Original Study
Deferred Systemic Therapy in Patients With Metastatic Renal Cell Carcinoma Aaron P. Mitchell,1 Bradford R. Hirsch,1,2 Michael R. Harrison,1 Amy P. Abernethy,1,2 Daniel J. George1 Abstract We analyzed a retrospective cohort of 60 patients with metastatic renal cell carcinoma who did not receive systemic therapy within the first year after diagnosis. Reasons for delayed therapy included surgical or other local management, and an active surveillance approach. The 5-year survival was 59%, suggesting that deferred therapy may be an appropriate strategy in selected patients. Background: With the advent of small-molecule “targeted” therapies, the prevailing treatment paradigm for metastatic renal cell carcinoma (mRCC) is that all patients who are able to tolerate systemic therapy should receive it. However, oncologists often defer the initiation of systemic therapy for patients with mRCC. The outcomes of and clinical reasoning behind the initial management of patients with mRCC without systemic therapy have not been well described. Methods: We conducted a retrospective cohort study of all patients with mRCC treated within the Duke University Health System and diagnosed from January 1, 2007, to January 1, 2011. We defined our cohort as patients who did not receive systemic therapy during the first year after mRCC diagnosis. The clinical rationale for the lack of immediate treatment was ascertained by manual chart review. Results: A total of 60 of 268 patients (22%) with mRCC managed without initial systemic therapy were included in our study. The median age was 61.2 years, the median duration from diagnosis of localized RCC to development of mRCC was 41.9 months, and 91% of patients had Eastern Cooperative Oncology Group functional status of 1. Of the patients, 60% were managed with surgical metastasectomy alone, 12% received multiple local treatment modalities, 13% received active surveillance, 7% were managed supportively, and 8% were categorized as “other.” Conclusions: The majority of patients in our cohort had favorable disease characteristics and experienced favorable outcomes with surgery alone. Our results suggest that this population could represent 20% of patients with mRCC in tertiary care settings. Prospective data are needed to evaluate deferred systemic therapy as a management strategy. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Active surveillance, Management strategy, Metastasectomy, Outcomes, Surgery
Introduction Between 17% and 30% of patients with renal cell carcinoma (RCC) have metastatic disease at the time of diagnosis,1-3 and another 20% to 40% of those who undergo a potentially curative nephrectomy for localized disease will later develop metastatic disease.1,4-6 For those who are diagnosed with metastatic RCC (mRCC), a number of systemic treatment options exist, including 7 new agents approved by the US Food and Drug Administration from December 2005 to February 2012.7 1
Division of Medical Oncology, Duke University Medical Center, Durham, NC Center for Learning Health Care, Duke Clinical Research Institute, Durham, NC
2
Submitted: Sep 28, 2014; Revised: Dec 23, 2014; Accepted: Dec 26, 2014 Address for correspondence: Daniel J. George, MD, DUMC 102002, Durham, NC 27710 E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.12.017
The management of patients with mRCC with oligometastatic disease using surgery alone has long been an accepted strategy and is a recommended option in National Comprehensive Cancer Network guidelines.8 However, with the new availability of effective and well-tolerated treatments, the prevailing view is moving toward offering systemic therapy for a greater number of patients. The potential role of targeted agents as adjuvant therapy in this setting, currently under investigation,9 may be a factor. Physicians also may be less comfortable managing mRCC without systemic therapy because of the relative lack of data; the study of mRCC generally occurs within the context of therapeutic trials or postmarketing studies, which include only patients who receive systemic therapy. As a result, the cohort of patients with mRCC who elect to defer—or never receive—systemic treatment often go unrecognized and unstudied. The size of the cohort, patient and disease
Clinical Genitourinary Cancer Month 2015
-1
Delayed Systemic Therapy in Patients With mRCC characteristics, and clinical outcomes are unknown, especially in the era of targeted therapies. Anecdotally, some patients with mRCC achieve favorable outcomes for prolonged periods without systemic therapy; a more complete understanding of this group would inform treatment decisions and potentially avoid drug toxicity in those unlikely to benefit. Physician recommendations, in addition to patient preferences, certainly influence a patient’s decision to defer therapy. However, the clinical reasoning behind the initial management of mRCC without systemic therapy has not been well described. Is this strategy recommended to patients who are surgical candidates or to those perceived as unlikely to tolerate systemic therapy? To address this void and to understand the appropriateness of such an approach with currently available treatments, we describe the experience at one academic medical center of patients who did not receive initial systemic treatment in the context of available targeted therapies.
