatic RCC (P = 0.09) [23]. Larger scale analyses using the Surveillance, Epidemiology, and End Results (SEER)Medicare-linked database assessed 50,147 and 3,709 patients with prostate and bladder cancer, respectively, finding significant associations between psychological distress
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Fig. 1. (A−D) Predicted local ipsilateral recurrence-free survival (A), metastases-free survival (B), cancer-specific survival (C), and overall survival (D) in patients with anxiety or depression versus patients without either diagnosis. Because these figures illustrate predicted rates, not observed rates, the numbers still at risk at 2, 4, 6, 8, and 10 years following surgery do not apply.
and inferior overall survival in these malignancies [25,30]. Palapattu and colleagues found that preoperatively identified somatic distress scores but not depression or anxiety predicted disease progression for 74 bladder cancer patients assessed by the Basic Symptom Inventory-18 instrument [32]. The results of these studies may have been influenced by differing methodology with regard to identification, type, and onset of psychologic diagnoses [23,25,30]. While our findings are hypothesis generating, more research is needed in the setting of localized RCC to clarify the association between distress and survival. The ultimate goal of understanding the relationship between distress and survival is to tailor management to improve oncologic outcomes. An important trial in 227 patients with breast cancer randomized patients to a control arm or psychologic intervention that included muscle relaxation, problem solving, improved family support, communication strategies, and increased activity and nutrition [15]. The intervention resulted in improved recurrence free survival (HR 0.55, P = 0.034), cancer-specific survival (HR 0.44, P = 0.016), and overall survival (HR 0.51, P = 0.028) [15]. While several oncologic guidelines recommend assessment of psychologic distress, there are sparse recommendations for interventions once the diagnosis is made [10−13]. Further studies delineating the relationship between distress and survival for RCC patients may
strengthen support for studying and implementing such interventions. There are several limitations to the current study. First, ascertainment bias may have occurred based on the reliance of billing data to identify anxiety and depression, although the diagnoses were verified by chart review in a subset of patients. Second, a validated instrument to quantify anxiety and depression was not utilized in our study, and the method of diagnosis was unknown. We suspect these issues resulted in underreporting of anxiety and depression. Third, the severity of diagnoses was not characterized or accounted for. Fourth, the timing of diagnosis of anxiety and depression was limited to prior to or at surgery, and the implications of postoperative onset of these conditions were unable to be explored. Finally, utilization of a selected surgical cohort precludes assessment of the impact of anxiety and depression on the overall localized RCC population. 5. Conclusions In summary, we demonstrate that neither anxiety nor depression is significantly associated with oncologic outcomes among a large cohort of patients with localized surgically treated clear cell RCC. However, there was a trend toward worse overall survival among patients with anxiety or depression that warrants further investigation.
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Conflicts of interest None.
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[16] Pinquart M, Duberstein PR. Depression and cancer mortality: A meta-analysis. Psychol Med 2010;40:1797–810. https://doi.org/ 10.1017/S0033291709992285. [17] Hamer M, Chida Y, Molloy GJ. Psychological distress and cancer mortality. J Psychosom Res 2009;66:255–8. https://doi.org/10.1016/j. jpsychores.2008.11.002. [18] Cassileth BR, Lusk EJ, Miller DS, Brown LL, Miller C. Psychosocial correlates of survival in advanced malignant disease? N Engl J Med 1985;312:1551–5. https://doi.org/10.1056/NEJM198506133122406. [19] Coyne JC, Pajak TF, Harris J, Konski A, Movsas B, Ang K, et al. Emotional well-being does not predict survival in head and neck cancer patients: A radiation therapy oncology group study. Cancer 2007;110:2568–75. https://doi.org/10.1002/cncr.23080. [20] Mykletun A, Bjerkeset O, øverland S, Prince M, Dewey M, Stewart R. Levels of anxiety and depression as predictors of mortality: The HUNT study. Br J Psychiatry 2009;195:118–25. https://doi.org/ 10.1192/bjp.bp.108.054866. [21] Brintzenhofe-Szoc KM, Levin TT, Li Y, Kissane DW, Zabora JR. Mixed anxiety/depression symptoms in a large cancer cohort: Prevalence by cancer type. Psychosomatics 2009;50:383–91. https://doi. org/10.1176/appi.psy.50.4.383. [22] Mitchell AJ, Chan M, Bhatti H, Halton M, Grassi L, Johansen C, et al. Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: A metaanalysis of 94 interview-based studies. Lancet Oncol 2011;12:160– 74. https://doi.org/10.1016/S1470-2045(11)70002-X. [23] Bergerot CD, Clark KL, Ashing KT, Bergerot PG, Obenchain R, Dizman N, et al. Biopsychosocial distress and clinical outcome in metastatic renal cell carcinoma. Palliat Support Care2018:1−3. doi:10.1017/S1478951518000342. [24] Bergerot CD, Battle D, Staehler MD, Pal SK. Distress in patients with renal cell carcinoma: a curious gap in knowledge. BJU Int 2018. https://doi.org/10.1111/bju.14564. [25] Jazzar U, Yong S, Klaassen Z, Huo J, Hughes BD, Esparza E, et al. Impact of psychiatric illness on decreased survival in elderly patients with bladder cancer in the United States. Cancer 2018;124:3127–35. https://doi.org/10.1002/cncr.31404. [26] Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of tumours of the urinary system and male genital organs—Part A: Renal, penile, and testicular tumours. Eur Urol 2016;70:93–105. https://doi.org/10.1016/j.eururo.2016.02.029. [27] Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the sign score. J Urol 2002;168:2395–400. https://doi.org/10.1016/S0022-5347(05)64153-5. [28] Fervaha G, Izard JP, Tripp DA, Rajan S, Leong DP, Siemens DR. Depression and prostate cancer: A focused review for the clinician. Urol Oncol Semin Orig Investig 2019. https://doi.org/10.1016/j.urolonc.2018.12.020. [29] Pompe RS, Kr€uger A, Preisser F, Karakiewicz PI, Michl U, Graefen M, et al. The impact of anxiety and depression on surgical and functional outcomes in patients who underwent radical prostatectomy. Eur Urol Focus 2018. https://doi.org/10.1016/j.euf.2018.12.008. [30] Jayadevappa R, Malkowicz SB, Chhatre S, Johnson JC, Gallo JJ. The burden of depression in prostate cancer: Depression and prostate cancer. Psychooncology 2012;21:1338–45. https://doi.org/10.1002/ pon.2032. [31] Pham H, Torres H, Sharma P. Mental health implications in bladder cancer patients: A review. Urol Oncol Semin Orig Investig 2019;37:97–107. https://doi.org/10.1016/j.urolonc.2018.12.006. [32] Palapattu GS, Haisfield-Wolfe ME, Walker JM, BrintzenhofeSzoc K, Trock B, Zabora J, et al. Assessment of perioperative psychological distress in patients undergoing radical cystectomy for bladder cancer. J Urol 2004;172:1814–7.
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Urologic Oncology: Seminars and Original Investigations 000 (2019) 1−9
Clinical-Kidney cancer
The association of anxiety and depression with perioperative and oncologic outcomes among patients with clear cell renal cell carcinoma undergoing nephrectomy Vignesh T. Packiam, M.D.a, Mark D. Tyson II, M.D.b, Matvey Tsivian, M.D.a, Christine M. Lohse, M.S.c, Stephen A. Boorjian, M.D.a, John C. Cheville, M.D.d, Brian A. Costello, M.D.e, Bradley C. Leibovich, M.D.a, R. Houston Thompson, M.D.a,* a
Mayo Clinic, Department of Urology, Rochester, MN Mayo Clinic, Department of Urology, Scottsdale, AZ c Mayo Clinic, Department of Health Sciences Research, Rochester, MN d Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, MN e Mayo Clinic, Department of Oncology, Rochester, MN b
Received 17 June 2019; received in revised form 25 August 2019; accepted 29 October 2019
Abstract Objectives: Anxiety and depression have been associated with inferior overall survival for several malignancies, including metastatic renal cell carcinoma (RCC). However, there is minimal data evaluating this association for localized RCC. We evaluated the association of anxiety or depression with survival in patients with surgically treated localized clear cell RCC (ccRCC). Patients and methods: We reviewed our institutional nephrectomy registry of 1,990 adults who underwent radical or partial nephrectomy for unilateral, sporadic, nonmetastatic ccRCC between 1995 and 2011. Baseline anxiety and depression were identified using ICD-9 codes. Associations of anxiety or depression with 30-day complications and oncologic outcomes were evaluated using Cox proportional hazards models as well as adjustment for propensity score (PS) quintile and re-weighting by stabilized inverse probability weights. Results: A total of 197 (10%) patients were identified with a diagnosis of anxiety or depression. Median follow-up among survivors was 10.0 (IQR 7.3−13.6) years, during which time 864 patients died, including 363 from RCC. After PS adjustment, clinical and pathologic features were well balanced between groups. Patients with anxiety or depression had increased overall 30-day complications compared to those without (17% vs. 11%, P = 0.011). No significant differences were noted in time to local ipsilateral recurrence (P = 0.54), distant metastases (P = 0.96), or death from RCC (P = 0.42) between patients with vs. without anxiety or depression, while patients with anxiety or depression trended toward worse overall survival (hazard ratio 1.29, 95%CI 0.98−1.69, P = 0.065). Conclusions: Neither anxiety nor depression were significantly associated with oncologic outcomes among patients who underwent surgery for localized ccRCC. The trend toward worse overall survival among patients with anxiety or depression warrants further investigation. Ó 2019 Elsevier Inc. All rights reserved.
