Abstract
Purpose
To study the overall survival and prognostic factors of patients with sarcomatoid renal cell carcinoma treated with nephrectomy and systemic therapy in the cytokine and targeted therapy eras.
Materials and Methods
This is a retrospective study of patients with sarcomatoid renal cell carcinoma who had nephrectomy and received systemic therapy at our center in the cytokine era (1987–2005) or the targeted therapy era (2006–2015). Multivariate regression models were used to determine the association of covariables with survival.
Results
Among 199 patients with sarcomatoid renal cell carcinoma, 167 (83.9%) have died (median overall survival 16.5 months; 95% CI: 15.2, 20.9). Survival of patients with clear-cell histology was significantly longer vs. those with non-clear cell histology (p = 0.034). Patients with synchronous metastatic disease had a significantly shorter survival compared with patients with metachronous metastatic disease (median 12.1 months vs. 23.3 months; p = 0.0064). Biopsy of the primary tumor or a metastatic site could detect the presence of sarcomatoid features in only 7.5% of cases. Although a significant improvement in survival rate was observed in the first year for patients treated in the targeted therapy era (p = 0.011), this effect was attenuated at year 2, disappeared at years 3–5 after diagnosis, and was not evident in patients with poor risk features.
Conclusions
Patients with sarcomatoid renal cell carcinoma still have poor prognosis with no clear long-term benefit of targeted therapy, underscoring the need to develop more effective systemic therapies for these patients.
Keywords: Sarcomatoid renal cell carcinoma, targeted therapies
INTRODUCTION
There are approximately 63,000 new renal cell carcinoma (RCC) cases and almost 14,000 deaths from RCC each year in the US1. Nephrectomy for clinically localized disease is the gold standard treatment for curative intent, with nephron-sparing surgery (partial nephrectomy) preferred in appropriately selected cases based on the extend of disease. However, RCC recurs in 20% to 40% of patients who undergo nephrectomy for clinically localized disease2. In addition, approximately 20% to 30% of patients with RCC present with metastatic disease2.
Sarcomatoid dedifferentiation can be an associated feature with any RCC histologic subtype. It is found in approximately 5% of all RCCs but accounts for 15–20% of patients with advanced disease. Histologically, renal cell carcinomas with sarcomatoid dedifferentiation (sRCC) contain pleomorphic spindle cells and giant cells interposed with an epithelial component3. Most sRCCs present with metastatic disease and are historically associated with a poor prognosis and a median overall survival of 4 to 9 months4–6.
Due to the rarity of sRCC, there is paucity of data on the optimal management of patients with advanced disease. Treatment with cytotoxic chemotherapy and/or cytokines historically produced very minimal responses and survival benefit3, 4, 7–10. Targeted therapies directed against the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways have revolutionized the treatment of advanced, clear-cell RCC; however, only small series exist that investigated the particular entity of sarcomatoid RCC6, 11–21. Herein, we present a retrospective analysis of our institutional sRCC database and describe the clinical and pathological characteristics of advanced sRCC. The study objective was to analyze the outcome of patients with metastatic sRCC in different therapeutic eras (before 2006 versus 2006 and later) and to explore factors associated with patient survival.
PATIENTS AND METHODS
Patients with sRCC who had nephrectomy, and received systemic therapy for metastatic disease at The University of Texas MD Anderson Cancer Center from 1987 to 2015 were retrospectively identified from a secure database. The study was approved by our institutional review board and was conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines. Patients had to have sarcomatoid features in their nephrectomy pathology specimen to be included in this analysis, regardless of the underlying histological RCC subtype.
Demographics, clinical features, performance status, symptoms at diagnosis, laboratory values, operative notes, pathological features, post-operative evaluation, systemic therapies and follow ups were recorded, and the Charlson comorbidity index (CCI) was calculated using this information. The CCI was not age-adjusted and no points were given for localized or metastatic sRCC. Points were added to the CCI if patients had localized or metastatic malignancies other than sRCC. Risk stratification was performed using both the international metastatic renal cell carcinoma database consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic models22, 23.
Systemic therapies were grouped as ‘targeted’ (sunitinib, sorafenib, bevacizumab, axitinib, pazopanib, erlotinib, temsirolimus, or everolimus), ‘immunotherapy’ (IL-2, IFNα, dendritic cells pulsed with tumor lysate vaccination, heat shock protein peptide complex-96 vaccination, nivolumab, ipilimumab), ‘chemotherapy’ (cyclophosphamide, doxorubicin, 5-fluorouracil, gemcitabine, cisplatin, capecitabine), or ‘combinations’ (this group consisted of two subgroups: one including targeted therapies, and another including therapies other than targeted therapies).