Figure 1 Cohort Selection
Materials and Methods
2
-
This retrospective cohort study received a waiver of informed consent from the institutional review board at Duke University. Eligible cases included all adult patients (aged > 18 years) with mRCC who received some portion of their mRCC care in the Duke University Health System. All patients were diagnosed with mRCC between January 1, 2007, and January 1, 2011, with the last data collection occurring in May 2013. Cases were initially identified by searching the Duke patient database using International Classification of Diseases, 9th Revision codes and were then confirmed by research coordinators. Study data were extracted from the Duke data warehouse (demographics, laboratory results, treatments) and supplemented by manual chart abstraction using a standardized case report form (histology, grade, metastatic burden, supplemental treatment history). Completed case report forms underwent quality review before entry into a secure study-specific data repository. The resulting registry contained 268 patients (Figure 1). The cohort of interest was defined as those patients who did not receive any systemic therapy before 1 year of follow-up had elapsed or death had occurred. Thus, patients who received systemic therapy within 1 year of diagnosis of mRCC were excluded, and those who went at least 1 year without receiving therapy or died in less than 1 year without receiving therapy were included. In addition, patients with insufficient documentation to confirm absence of systemic therapy before death or 1 year of follow-up were excluded, narrowing the cohort to 82 patients. During subsequent manual chart review, 22 patients were excluded from the analytic cohort; 14 had less than 1 year of follow-up, 6 did not have a pathologic diagnosis of mRCC, and 2 were duplicates. Sixty patients remained in the final analytic cohort. Dates of death were confirmed for all patients by searching the public record. A detailed review of clinical notes was used to define why each patient did not receive systemic therapy (eg, patient refusal, hospice referral). Patients were divided into the following 5 categories according to the treatment strategy during the first year after diagnosis with mRCC: (1) surgical metastasectomy; (2) multiple local treatment modalities (eg, surgery, radiofrequency ablation, cryoablation); (3) active surveillance (defined as patients with known disease for whom treatment was deferred pending evidence of
Clinical Genitourinary Cancer Month 2015
Abbreviation: mRCC ¼ metastatic renal cell carcinoma.
progression or other clinical changes); (4) deemed not a candidate for therapy and managed with best supportive care alone or referral to hospice care; and (5) other. Those patients in group 1, who received surgical metastasectomy, were subdivided according to further treatments received during the first year after diagnosis: (1a) followed with no evidence of disease, (1b) had recurrence and underwent 1 or more additional metastasectomies, and (1c) had recurrence and an active surveillance strategy was used. Recorded Karnofsky status was converted to Eastern Cooperative Oncology Group functional status according to previously published recommendations10 where appropriate.
Results The cohort included 37 men and 23 women for a total of 60 patients, representing 22% of all patients with mRCC treated (Table 1). Median age at diagnosis was 61.2 years. Median time from date of RCC diagnosis to the diagnosis of mRCC was 41.9 months, including 5 patients (8%) who were already metastatic at time of RCC diagnosis. Most patients had favorable or intermediate risk disease by Memorial Sloan Kettering Cancer Center criteria, at 40% and 35%, respectively. Some 91% of the 44 patients with recorded functional status had an Eastern Cooperative Oncology Group score of 0 to 1. Disease burden was low, with 83% patients having a single metastatic site at the time of mRCC diagnosis. Of the 60 patients, 36 (60%) were initially managed with surgical metastasectomy alone (Table 2); of these 36, 22 (37% of cohort) received a single metastasectomy within 1 year of diagnosis and were thereafter followed with no evidence of disease, 9 patients (15%) received multiple metastasectomies within the first year of diagnosis, and 5 patients (8%) elected for an active surveillance approach after recurrence. The anatomic site of metastasectomy for these
Aaron P. Mitchell et al Table 1 Aggregate Patient Characteristics at Time of Diagnosis of Metastatic Renal Cell Carcinoma Characteristic (n [ 60)
Overall (%) (n [ 60)
Sex Male
62
Female
38
Ethnicity Caucasian
75
African American
20
Hispanic
2
Asian
2
American Indian
2
MSKCC Risk Favorable
40
Intermediate
35
Poor Unknown ECOG Performance Status
7 17 (N [ 44)
0
42
1
25
2
5
3 Undocumented
2 27
Histology Clear cell
80
Chromophobe
3
Papillary
3
Sarcomatoid
3
Other
3
Unknown
7
No. of Metastatic Sites 1
83
2
13
3
3
Sites Involved Lung
57
Bone
17
Liver
12
Adrenal
10
Retroperitoneum
5
Pancreas
5
CNS
2
Other
13
Comorbidities Hypertension
68
Hyperlipidemia
28
Diabetes mellitus
18
Chronic kidney disease
17
COPD
8
Management of Primary Lesion Nephrectomy Nephrectomy þ LND
80 7
Table 1 Continued Characteristic (n [ 60)
Overall (%) (n [ 60)
Partial nephrectomy
7
No surgery
7
N ¼ 60 except as specified for Eastern Cooperative Oncology Group performance status. Abbreviations: CNS ¼ central nervous system; COPD ¼ chronic obstructive pulmonary disease; ECOG ¼ Eastern Cooperative Oncology Group; LND ¼ lymph node dissection; MSKCC ¼ Memorial Sloan Kettering Cancer Center.