Keywords: Kidney cancer; Mortality; Survival; Depression; anxiety
1. Introduction There were an estimated 65,340 new cases and 14,970 deaths from kidney cancer in the United States in 2018 [1]. Funding sources: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. *Corresponding author. E-mail address: [email protected] (R.H. Thompson). https://doi.org/10.1016/j.urolonc.2019.10.017 1078-1439/Ó 2019 Elsevier Inc. All rights reserved.
Over 90% of kidney cancers are renal cell carcinoma (RCC), predominantly of clear cell histology [2]. Growing utilization of cross-sectional imaging has resulted in increased incidental detection of localized RCC, with approximately 70% to 75% newly diagnosed cases staged nonmetastatic [3]. While management for localized disease has evolved to include consideration of active surveillance and ablative techniques, there has been an increasing trend
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towards surgical management for patients with localized RCC [4−6]. Overall survival for RCC has slowly improved over time with advances in surgical and systemic management [7]. Psychological distress impacts patients with cancer throughout the course of their care from time of diagnosis to treatment and post-treatment surveillance [8]. Accumulating evidence from animal and clinical studies suggests that anxiety and depression modulate angiogenesis and immune response that may result in increased mortality [9]. Partly due to these findings, the American Society of Clinical Oncology and Centers for Medicare and Medicaid Services have strengthened recommendations to assess and address psychosocial needs in oncologic care plans, which is now mandated for cancer center hospital accreditation [10−13]. Randomized data have demonstrated that psychologic intervention in cancer patients improves both overall survival and quality of life [14,15]. However, while some reports have corroborated the association between distress and survival for certain malignancies, others have shown conflicting data [16−20]. Anxiety and depression are common among kidney cancer patients [21,22]. Whereas an association between biopsychosocial distress and mortality in patients with metastatic kidney cancer has been reported [23], little is known regarding psychological conditions and mortality for surgically treated localized kidney cancer [24]. In this context, we tested the hypothesis that anxiety and depression are associated with survival in a large institutional cohort of patients with surgically treated localized clear cell RCC. 2. Patients and methods
nephrectomy for unilateral, sporadic, M0, noncystic clear cell RCC between 1995 and 2011. 2.2. Assessment of data Clinical features studied included year of surgery, age at surgery, sex, race, symptoms, constitutional symptoms, smoking status, Eastern Cooperative Oncology Group performance status, Charlson score, body mass index (BMI), preoperative estimated glomerular filtration rate (eGFR) calculated using the Chronic Kidney Disease Epidemiology Collaboration formula and expressed as mL/min/1.73m2, radiographic tumor size, surgical approach, and surgical margin status. The diagnoses of anxiety or depression prior to or at surgery were determined by ICD-9 codes for these diagnoses adapted from previous studies (Table 1) [25]. A medical record chart review was conducted on a random 10% sample of the population which demonstrated 98% accuracy of these diagnoses based on ICD-9 codes. Patients with a palpable flank or abdominal mass, discomfort, gross hematuria, acute onset varicocele, or constitutional symptoms including rash, sweats, weight loss, fatigue, early satiety, and anorexia were considered symptomatic. Pathologic features included pathologic tumor size, 2018 pT and N classifications, WHO/ISUP grade, coagulative tumor necrosis, sarcomatoid differentiation, and the Mayo Clinic SSIGN score [26,27]. To obtain these pathologic features, 1 urologic pathologist (J.C.C.) reviewed all microscopic slides from the surgery over time as the database was prospectively maintained, without knowledge of patient outcome. Outcomes studied included 30-day postoperative complications and local ipsilateral recurrence, distant metastases, death from any cause, and death from RCC.