Statistical Methods
Unless otherwise specified, overall survival (OS) was measured from time of diagnosis until death of any cause or last follow-up. Patients who were alive at the time of last contact were censored on that date. OS curves were estimated by the Kaplan-Meier method and were compared using the log-rank test. Median follow-up time was calculated using the reverse Kaplan-Meier method. Cox regression models were used to determine the association of variables with OS. A p value <0.05 was considered statistically significant. A multivariate analysis was conducted using backward variable selection, and cut-points for numeric variables were selected based on univariate analysis of terciles. Plots of median OS, and OS probabilities at selected times as smooth functions of year of diagnosis, were generated using nonparametric quantile regression adapted for right censored data24.
RESULTS
Clinical and pathological characteristics
We identified 199 patients with sRCC who had undergone nephrectomy and received systemic therapy. The median age of all patients at initial diagnosis was 57 years, with a 2:1 male preponderance (Table 1). The vast majority of patients were symptomatic at initial diagnosis (92%), with pain being the most common symptom (52.3%), followed by hematuria (34.7%). The majority of the patients were Caucasian (79.9%). The median time to initiation of systemic therapy from nephrectomy was 3.7 months (range 0 – 88 months). Median follow-up was 8.8 years from diagnosis and 8.6 years from nephrectomy.
Table 1.
Clinical and pathological characteristics of study patients (N=199)
| Age – Median, years (range) | 57 (22–82) |
| Gender | |
| Female | 69 (34.7%) |
| Male | 130 (65.7%) |
| Race | |
| White | 159 (79.9%) |
| Hispanic | 25 (12.6%) |
| Black | 8 (4%) |
| Other | 7 (3.5%) |
| ECOG Performance Status | |
| 0 | 35 (17.6%) |
| 1 | 126 (63.3%) |
| ≥2 | 38 (19.1%) |
| Symptoms Any Relevant | 183 (92%) |
| Pain | 104 (52.3%) |
| Hematuria | 69 (34.7%) |
| Weight Loss | 45 (22.6%) |
| Night Sweats | 25 (12.6%) |
| Fever | 21 (10.6%) |
| Charlson Comorbidity Index | |
| 0 | 130 (65.3%) |
| 1 | 42 (21.1%) |
| 2 | 18 (9.0%) |
| 3 | 6 (3.0%) |
| 4 | 1 (0.5%) |
| 6 | 1 (0.5%) |
| Missing | 1 (0.5%) |
| Smoking History | |
| Yes | 117 (59%) |
| No | 82 (41%) |
| Tumor Size – Median, cm (range) | 11 (1.8 – 27) |
| Pathologic Tumor Stage | |
| T1/T2 | 38 (19.1%) |
| T3 | 131 (65.8%) |
| T4 | 27 (13.6%) |
| Missing | 3 (1.5%) |
| Primary Epithelial Histology | |
| Clear cell | 161 (80.9%) |
| Non-clear cell | 38 (19.1%) |
| Pathological Nodal Stage | |
| N0/Nx | 127 (63.8%) |
| N1 | 63 (31.7%) |
| Missing | 9 (4.5%) |
| Positive Surgical Margins* | |
| Yes | 35 (17.6%) |
| No | 162 (81.4%) |
Soft tissue and/or vein wall margins
Preoperative biopsy was performed on 133 patients (76 patients had a biopsy of their primary tumor, and 57 patients had a biopsy of a metastatic site), but the diagnosis of sRCC was made in only 10 cases (3 kidney biopsies and 7 biopsies of a metastatic site) based on this biopsy. Out of the 199 patients, 139 (69.9%) had metastatic disease at initial presentation, and 60 (30.1%) developed metastatic disease after nephrectomy was performed with curative intent. All 199 patients had confirmed sarcomatoid features in their nephrectomy specimens; 181 patients had their nephrectomy at MDACC, and 18 patients had it elsewhere but received systemic therapy and were followed at MDACC. The primary epithelial component was clear-cell RCC in the majority of cases (80.9%).