patients is shown in Table 3. Of the remaining 24 patients (40%), 7 (12%) received multiple local treatment modalities, 8 (13%) received active surveillance, 4 (7%) were managed with supportive care, and 5 (8%) were classified as “other”; 2 (3%) of these declined systemic therapy, 1 (2%) had an acute clinical decline before treatment could be started, 1 (2%) could not receive treatment because of financial barriers, and for 1 (2%) the initial treatment plan was not clear from documentation. Examination of patient baseline characteristics by treatment strategy showed that patients managed with active surveillance or supportive care tended to be older on average than other patients (Table 3). The distribution of Memorial Sloan Kettering Cancer Center risk was similar among patients receiving metastasectomy, multiple therapies, and active surveillance; relatively more patients receiving supportive care or categorized as “other” had intermediate or poor risk. Some 92% of patients managed with metastasectomy had only a single metastatic site. Median follow-up was 52.9 months, and 3-year survival was 83% (44 of 53) overall and 94% (29 of 31) for those who received surgical metastasectomy as the initial management strategy. At 3 years, 49% had no evidence of disease, whereas 19% had died or been transitioned to hospice (Table 4). The 5-year survival rate was 59% (24 of 41) (Figure 2), and 24% still had no evidence of disease at this point. There were a variety of clinical rationales documented for the 8 patients who received active surveillance as the initial strategy. For 6 of these 8 patients, treatment was deferred because of the perceived indolent nature of the disease, based on a prolonged interval between initial diagnosis of RCC and recurrence, or an absence of progression on serial restaging. Of these 6 patients, 5 were later started on systemic therapy after a mean duration of 20.9 months (range, 14.9-32.0 months), when evidence of progression became apparent.
Discussion In a time of quickly evolving treatment choices for patients with mRCC, it is critical that we understand treatment patterns and outcomes in routine clinical practice. The need to better understand the observed practice of delayed systemic therapy for patients with mRCC is such an example. We report on a cohort of patients from an academic center who were followed for more than 1 year after diagnosis with mRCC without receiving systemic therapy. They represent a heterogeneous clinical population with a range of medical rationales for delaying treatment. Initial management strategies for the patients in our cohort fell into several categories, including surgical metastasectomy, active
Clinical Genitourinary Cancer Month 2015
-3
Delayed Systemic Therapy in Patients With mRCC Table 2 Cohort of Patients With Metastatic Renal Cell Carcinoma Grouped by Management Strategy During the First Year After Diagnosis Treatment Strategy
N
%
Metastasectomy
36
60
Multiple local treatment modalities
7
12
Active surveillance
8
13
Supportive care
4
7
Other
5
8
NED
22
37
Multiple metastasectomies
9
15
Active surveillance
5
8
Abbreviations: NED ¼ no evidence of disease.