2.1. Study population 2.3. Statistical analyses After Institutional Review Board approval was obtained, the Mayo Clinic Rochester Nephrectomy Registry was queried to identify 1,990 adults treated with radical or partial
Continuous features were summarized with means and standard deviations when approximately normally distributed
Table 1 Summary of anxiety and depression ICD-9 codes, N = 1,990 Diagnosis
ICD-9 codes
n
Anxiety disorders Acute reaction to stress Adjustment disorder with anxiety or mixed anxiety/depressed mood Post-traumatic stress disorder or other reactions to severe stress Single episode depressive disorders Recurrent depressive disorders Atypical depressive disorder Unspecified episodic mood disorder Dysthymic disorder Affective personality disorder/cyclothymia Depression NEC (not elsewhere classifiable)
293.84, 293.89, 300.0, 300.00, 300.01, 300.02, 300.09, 300.21 308.0, 308.1, 308.2, 308.3, 308.4, 308.9 309.24, 309.28 309.81, 309.82, 309.83, 309.89 296.2, 296.20, 296.21, 296.22, 296.23, 296.24, 296.25, 296.26 296.3, 296.30, 296.31, 296.32, 296.33, 296.34, 296.35, 296.36 296.82 296.90 300.4 301.1, 301.10, 301.12, 301.13 311
91 8 11 6 20 46 1 3 33 1 116
*Some patients had multiple diagnoses. **No patients in this cohort had the following ICD-9 codes: 293.89, 300.0, 300.09, 308.0, 308.1, 308.2, 308.4, 309.82, 309.83, 296.2, 296.22, 296.23, 296.24, 296.3, 298.0, 301.1, 301.10, 301.12, 313.1.
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and with medians and interquartile ranges (IQRs) otherwise. Categorical features were summarized with frequency counts and percentages. Clinical and pathologic features were compared between patients with and without anxiety or depression using 2-sample t, Wilcoxon rank sum, and chi-square tests. Observed local ipsilateral recurrence-free, distant metastases-free, overall, and cancer-specific survival rates were obtained using the Kaplan-Meier method. The duration of follow-up was calculated from the date of surgery to the date of the outcome of interest or the date of last clinical follow-up. Propensity scores (PS) for being diagnosed with anxiety or depression were obtained using a logistic regression model with anxiety or depression as the outcome and the clinical and pathologic features listed above, except for race and radiographic tumor size, as covariates. These 2 features were not included in the model because of the amount of missing data. The pattern of missing data for the remaining features was assumed to be arbitrary, and all analyses were conducted using a complete case approach. Associations of anxiety or depression with 30-day postoperative complications were evaluated using chi-square tests in the pseudo cohort after re-weighting by stabilized IPWs. Associations of anxiety or depression with time to ipsilateral local recurrence, distant metastases, death from RCC, and death from any cause were evaluated using Cox proportional hazards regression models and summarized with hazard ratios (HRs) and 95% confidence intervals (CIs). Two PS techniques were used to evaluate these associations: adjustment for PS quintile and re-weighting by stabilized inverse probability weights (IPWs). Predicted local ipsilateral recurrence-free, distant metastases-free, cancer-specific, and overall survival rates were obtained for the pseudo cohort using Cox proportional hazards regression models after re-weighting by stabilized IPWs. Statistical analyses were performed using SAS version 9.4 (SAS Institute; Cary, NC). All tests were 2-sided, and P values <0.05 were considered statistically significant. 3. Results 3.1. Patient characteristics Among the 1,990 patients included, 57 were diagnosed with anxiety alone, 107 diagnosed with depression alone, and 33 diagnosed with both anxiety and depression (Table 1). Comparisons of clinical and pathologic features between the 1,793 (90%) patients without anxiety or depression and the 197 (10%) patients with anxiety or depression are shown in Table 2. The most significant differences between groups were for the variables age, year of surgery, gender, Eastern Cooperative Oncology Group performance status, and surgical approach (all P < 0.001), while there were also differences in BMI, preoperative eGFR, pathologic tumor size and T stage, SSIGN score, symptomatic presentation, and pathologic grade.