Overall survival of patients with metastatic sRCC
Of the total cohort of 199 patients, 167 (83.9%) patients have died during the study follow-up (median OS 16.5 months, 95% CI: 15.2, 20.9). The OS rates were 94% (95% CI: 91%, 98%) at 6 months, 67% (95% CI: 61%, 74%) at 12 months, 38% (95% CI: 31%, 45%) at 2 years, and 14% (95% CI:10%, 21%) at 5 years (Figure 1). Compared with those who were diagnosed with localized disease, patients who presented with metastatic disease at initial diagnosis had a significantly shorter median OS (12.1 months vs. 23.3 months; p=0.0064).
Figure 1.
Probability of survival from time of diagnosis in patients with sRCC
Two preoperative laboratory values were found to be significantly associated with OS on multivariable analysis: preoperative corrected serum calcium (Ca) greater than 9.2 mg/dL [hazard ratio (HR) = 2.17, 95% CI: 1.4–3.35, p=0.0005) and preoperative white blood cell count (WBC) greater than 9.3 K/μL (HR = 1.64, 95% CI: 1.05–2.58, p=0.030). The neutrophil/lymphocyte ratio prior to nephrectomy was evaluable in 153 patients. Only 4 patients (2.6%) had a neutrophil/lymphocyte ratio < 3.0. However, when this ratio was dichotomized at the median of 3.23, it was significantly associated with OS (HR=2.0, 95% CI: 1.1 – 3.3, p= 0.021). Tumor stage at presentation (localized vs regional/distant metastases) and histology of the epithelial component (clear-cell vs non-clear cell) were also independently associated with OS on the multivariable analysis (HR=1.94, 95% CI 1.16–3.22, p=0.011, and HR=1.76, 95% CI 1.11–2.77, p=0.015 respectively). The OS for clear-cell vs. non-clear cell patients was similar during the first 12 months, but afterwards favored patients with underlying clear-cell histology (p=0.026) (Figure 2). Most patients had a large primary tumor (median tumor size 11 cm) staged as pT3 or pT4 (79.4%) (Table 1). Tumor size was not significantly associated with OS. The IMDC and MSKCC prognostic classification systems were able to distinguish OS differences between poor-risk and intermediate-risk groups in metastatic sRCC patients. Patients classified as “poor-risk” did significantly worse that those classified as “intermediate-risk” (p=0.017 by IMDC, and p=0.061 by MSKCC). There were patients with missing data (43 patients by IMDC, 60 patients by MSKCC) in both groups. Only four patients were classified as having favorable-risk by IMDC criteria, and none by MSKCC criteria (Figure 5).
Figure 2.
Overall survival (OS) after nephrectomy in patients with sRCC stratified by A. stage at presentation and B. underlying histology
Figure 5.
Overall survival (OS) in patients with sRCC stratified by A. the Memorial Sloan Kettering Cancer Center (MSKCC) and B. the international metastatic renal cell carcinoma database consortium (IMDC) criteria
Effect of systemic therapies on survival
As first-line therapy, 77 patients (38.6%) received targeted therapies, whereas 122 patients (61.3%) received chemotherapy or immunotherapy. Patients who received a combination of therapies were classified in two subgroups: A subgroup that included targeted therapies (n=13) and a subgroup that did not (n=43). Overall, there was no significant OS difference according to the type of first-line systemic therapy that patients received (Supplemental Figures 1 and 2).
To assess the potential impact of targeted therapy on OS, we compared the OS for patients in two eras: those diagnosed in 1987–2005, and those diagnosed in 2006–2015. As shown in Table 2, the baseline characteristics, including histology and tumor stage, were very similar between the two groups. There was no significant difference in the rates of stage IV disease (p=0.3) or of clear cell vs non-clear cell histology (p=0.62) between patients diagnosed in 1987–2005 compared with those diagnosed in 2006–2015. There was a significant improvement in OS at 12 months for patients diagnosed in the targeted therapy era (p = 0.011), but this effect was attenuated at year 2 and disappeared at years 3–5 after diagnosis (Figures 3&4 and Table 3). Of note, the improvement in OS was seen in patients with intermediate-risk by MSKCC or IMDC but not in patients with poor-risk (Supplementary Figure 3). Supplementary Figure 4 shows the association between sarcomatoid percentage and OS.
Table 2.