surveillance, multiple local modalities, and supportive care. The outcomes of the cohort differed significantly by initial treatment strategy. The small subgroup of patients who were not deemed to be candidates for systemic therapy and were managed with supportive care alone had the expected poor outcomes; 50% of patients had died within 3 months of diagnosis. In contrast, 50% of the 36 patients who received a metastasectomy had no evidence of disease 3 years after their diagnosis with mRCC, and 5-year survival in this group was 83%. Only 31% of these patients had received systemic therapy as of the date of last follow-up, at a median time of 4.7 years after surgery. Surgical management of oligometastatic mRCC has long been a treatment option, either alone or in combination with systemic
therapy, and our data suggest that it is the most common reason for deferral of systemic therapy. Previous research has shown that patients with mRCC with surgically resectable metastatic sites can achieve long-term survival after metastasectomy. Even before the era of targeted therapies, 5-year survival was between 33% and 45% in patients who were candidates for a metastasectomy,11-15 with 10-year survival as high as 33% after pulmonary metastasectomy.16 Disease-free survival after metastasectomy has been reported to be as high as 50% at 2 years,17 although the proportion of patients without recurrence after first metastasectomy may decrease to as low as 7% after 5 years of follow-up.12,18 However, it is unknown if, or to what extent, these patients may benefit from subsequent systemic
Table 3 Baseline Characteristics According to Management Strategy Characteristic N
Overall
Metastasectomy
Multiple Local Treatmenta
Active Surveillance
Supportive Care
Other
60
36
7
8
4
5
Median Age at Diagnosis, years
61.2
60.5
66.3
71.3
71.2
59.4
Median Time From RCC to mRCC (mo)b
41.9
40.1
36.8
50.4
56.1
0 1 (20)
MSKCC Risk at Diagnosis (%) Favorable
24 (40)
17 (47)
3 (43)
3 (38)
0
Intermediate
21 (35)
12 (33)
3 (43)
3 (38)
3 (75)
0
4 (7)
1 (3)
0
0
1 (25)
2 (40)
10 (17)
5 (14)
1 (14)
2 (25)
0
2 (40)
4 (57)
7 (88)
2 (50)
3 (60)
Poor Unknown No. of Metastatic sites (%) 1
50 (83.3)
33 (92)
2
8 (13.3)
3 (8)
2 (29)
1 (12)
1 (25)
2 (40)
3
2 (3.3)
0
1 (14)
0
1 (25)
0
Lung
34 (56.7)
19 (53)
3 (43)
5 (63)
4 (100)
3 (60)
Bone
10 (16.7)
2 (6)
3 (43)
0
2 (50)
3 (60)
Liver
7 (11.7)
3 (8)
3 (43)
0
1 (25)
0
Adrenal
6 (10.0)
6 (17)
0
0
0
0
Retroperitoneum
3 (5.0)
3 (8)
0
0
0
0
Pancreas
3 (5.0)
0
1 (14)
2 (25)
0
0
Central nervous system
2 (3.3)
1 (3)
1 (14)
0
0
0
Other
8 (13.3)
5 (14)
0
2 (25)
0
1 (20)
Sites Involved (%)
Abbreviations: mRCC ¼ metastatic renal cell carcinoma; MSKCC ¼ Memorial Sloan Kettering Cancer Center; RCC ¼ renal cell carcinoma. a Received multiple local treatment modalities within the first year after diagnosis. b Median number of months between diagnosis of RCC and mRCC.