3
Fifty-eight patients without anxiety or depression and 5 patients with anxiety or depression had missing data for 1 or more of the clinical and pathologic features included in the PS model. In addition, 26 patients without anxiety or depression and 1 patient with anxiety or depression had PS that did not fall within the common range for the 2 groups and were excluded. As such, a total of 1,900 patients formed the cohort for the PS analyses, including 1,709 (90%) without anxiety or depression and 191 (10%) with anxiety or depression. After PS adjustment, the clinical and pathologic features were wellbalanced between the 2 groups. Specifically, no clinical or pathologic feature was statistically significantly different between patients with and without anxiety or depression after adjusting for PS quintile (data not shown) or in the pseudo cohort after re-weighting by stabilized IPWs (Table 3). 3.2. Complications Among the 1,900 included in the PS analyses, there were 215 (11%) who experienced at least 1 complication, including 96 (5%) who experienced a Clavien grade 3/4/5 complication. Comparisons of 30-day postoperative complications between patients with and without anxiety or depression in the pseudo cohort are also shown in Table 4. Patients with anxiety or depression had higher rates of any 30-day postoperative complication (17% vs. 11%, P = 0.011), 30-day myocardial infarction (4% vs. 1%, P = 0.001), and 30-day urine leak (4% vs. 1%, P = 0.004) compared to those neither diagnosis. 3.3. Survival outcomes 3.3.1. Overall survival outcomes At last follow-up, 160 of the 1,900 patients included in the PS analyses experienced a local ipsilateral recurrence at a median of 1.6 (IQR 0.6−4.6) years following surgery. The observed local ipsilateral recurrence-free survival rate (95% CI; number still at risk) at 10 years was 90% (89−92; 670). There were 494 patients who experienced distant metastases at a median of 1.6 (IQR 0.5−4.5) years following surgery. The observed metastases-free survival rate at 10 years was 73% (70−75; 622). A total of 864 patients died at a median of 5.1 (IQR 2.0−9.2) years following surgery, including 363 who died from RCC at a median of 3.0 (IQR 1.3−6.8) years. Seventy-three patients who died from unknown causes were excluded from the analyses of cancer-specific survival. The median duration of follow-up for the 1,036 patients who were still alive at last follow-up was 10.0 (IQR 7.3−13.6) years. The observed overall and cancer-specific survival rates at 10 years following surgery were 60% (58−63; 702) and 79% (77−81; 662), respectively. 3.3.2. Survival outcomes stratified by presence of anxiety and depression We found no statistically significant associations of anxiety or depression with time to ipsilateral local
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Table 2 Comparisons of clinical and pathologic features by anxiety or depression Mean (SD) All N = 1,990
Neither N = 1,793
Feature Age at surgery in years BMI in kg/m2 (N = 1,988) Preoperative eGFR (N = 1,961) Radiographic tumor size in cm (N = 1,784) Pathologic tumor size in cm (N = 1,985)
62.0 (12.0) 30.3 (6.2) 66.1 (20.2) 5.6 (3.4) 5.9 (3.7)