Baseline characteristics of patients diagnosed during the cytokine therapy era (1987–2005) and the targeted therapy era (2006–2015)
| 1987–2005 | 2006–2015 | |
|---|---|---|
| Number Of Patients | 116 | 83 |
| Median age | 55 | 58 |
| AJCC Stage | ||
| I | 5 (4%) | 2 (2%) |
| II | 9 (8%) | 1 (1%) |
| III | 25 (21%) | 31 (38%) |
| IV | 77 (67%) | 49 (59%) |
| Pathological Tumor Stage | ||
| T1a | 4 (4%) | 2 (2%) |
| T1b | 8 (7%) | 2 (2%) |
| T2a | 9 (8%) | 3 (3%) |
| T2b | 10 (9%) | 1 (1%) |
| T3a | 56 (50%) | 47 (58%) |
| T3b | 10 (9%) | 15 (18%) |
| T3c | 1 (1%) | 0 (0) |
| T4 | 13 (12%) | 13 (16%) |
| Histology | ||
| Clear Cell | 87 (74.5%) | 65 (78.3%) |
| Non-Clear Cell | 29 (25.5%) | 18 (21.7%) |
Figure 3.
Association between year of diagnosis and median overall survival (OS) from time of diagnosis.
Figure 4.
Association between year of diagnosis and overall survival (OS) at 1 year, 3 years and 5 years
Table 3.
Comparison of overall survival (OS) rates with 95% confidence intervals for patients diagnosed during the cytokine era (1987–2005) and the targeted therapy era (2006–2015)
| 1987–2005 | 2006–2015 | |
|---|---|---|
| 1-year OS | 61% (53%, 70%) | 79% (70%, 89%) |
| 2-year OS | 33% (26%, 42%) | 46% (36%, 60%) |
| 3-year OS | 26% (20%, 36%) | 29% (19%, 43%) |
| 4-year OS | 17% (12%, 26%) | 19% (11%, 34%) |
| 5-year OS | 14% (9%, 22%) | 13% (6%, 28%) |
Numbers in parentheses represent 95% confidence intervals
DISCUSSION
The majority of our patients (69.9%) presented with metastatic disease at initial diagnosis, while the rest developed metastasis after nephrectomy. This is consistent with prior literature suggesting that sRCC patients are more likely to be diagnosed at a higher clinical stage than those with clear-cell RCC without sarcomatoid dedifferentation25. In addition, the vast majority of our patients (92%) presented with symptoms related to their primary tumor or metastatic disease. Consistent with previous reports,26 our analysis suggested that patients with higher percentages of sarcomatoid component have shorter median OS (Supplementary Figure 4). Detecting sarcomatoid features by biopsy of the primary renal tumor or a metastatic site prior to nephrectomy is challenging. Currently, there are no biochemical or immunologic markers specific to sRCC, and the sensitivity of preoperative biopsies for sRCC is low, although it may improve by multiquadrant biopsies27. Indeed, in our large cohort, only 7.5% of sRCC patients were identified by biopsy prior to nephrectomy. Some authors have accordingly suggested the use of preoperative imaging modalities, such as MRI, to identify sRCC, although these approaches have not yet significantly improved diagnostic accuracy28. Of note, we did not include in our analysis patients diagnosed with biopsy-proven sRCC that did not undergo nephrectomy.
Although various cytotoxic chemotherapeutics have been studied in metastatic sRCC, none has shown a clear benefit. An earlier series published in 1987 from our institution, did not find any significant advantage of any particular chemotherapy, although doxorubicin-based chemotherapy did produce complete responses in 2/8 patients3. In 2011, the Eastern Cooperative Oncology Group (ECOG) published the results of a phase II trial of doxorubicin and gemcitabine in 39 patients with metastatic sRCC, and reported a 16% response rate, with significant toxicity associated with the regimen29. In the present study, 7% of patients received cytotoxic chemotherapy, with no observed meaningful survival benefit compared with other therapeutic modalities (Supplemental Figure 1).
There are few studies (listed in Supplementary Table 1) focusing on the treatment modalities of sRCC in the targeted therapy era. In the present manuscript, we report the largest single-institution experience studying the management and outcomes of patients with metastatic sRCC, who had nephrectomy as part of their treatment and who received systemic therapy. One of the goals of our study was to determine whether the introduction of targeted therapies has led to improved survival outcomes in these patients. Since VEGF-directed therapies and mTOR inhibitors entered the clinic in 2005, there has been a dramatic improvement in the outcomes of RCC patients in general, mainly those harboring the clear-cell RCC subtype. Published studies investigating targeted therapies alone or in combination with cytotoxic chemotherapy for sRCC have shown modest or no improvement in survival outcomes16, 18–20. In this report, we have shown a 1-year OS benefit for patients diagnosed after 2005, compared with those who were diagnosed before 2005. However, this improvement in OS was not durable, as the 3-year and 5-year overall survival rates were very similar for patients diagnosed in the cytokine era and those diagnosed in the targeted therapy era. Of note, we were unable to detect a statistically significant difference in OS among patients treated with first-line targeted therapies compared with other treatments. Therefore, it is clear that novel and more effective therapies are needed to achieve better clinical outcomes and prolong survival in patients with sRCC. The outcomes of patients with sRCC may be different from between studies, as we only included patients with sRCC who had nephrectomy. At present, it is unclear how much nephrectomy affects survival outcomes of patients with sRCC.