4
-
Clinical Genitourinary Cancer Month 2015
Aaron P. Mitchell et al Table 4 Patient Outcomes According to Management Strategy Characteristic N Median Follow-up (mo) Received Systemic Therapy (%)b c
Mean Time to Systemic Therapy (mo)
Overall
Metastasectomy
Multiple Local Treatmenta
60
36
7
8
4
5
52.9
55.9
42.2
53.6
11.9
81.3
23 (38)
11 (31)
4 (57)
5 (63)
0 (0)
3 (60)
36.8
36.5
16.3
20.9
N/A
92.0
Active Supportive Surveillance Care
Other
Subsequent Agent Received (%) Sunitinib
13 (57)
5 (14)
3 (43)
4 (50)
0
1 (20)
Pazopanib
3 (13)
2 (6)
0
0
0
1 (20)
Sorafenib
2 (9)
2 (6)
0
0
0
0
Everolimus
2 (9)
0
0
1 (25)
0
1 (20)
IL-2
2 (9)
1 (3)
1 (14)
0
0
0
Decitabine
1 (2)
1 (3)
0
0
0
0
Outcome at 3 years (%)
Deferred Systemic Therapy in Patients With Metastatic Renal Cell Carcinoma Aaron P. Mitchell,1 Bradford R. Hirsch,1,2 Michael R. Harrison,1 Amy P. Abernethy,1,2 Daniel J. George1 Abstract We analyzed a retrospective cohort of 60 patients with metastatic renal cell carcinoma who did not receive systemic therapy within the first year after diagnosis. Reasons for delayed therapy included surgical or other local management, and an active surveillance approach. The 5-year survival was 59%, suggesting that deferred therapy may be an appropriate strategy in selected patients. Background: With the advent of small-molecule “targeted” therapies, the prevailing treatment paradigm for metastatic renal cell carcinoma (mRCC) is that all patients who are able to tolerate systemic therapy should receive it. However, oncologists often defer the initiation of systemic therapy for patients with mRCC. The outcomes of and clinical reasoning behind the initial management of patients with mRCC without systemic therapy have not been well described. Methods: We conducted a retrospective cohort study of all patients with mRCC treated within the Duke University Health System and diagnosed from January 1, 2007, to January 1, 2011. We defined our cohort as patients who did not receive systemic therapy during the first year after mRCC diagnosis. The clinical rationale for the lack of immediate treatment was ascertained by manual chart review. Results: A total of 60 of 268 patients (22%) with mRCC managed without initial systemic therapy were included in our study. The median age was 61.2 years, the median duration from diagnosis of localized RCC to development of mRCC was 41.9 months, and 91% of patients had Eastern Cooperative Oncology Group functional status of 1. Of the patients, 60% were managed with surgical metastasectomy alone, 12% received multiple local treatment modalities, 13% received active surveillance, 7% were managed supportively, and 8% were categorized as “other.” Conclusions: The majority of patients in our cohort had favorable disease characteristics and experienced favorable outcomes with surgery alone. Our results suggest that this population could represent 20% of patients with mRCC in tertiary care settings. Prospective data are needed to evaluate deferred systemic therapy as a management strategy. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Active surveillance, Management strategy, Metastasectomy, Outcomes, Surgery
Introduction Between 17% and 30% of patients with renal cell carcinoma (RCC) have metastatic disease at the time of diagnosis,1-3 and another 20% to 40% of those who undergo a potentially curative nephrectomy for localized disease will later develop metastatic disease.1,4-6 For those who are diagnosed with metastatic RCC (mRCC), a number of systemic treatment options exist, including 7 new agents approved by the US Food and Drug Administration from December 2005 to February 2012.7 1
Division of Medical Oncology, Duke University Medical Center, Durham, NC Center for Learning Health Care, Duke Clinical Research Institute, Durham, NC
2
Submitted: Sep 28, 2014; Revised: Dec 23, 2014; Accepted: Dec 26, 2014 Address for correspondence: Daniel J. George, MD, DUMC 102002, Durham, NC 27710 E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.12.017
The management of patients with mRCC with oligometastatic disease using surgery alone has long been an accepted strategy and is a recommended option in National Comprehensive Cancer Network guidelines.8 However, with the new availability of effective and well-tolerated treatments, the prevailing view is moving toward offering systemic therapy for a greater number of patients. The potential role of targeted agents as adjuvant therapy in this setting, currently under investigation,9 may be a factor. Physicians also may be less comfortable managing mRCC without systemic therapy because of the relative lack of data; the study of mRCC generally occurs within the context of therapeutic trials or postmarketing studies, which include only patients who receive systemic therapy. As a result, the cohort of patients with mRCC who elect to defer—or never receive—systemic treatment often go unrecognized and unstudied. The size of the cohort, patient and disease
Clinical Genitourinary Cancer Month 2015
-1
Delayed Systemic Therapy in Patients With mRCC characteristics, and clinical outcomes are unknown, especially in the era of targeted therapies. Anecdotally, some patients with mRCC achieve favorable outcomes for prolonged periods without systemic therapy; a more complete understanding of this group would inform treatment decisions and potentially avoid drug toxicity in those unlikely to benefit. Physician recommendations, in addition to patient preferences, certainly influence a patient’s decision to defer therapy. However, the clinical reasoning behind the initial management of mRCC without systemic therapy has not been well described. Is this strategy recommended to patients who are surgical candidates or to those perceived as unlikely to tolerate systemic therapy? To address this void and to understand the appropriateness of such an approach with currently available treatments, we describe the experience at one academic medical center of patients who did not receive initial systemic treatment in the context of available targeted therapies.