Charlson score SSIGN score (N = 1,985) Year of surgery 1995−1999 2000−2004 2005−2011 Sex Female Male Race (N = 1,807) All others White Symptoms (N = 1,988) Constitutional symptoms (N = 1,988) Smoking status (N = 1,966) Never Current Former ECOG performance status 0 1 2 3 4 BMI ≥30 kg/m2 (N = 1,988) Preoperative eGFR (N = 1,961) ≥90 60 to <90 45 to <60 30 to <45 15 to <30 <15 Surgical approach Open radical Open partial Laparoscopic radical Laparoscopic partial Positive surgical margins (N = 1,988) 2018 pT (N = 1,986) pT1a pT1b pT2a pT2b pT3a pT3b pT3c pT4 2018 pN pNx pN0
1 (0−2) 2 (0−5) 398 (20) 601 (30) 991 (50)
62.4 (11.9) 30.1 (6.2) 65.6 (19.9) 5.6 (3.4) 5.9 (3.8) Median (IQR) 1 (0−2) 2 (0−5) n (%) 382 (21) 567 (32) 844 (47)
Anxiety or depression N = 197
P value
58.8 (12.1) 31.3 (6.8) 70.4 (21.9) 5.3 (3.2) 5.4 (3.4)
<0.001 0.011 0.002 0.25 0.047
1 (0−2) 1 (0−4)
0.86 0.019
16 (8) 34 (17) 147 (75)
<0.001
701 (35) 1,289 (65)
598 (33) 1,195 (67)
103 (52) 94 (48)
<0.001
64 (4) 1,743 (96) 932 (47) 323 (16)
55 (3) 1,564 (97) 862 (48) 295 (16)
9 (5) 179 (95) 70 (36) 28 (14)
0.33
808 (41) 349 (18) 809 (41)
737 (42) 306 (17) 726 (41)
71 (36) 43 (22) 83 (42)
0.18
1,708 (86) 197 (10) 52 (3) 30 (2) 3 (<1) 900 (45)
1,555 (87) 169 (9) 45 (3) 22 (1) 2 (<1) 794 (44)
153 (78) 28 (14) 7 (4) 8 (4) 1 (1) 106 (54)
<0.001
248 (13) 969 (49) 469 (24) 200 (10) 56 (3) 19 (1)
209 (12) 870 (49) 438 (25) 181 (10) 53 (3) 16 (1)
39 (20) 99 (51) 31 (16) 19 (10) 3 (2) 3 (2)
0.001
943 (47) 726 (36) 201 (10) 120 (6) 59 (3)
879 (49) 630 (35) 177 (10) 107 (6) 54 (3)
64 (32) 96 (49) 24 (12) 13 (7) 5 (3)
<0.001
777 (39) 461 (23) 165 (8) 69 (3) 373 (19) 107 (5) 13 (1) 21 (1)
688 (38) 418 (23) 144 (8) 65 (4) 344 (19) 97 (5) 13 (1) 21 (1)
89 (45) 43 (22) 21 (11) 4 (2) 29 (15) 10 (5) 0 0
0.027
1,509 (76) 402 (20)
1,352 (75) 368 (21)
157 (80) 34 (17)
0.40
0.001 0.43
0.011
0.71
(continued)
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Table 2 (Continued) Mean (SD) All N = 1,990
Neither N = 1,793
Feature pN1 Grade 1 2 3 4 Coagulative Necrosis Sarcomatoid features
Anxiety or depression N = 197
79 (4)
73 (4)
6 (3)
155 (8) 887 (45) 773 (39) 175 (9) 440 (22) 45 (2)
132 (7) 790 (44) 713 (40) 158 (9) 402 (22) 42 (2)
23 (12) 97 (49) 60 (30) 17 (9) 38 (19) 3 (2)
P value
0.010
0.31 0.46
*Sample sizes for features with missing data are indicated in italics in parentheses.
Table 3 Comparisons of clinical and pathologic features by anxiety or depression in the pseudo cohort after re-weighting by stabilized IPWs
Table 3 (Continued) Mean (SD)
Mean (SD) Neither N = 1,707
P value
61.9 (11.9)
62.4 (12.3)
0.63
30.3 (6.3) 66.1 (20.2) 5.6 (3.4)
30.3 (6.1) 65.5 (20.2) 5.6 (3.3)
0.96 0.70 0.86
5.9 (3.7)
5.6 (3.4)
0.45
Feature Age at surgery in years BMI in kg/m2 Preoperative eGFR Radiographic tumor size in cm (N = 1,712) Pathologic tumor size in cm Charlson score SSIGN score Year of surgery 1995−1999 2000−2004 2005−2011 Sex Female Male Race (N = 1,729) All others White Symptoms Constitutional symptoms Smoking status Never Current Former ECOG performance status 0 1 2 3
Neither N = 1,707
Anxiety or depression N = 192
Median (IQR) 1 (0−2) 0 (0−2) 2 (0−5) 2 (0−4) n (%) 327 (19) 34 (18) 509 (30) 62 (32) 871 (51) 96 (50)
Feature
0.33 0.86 0.99
606 (36) 1,101 (64)
70 (36) 122 (64)
0.83
55 (4) 1,496 (96) 793 (46) 275 (16)