Potential confounders such as earlier diagnosis and improved supportive care may also account for the improved outcomes over time and may explain why the improvement in survival began in 2000, before targeted therapies became common practice, rather than 2005 (Figure 3). Indeed, Table 2 suggests a trend towards lower rates of Stage IV disease in patients diagnosed in the targeted therapy era, although this did not reach statistical significance. In addition, patients with poor-risk classification by either the MSKCC or IMDC criteria have not experienced any improvement in survival outcomes in over 2 decades (Supplementary Figure 3). These patients carry the worst prognosis and are in dire need for novel treatment strategies.
Our study differs from prior data in terms of longer follow up time and in being the largest single-institution cohort to date. In addition, we were able to study systemic therapies used over a long period of time, therefore allowing us to compare therapies in different eras. The limitations of our study include its retrospective nature and heterogeneous systemic therapies that patients received over the years. However, we controlled for several clinical and pathological variables known to influence survival outcomes, including the CCI, a validated risk adjustment tool that accounts for the effect of comorbidities on mortality30. We were unable to specifically control for the survival effect of targeted therapies when given beyond the first-line setting. Despite these limitations, we confirmed that the survival of sRCC patients without poor-risk features, who had nephrectomy, has improved over time in a large single-center analysis of sRCC spanning 3 decades of experience.
In conclusion, we have shown that the survival of patients with advanced sRCC who had nephrectomy has been steadily improving since 2000. The reasons for this may be the introduction of targeted therapies, earlier diagnosis, and improved supportive care. This survival benefit, however, does not extend beyond the first 2 years after diagnosis, and is not seen in patients with poor-risk features. Therefore, there is an unmet need to develop more effective therapies for patients with sRCC. The availability of immune checkpoint inhibitors for the salvage of patients with RCC after first-line therapy with VEGF directed therapies, and the launch of several phase 3 trials in the first-line setting combining two immune checkpoint inhibitors, or an immune checkpoint inhibitor with a VEGF directed agent, may hopefully improve the outcome of patients with sRCC.
Supplementary Material
Supplementary Figure 1. Overall survival (OS) in patients with sRCC stratified by the type of first-line therapy.
Supplementary Figure 2. Overall survival (OS) in patients with sRCC stratified by the type of first-line therapy and whether patients were: A. intermediate risk or B. poor risk by the international metastatic renal cell carcinoma database consortium (IMDC) criteria.
Supplementary Figure 3. Association between year of diagnosis and median overall survival (OS) in patients with sRCC stratified by A. the Memorial Sloan Kettering Cancer Center (MSKCC) and B. the international metastatic renal cell carcinoma database consortium (IMDC) criteria.
Supplementary Figure 4. A. Distribution of the percentage of the sarcomatoid component among 199 patients with sRCC. B. Association between the percentage of the sarcomatoid component and median overall survival (OS) from the time of diagnosis.
Acknowledgments
Pavlos Msaouel is supported by the National Institutes of Health T32 CA009666 grant.
The Biostatistics Resource Group is supported by MD Anderson’s National Cancer Institute Cancer Center Support Grant P30CA016672.
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Associated Data
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Supplementary Materials
Supplementary Figure 1. Overall survival (OS) in patients with sRCC stratified by the type of first-line therapy.
Supplementary Figure 2. Overall survival (OS) in patients with sRCC stratified by the type of first-line therapy and whether patients were: A. intermediate risk or B. poor risk by the international metastatic renal cell carcinoma database consortium (IMDC) criteria.
Supplementary Figure 3. Association between year of diagnosis and median overall survival (OS) in patients with sRCC stratified by A. the Memorial Sloan Kettering Cancer Center (MSKCC) and B. the international metastatic renal cell carcinoma database consortium (IMDC) criteria.
Supplementary Figure 4. A. Distribution of the percentage of the sarcomatoid component among 199 patients with sRCC. B. Association between the percentage of the sarcomatoid component and median overall survival (OS) from the time of diagnosis.