Figure 1 Cohort Selection
Materials and Methods
2
-
This retrospective cohort study received a waiver of informed consent from the institutional review board at Duke University. Eligible cases included all adult patients (aged > 18 years) with mRCC who received some portion of their mRCC care in the Duke University Health System. All patients were diagnosed with mRCC between January 1, 2007, and January 1, 2011, with the last data collection occurring in May 2013. Cases were initially identified by searching the Duke patient database using International Classification of Diseases, 9th Revision codes and were then confirmed by research coordinators. Study data were extracted from the Duke data warehouse (demographics, laboratory results, treatments) and supplemented by manual chart abstraction using a standardized case report form (histology, grade, metastatic burden, supplemental treatment history). Completed case report forms underwent quality review before entry into a secure study-specific data repository. The resulting registry contained 268 patients (Figure 1). The cohort of interest was defined as those patients who did not receive any systemic therapy before 1 year of follow-up had elapsed or death had occurred. Thus, patients who received systemic therapy within 1 year of diagnosis of mRCC were excluded, and those who went at least 1 year without receiving therapy or died in less than 1 year without receiving therapy were included. In addition, patients with insufficient documentation to confirm absence of systemic therapy before death or 1 year of follow-up were excluded, narrowing the cohort to 82 patients. During subsequent manual chart review, 22 patients were excluded from the analytic cohort; 14 had less than 1 year of follow-up, 6 did not have a pathologic diagnosis of mRCC, and 2 were duplicates. Sixty patients remained in the final analytic cohort. Dates of death were confirmed for all patients by searching the public record. A detailed review of clinical notes was used to define why each patient did not receive systemic therapy (eg, patient refusal, hospice referral). Patients were divided into the following 5 categories according to the treatment strategy during the first year after diagnosis with mRCC: (1) surgical metastasectomy; (2) multiple local treatment modalities (eg, surgery, radiofrequency ablation, cryoablation); (3) active surveillance (defined as patients with known disease for whom treatment was deferred pending evidence of
Clinical Genitourinary Cancer Month 2015
Abbreviation: mRCC ¼ metastatic renal cell carcinoma.
progression or other clinical changes); (4) deemed not a candidate for therapy and managed with best supportive care alone or referral to hospice care; and (5) other. Those patients in group 1, who received surgical metastasectomy, were subdivided according to further treatments received during the first year after diagnosis: (1a) followed with no evidence of disease, (1b) had recurrence and underwent 1 or more additional metastasectomies, and (1c) had recurrence and an active surveillance strategy was used. Recorded Karnofsky status was converted to Eastern Cooperative Oncology Group functional status according to previously published recommendations10 where appropriate.
Results The cohort included 37 men and 23 women for a total of 60 patients, representing 22% of all patients with mRCC treated (Table 1). Median age at diagnosis was 61.2 years. Median time from date of RCC diagnosis to the diagnosis of mRCC was 41.9 months, including 5 patients (8%) who were already metastatic at time of RCC diagnosis. Most patients had favorable or intermediate risk disease by Memorial Sloan Kettering Cancer Center criteria, at 40% and 35%, respectively. Some 91% of the 44 patients with recorded functional status had an Eastern Cooperative Oncology Group score of 0 to 1. Disease burden was low, with 83% patients having a single metastatic site at the time of mRCC diagnosis. Of the 60 patients, 36 (60%) were initially managed with surgical metastasectomy alone (Table 2); of these 36, 22 (37% of cohort) received a single metastasectomy within 1 year of diagnosis and were thereafter followed with no evidence of disease, 9 patients (15%) received multiple metastasectomies within the first year of diagnosis, and 5 patients (8%) elected for an active surveillance approach after recurrence. The anatomic site of metastasectomy for these
Aaron P. Mitchell et al Table 1 Aggregate Patient Characteristics at Time of Diagnosis of Metastatic Renal Cell Carcinoma Characteristic (n [ 60)
Overall (%) (n [ 60)
Sex Male
62
Female
38
Ethnicity Caucasian
75
African American
20
Hispanic
2
Asian
2
American Indian
2
MSKCC Risk Favorable
40
Intermediate
35
Poor Unknown ECOG Performance Status
7 17 (N [ 44)
0
42
1
25
2
5
3 Undocumented
2 27
Histology Clear cell
80
Chromophobe
3
Papillary
3
Sarcomatoid
3
Other
3
Unknown
7
No. of Metastatic Sites 1
83
2
13
3
3
Sites Involved Lung
57
Bone
17
Liver
12
Adrenal
10
Retroperitoneum
5
Pancreas
5
CNS
2
Other
13
Comorbidities Hypertension
68
Hyperlipidemia
28
Diabetes mellitus
18
Chronic kidney disease
17
COPD
8
Management of Primary Lesion Nephrectomy Nephrectomy þ LND
80 7
Table 1 Continued Characteristic (n [ 60)
Overall (%) (n [ 60)
Partial nephrectomy
7
No surgery
7
N ¼ 60 except as specified for Eastern Cooperative Oncology Group performance status. Abbreviations: CNS ¼ central nervous system; COPD ¼ chronic obstructive pulmonary disease; ECOG ¼ Eastern Cooperative Oncology Group; LND ¼ lymph node dissection; MSKCC ¼ Memorial Sloan Kettering Cancer Center.