5 (3) 173 (97) 93 (48) 26 (13)
0.54
693 (41) 306 (18) 708 (41)
89 (46) 39 (20) 64 (34)
0.10
1,467 (86) 166 (10) 49 (3) 24 (1)
159 (83) 25 (13) 4 (2) 4 (2)
0.39
0.59 0.34
(continued)
4 BMI ≥30 kg/m2 Preoperative eGFR ≥90 60 to <90 45 to <60 30 to <45 15 to <30 <15 Surgical approach Open radical Open partial Laparoscopic radical Laparoscopic partial Positive surgical margins 2018 pT pT1a pT1b pT2a pT2b pT3a pT3b pT3c pT4 2018 pN pNx pN0 pN1 Grade 1 2 3 4 Necrosis Sarcomatoid
Anxiety or depression N = 192
P value
1 (<1) 774 (45)
0 95 (49)
215 (13) 846 (50) 408 (24) 170 (10) 51 (3) 17 (1)
24 (12) 104 (54) 37 (19) 23 (12) 1 (1) 3 (2)
0.55
803 (47) 627 (37) 174 (10)
90 (47) 76 (40) 18 (9)
0.76
103 (6)
8 (4)
52 (3)
5 (3)
0.81
678 (40) 401 (23) 136 (8) 55 (3) 322 (19) 88 (5) 11 (1) 16 (1)
77 (40) 42 (22) 19 (10) 4 (2) 34 (18) 16 (8) 0 0
0.91
1,294 (76) 346 (20) 67 (4)
138 (72) 47 (24) 7 (4)
0.34
135 (8) 766 (45) 660 (39) 146 (9) 372 (22) 35 (2)
21 (11) 76 (39) 80 (42) 15 (8) 37 (19) 4 (2)
0.82
0.28
0.39 0.96
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Table 4 Comparisons of 30-day postoperative complications by anxiety or depression in the pseudo cohort after re-weighting by stabilized IPWs n (%) Neither N = 1,707 Feature 30-day postoperative complications Death Hemorrhage Deep vein thrombosis Pulmonary embolism Myocardial infarction Wound infection or dehiscence Abscess Urine leak Sepsis Acute renal failure Dialysis Pneumothorax Other Any of the above Any of the above Clavien grade ≥3
8 (<1) 46 (3) 14 (1) 12 (1) 9 (1) 36 (2) 11 (1) 25 (1) 13 (1) 61 (4) 12 (1) 10 (1) 12 (1) 181 (11) 79 (5)
Anxiety or depression N = 192
P value
1 (1) 6 (3) 1 (<1) 2 (1) 7 (4) 8 (4) 2 (1) 8 (4) 3 (1) 8 (4) 1 (1) 1 (1) 2 (1) 32 (17) 13 (7)
0.85 0.85 0.44 0.75 <0.001 0.046 0.38 0.004 0.32 0.67 0.83 0.88 0.91 0.011 0.24
recurrence, distant metastases, death from RCC, and death from any cause. Of note, we did identify a trend toward an association between anxiety or depression and death from any cause (HR in pseudo cohort after re-weighting 1.29; 95% CI 0.98−1.69, P = 0.065; Table 5). Predicted local ipsilateral recurrence-free, distant metastases-free, cancerspecific, and overall survival rates in the pseudo cohort after re-weighting by stabilized IPWs are illustrated in Fig. 1(A−D), respectively. 4. Discussion Our study suggests that compared to patients without anxiety or depression, patients with anxiety or depression: (1) are more likely female with more recent operations, (2) have higher overall 30-day rates of complications, (3) have Table 5 Associations of anxiety or depression with survival outcomes Local ipsilateral recurrence
HR (95% CI)a
P value
Adjusted for PS quintiles In pseudo cohort after re-weighting Distant metastases Adjusted for PS quintile In pseudo cohort after re-weighting Death from RCC Adjusted for PS quintile In pseudo cohort after re-weighting Death from any cause Adjusted for PS quintile In pseudo cohort after re-weighting
1.12 (0.66−1.91) 1.26 (0.60−2.63)
0.68 0.54
1.04 (0.73−1.47) 0.99 (0.64−1.52)
0.84 0.96
1.12 (0.75−1.69) 1.23 (0.75−2.02)
0.58 0.42
1.20 (0.94−1.54) 1.29 (0.98−1.69)
0.15 0.065
a
HR represents the association of anxiety or depression with outcome.