patients is shown in Table 3. Of the remaining 24 patients (40%), 7 (12%) received multiple local treatment modalities, 8 (13%) received active surveillance, 4 (7%) were managed with supportive care, and 5 (8%) were classified as “other”; 2 (3%) of these declined systemic therapy, 1 (2%) had an acute clinical decline before treatment could be started, 1 (2%) could not receive treatment because of financial barriers, and for 1 (2%) the initial treatment plan was not clear from documentation. Examination of patient baseline characteristics by treatment strategy showed that patients managed with active surveillance or supportive care tended to be older on average than other patients (Table 3). The distribution of Memorial Sloan Kettering Cancer Center risk was similar among patients receiving metastasectomy, multiple therapies, and active surveillance; relatively more patients receiving supportive care or categorized as “other” had intermediate or poor risk. Some 92% of patients managed with metastasectomy had only a single metastatic site. Median follow-up was 52.9 months, and 3-year survival was 83% (44 of 53) overall and 94% (29 of 31) for those who received surgical metastasectomy as the initial management strategy. At 3 years, 49% had no evidence of disease, whereas 19% had died or been transitioned to hospice (Table 4). The 5-year survival rate was 59% (24 of 41) (Figure 2), and 24% still had no evidence of disease at this point. There were a variety of clinical rationales documented for the 8 patients who received active surveillance as the initial strategy. For 6 of these 8 patients, treatment was deferred because of the perceived indolent nature of the disease, based on a prolonged interval between initial diagnosis of RCC and recurrence, or an absence of progression on serial restaging. Of these 6 patients, 5 were later started on systemic therapy after a mean duration of 20.9 months (range, 14.9-32.0 months), when evidence of progression became apparent.
Discussion In a time of quickly evolving treatment choices for patients with mRCC, it is critical that we understand treatment patterns and outcomes in routine clinical practice. The need to better understand the observed practice of delayed systemic therapy for patients with mRCC is such an example. We report on a cohort of patients from an academic center who were followed for more than 1 year after diagnosis with mRCC without receiving systemic therapy. They represent a heterogeneous clinical population with a range of medical rationales for delaying treatment. Initial management strategies for the patients in our cohort fell into several categories, including surgical metastasectomy, active
Clinical Genitourinary Cancer Month 2015
-3
Delayed Systemic Therapy in Patients With mRCC Table 2 Cohort of Patients With Metastatic Renal Cell Carcinoma Grouped by Management Strategy During the First Year After Diagnosis Treatment Strategy
N
%
Metastasectomy
36
60
Multiple local treatment modalities
7
12
Active surveillance
8
13
Supportive care
4
7
Other
5
8
NED
22
37
Multiple metastasectomies
9
15
Active surveillance
5
8
Abbreviations: NED ¼ no evidence of disease.
surveillance, multiple local modalities, and supportive care. The outcomes of the cohort differed significantly by initial treatment strategy. The small subgroup of patients who were not deemed to be candidates for systemic therapy and were managed with supportive care alone had the expected poor outcomes; 50% of patients had died within 3 months of diagnosis. In contrast, 50% of the 36 patients who received a metastasectomy had no evidence of disease 3 years after their diagnosis with mRCC, and 5-year survival in this group was 83%. Only 31% of these patients had received systemic therapy as of the date of last follow-up, at a median time of 4.7 years after surgery. Surgical management of oligometastatic mRCC has long been a treatment option, either alone or in combination with systemic
therapy, and our data suggest that it is the most common reason for deferral of systemic therapy. Previous research has shown that patients with mRCC with surgically resectable metastatic sites can achieve long-term survival after metastasectomy. Even before the era of targeted therapies, 5-year survival was between 33% and 45% in patients who were candidates for a metastasectomy,11-15 with 10-year survival as high as 33% after pulmonary metastasectomy.16 Disease-free survival after metastasectomy has been reported to be as high as 50% at 2 years,17 although the proportion of patients without recurrence after first metastasectomy may decrease to as low as 7% after 5 years of follow-up.12,18 However, it is unknown if, or to what extent, these patients may benefit from subsequent systemic
Table 3 Baseline Characteristics According to Management Strategy Characteristic N
Overall
Metastasectomy
Multiple Local Treatmenta
Active Surveillance
Supportive Care
Other
60
36
7
8
4
5
Median Age at Diagnosis, years
61.2
60.5
66.3
71.3
71.2
59.4
Median Time From RCC to mRCC (mo)b
41.9
40.1
36.8
50.4
56.1
0 1 (20)
MSKCC Risk at Diagnosis (%) Favorable
24 (40)
17 (47)
3 (43)
3 (38)
0
Intermediate
21 (35)
12 (33)
3 (43)
3 (38)
3 (75)
0
4 (7)
1 (3)
0
0
1 (25)
2 (40)
10 (17)
5 (14)
1 (14)
2 (25)
0
2 (40)
4 (57)
7 (88)
2 (50)
3 (60)
Poor Unknown No. of Metastatic sites (%) 1
50 (83.3)
33 (92)
2
8 (13.3)
3 (8)
2 (29)
1 (12)
1 (25)
2 (40)
3
2 (3.3)
0
1 (14)
0
1 (25)
0
Lung
34 (56.7)
19 (53)
3 (43)
5 (63)
4 (100)
3 (60)
Bone
10 (16.7)
2 (6)
3 (43)
0
2 (50)
3 (60)
Liver
7 (11.7)
3 (8)
3 (43)
0
1 (25)
0
Adrenal
6 (10.0)
6 (17)
0
0
0
0
Retroperitoneum
3 (5.0)
3 (8)
0
0
0
0
Pancreas
3 (5.0)
0
1 (14)
2 (25)
0
0
Central nervous system
2 (3.3)
1 (3)
1 (14)
0
0
0
Other
8 (13.3)
5 (14)
0
2 (25)
0
1 (20)
Sites Involved (%)
Abbreviations: mRCC ¼ metastatic renal cell carcinoma; MSKCC ¼ Memorial Sloan Kettering Cancer Center; RCC ¼ renal cell carcinoma. a Received multiple local treatment modalities within the first year after diagnosis. b Median number of months between diagnosis of RCC and mRCC.
4
-
Clinical Genitourinary Cancer Month 2015
Aaron P. Mitchell et al Table 4 Patient Outcomes According to Management Strategy Characteristic N Median Follow-up (mo) Received Systemic Therapy (%)b c
Mean Time to Systemic Therapy (mo)
Overall
Metastasectomy
Multiple Local Treatmenta
60
36
7
8
4
5
52.9
55.9
42.2
53.6
11.9
81.3
23 (38)
11 (31)
4 (57)
5 (63)
0 (0)
3 (60)
36.8
36.5
16.3
20.9
N/A
92.0
Active Supportive Surveillance Care
Other
Subsequent Agent Received (%) Sunitinib
13 (57)
5 (14)
3 (43)
4 (50)
0
1 (20)
Pazopanib
3 (13)
2 (6)
0
0
0
1 (20)
Sorafenib
2 (9)
2 (6)
0
0
0
0
Everolimus
2 (9)
0
0
1 (25)
0
1 (20)
IL-2
2 (9)
1 (3)
1 (14)
0
0
0
Decitabine
1 (2)
1 (3)
0
0
0
0
Outcome at 3 years (%)