comparable local ipsilateral recurrence-free, distant metastases-free, and cancer-specific survival, and (4) have a trend to worse overall survival. To our knowledge, this report is the first to assess the association between anxiety or depression and oncologic outcomes in a nonmetastatic RCC cohort. This study adds to the emerging literature characterizing distress for other urologic malignancies such as prostate and bladder cancer [25,28−32]. Importantly, psychological distress is increasingly recognized as a crucial component of oncologic care, reflected by the consideration of distress as the “sixth vital sign” in NCCN recommendations [33]. The influence of baseline psychiatric distress on other baseline characteristics, tumor characteristics, and postoperative complications has previously been unexplored for nonmetastatic RCC. Our study found statistically significant but clinically minor differences in several baseline and tumor characteristics between patients with and without anxiety or depression; those with anxiety or depression had lower age, higher BMI, higher eGFR, smaller pathologic tumor size, lower SSIGN score, and less symptomatic disease compared to those without anxiety or depression. Larger differences were seen with respect to more recent surgery year and higher rate of female gender among patients with anxiety or depression. These findings are concordant with previous studies demonstrating that psychological distress is increasingly prevalent over time and almost twice as common in women than men [34−36]. Notably, our study did not identify a significant association between anxiety or depression and high grade postoperative complications. This is in contrast to a report by Sharma et al. that found an association with poor patient-reported mental health metrics and high grade complications after radical cystectomy [37]. This discordance may be secondary to the much lower event rate for high grade complications for kidney cancer in this study vs. for bladder cancer in Sharma et al.’s (5% vs. 16.8%, respectively) [37]. There are many mechanisms by which anxiety and depression may influence oncologic outcomes, including altered angiogenesis and immune dysregulation [9]. Our study found that after PS adjustment for baseline clinical and tumor characteristics, there was no statistically significant association between anxiety or depression and any survival measures. However, there was a nonsignificant reduction in overall survival (P = 0.065) in patients with anxiety or depression after re-weighting by stabilized IPWs. The implications of this finding are unclear, especially in light of no previously existing data assessing this association. Interestingly, Bergerot et al. identified a similar nonstatistically significant trend between biopsychosocial distress and poorer overall survival in 102 patients with metastatic RCC (P = 0.09) [23]. Larger scale analyses using the Surveillance, Epidemiology, and End Results (SEER)Medicare-linked database assessed 50,147 and 3,709 patients with prostate and bladder cancer, respectively, finding significant associations between psychological distress
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Fig. 1. (A−D) Predicted local ipsilateral recurrence-free survival (A), metastases-free survival (B), cancer-specific survival (C), and overall survival (D) in patients with anxiety or depression versus patients without either diagnosis. Because these figures illustrate predicted rates, not observed rates, the numbers still at risk at 2, 4, 6, 8, and 10 years following surgery do not apply.
and inferior overall survival in these malignancies [25,30]. Palapattu and colleagues found that preoperatively identified somatic distress scores but not depression or anxiety predicted disease progression for 74 bladder cancer patients assessed by the Basic Symptom Inventory-18 instrument [32]. The results of these studies may have been influenced by differing methodology with regard to identification, type, and onset of psychologic diagnoses [23,25,30]. While our findings are hypothesis generating, more research is needed in the setting of localized RCC to clarify the association between distress and survival. The ultimate goal of understanding the relationship between distress and survival is to tailor management to improve oncologic outcomes. An important trial in 227 patients with breast cancer randomized patients to a control arm or psychologic intervention that included muscle relaxation, problem solving, improved family support, communication strategies, and increased activity and nutrition [15]. The intervention resulted in improved recurrence free survival (HR 0.55, P = 0.034), cancer-specific survival (HR 0.44, P = 0.016), and overall survival (HR 0.51, P = 0.028) [15]. While several oncologic guidelines recommend assessment of psychologic distress, there are sparse recommendations for interventions once the diagnosis is made [10−13]. Further studies delineating the relationship between distress and survival for RCC patients may
strengthen support for studying and implementing such interventions. There are several limitations to the current study. First, ascertainment bias may have occurred based on the reliance of billing data to identify anxiety and depression, although the diagnoses were verified by chart review in a subset of patients. Second, a validated instrument to quantify anxiety and depression was not utilized in our study, and the method of diagnosis was unknown. We suspect these issues resulted in underreporting of anxiety and depression. Third, the severity of diagnoses was not characterized or accounted for. Fourth, the timing of diagnosis of anxiety and depression was limited to prior to or at surgery, and the implications of postoperative onset of these conditions were unable to be explored. Finally, utilization of a selected surgical cohort precludes assessment of the impact of anxiety and depression on the overall localized RCC population. 5. Conclusions In summary, we demonstrate that neither anxiety nor depression is significantly associated with oncologic outcomes among a large cohort of patients with localized surgically treated clear cell RCC. However, there was a trend toward worse overall survival among patients with anxiety or depression that warrants further investigation.
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Conflicts of interest None.
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