Abstract
Objective
Tumor shrinkage of at least 10% after presurgical targeted molecular therapy (TMT) in renal cell carcinoma (RCC) patients has been associated with better overall survival (OS) outcomes. We characterized primary and metastatic tumor diameter response and OS in patients with metastatic clear cell RCC (ccRCC) who received preoperative TMT, immunotherapy, or both followed by deferred cytoreductive nephrectomy (dCN).
Materials and Methods
Patients with metastatic ccRCC (n = 198) who underwent preoperative therapy and dCN from 2005 to 2019 were identified retrospectively. Longest primary and metastatic tumor diameters were calculated using cross-sectional images obtained before systemic therapy and dCN using the Response Evaluation Criteria in Solid Tumors. Patients were stratified by tumor shrinkage of at least 10% in the primary and/or metastatic tumors after systemic therapy. The Kaplan-Meier method was used to estimate OS, and Cox proportional hazards models were used to assess the association of patient characteristics with OS.
Results
In total, 31.31% of patients had only metastatic tumor shrinkage (MTS) ≥ 10%, 8.08% had only primary tumor shrinkage (PTS) ≥ 10%, 32.32% had PTS and MTS ≥ 10%, and 28.28% had PTS/MTS < 10%. The median OS, number of patients with tumor shrinkage ≥ 10%, and International Metastatic Database Consortium (IMDC) scores were similar among the three systemic therapy groups (all P ≥ 0.80). Patients with MTS ≥ 10%, PTS ≥ 10%, and PTS/MTS ≥ 10% had significantly longer median OS compared to patients with PTS/MTS < 10% (P < 0.01). Patients with intermediate-risk IMDC scores had significantly longer median OS compared to patients in the poor-risk group. After adjusting for preoperative therapy and IMDC risk group, MTS ≥ 10%, PTS ≥ 10%, and PTS/MTS ≥ 10% were associated with better OS outcomes (HR 0.48 95% CI 0.32–0.73, P < 0.001; HR 0.48, 95% CI 0.23–0.98, P = 0.04; HR 0.44, 95% CI 0.29–0.67, P < 0.001, respectively).
Conclusions
Intermediate risk score and shrinkage of at least 10% in the primary tumor, metastases, or both were associated with better OS outcomes in patients with metastatic ccRCC who underwent dCN independent of the type of preoperative systemic therapy.
Keywords: clear cell renal cell carcinoma, cytoreductive nephrectomy, immunotherapy, targeted molecular therapy, overall survival
1. Introduction
In 2020, the number of new kidney cancer cases in the United States was estimated to be 73,750, with 14,830 estimated deaths [1]. Most kidney cancer patients present with localized disease at diagnosis, whereas 17% present with distant metastasis [2]. Renal cell carcinoma (RCC) accounts for 90% of kidney cancer cases, with the most common histological subtype being clear cell RCC (ccRCC) [3].
The management of metastatic RCC, especially ccRCC, has evolved with increased understanding of the disease’s pathophysiology and the development of new systemic treatments. Patients with intermediate or poor prognostic risk in the CARMENA trial, based on the Memorial Sloan Kettering Cancer Center prognostic model, did not benefit from upfront cytoreductive nephrectomy followed by treatment with sunitinib compared with the use of sunitinib alone [4]. Of the sunitinib-alone group, 17% underwent deferred cytoreductive nephrectomy (dCN), with most experiencing near-complete responses at metastatic sites [4].
The role of dCN in metastatic RCC is still widely debated in the oncology community [5–8]. A recent study comparing overall survival (OS) and time to treatment failure in patients who received sunitinib alone, upfront cytoreductive nephrectomy followed by sunitinib, or sunitinib followed by dCN showed that use of sunitinib followed by dCN was markedly associated with better OS and time to treatment failure [8]. Also, the SURTIME randomized clinical trial comparing immediate cytoreductive nephrectomy followed by treatment with sunitinib with treatment with sunitinib followed by dCN suggested an OS benefit for dCN [9].
Multiple studies have identified risk factors associated with survival in the era of targeted molecular therapy (TMT) [10–12]. In patients who received preoperative TMT followed by dCN, 10% primary tumor shrinkage (PTS) according to the Response Evaluation Criteria in Solid Tumors (RECIST) was associated with better OS outcomes and time to treatment failure [12, 13].
Current National Comprehensive Cancer Network guidelines recommend using immunotherapy (IO) as one of the preferred regimens to treat metastatic ccRCC [14]. Immunotherapy alone and combined with TMT have been associated with better OS outcomes and complete responses, with treatment-related adverse events similar to those for TMT alone [15, 16]. However, the tumor response and OS in patients who receive immunotherapy followed by dCN have yet to be characterized. In the present study, we compared tumor diameter response of at least 10% and OS in patients with metastatic ccRCC who received immunotherapy, TMT, or immunotherapy plus TMT followed by dCN. Tumor response of at least 10% was selected base on prior publications showing the association of tumor response and overall survival [11–13].
2. Materials and Methods
After our protocol received institutional review board approval, The University of Texas MD Anderson Cancer Center nephrectomy registry was reviewed retrospectively, identifying 198 patients with metastatic ccRCC who underwent systemic therapy followed by dCN from January 1, 2005, to December 31, 2019. Clinical features studied included age, sex, race, performance status, International Metastatic Database Consortium (IMDC) score at presentation, and clinical stage. Pathological features collected included clear cell histology, tumor stage per the 2017 American Joint Committee on Cancer (eighth edition) TNM system, the presence of sarcomatoid differentiation, and the location and number of metastases before and after systemic therapy. Data were abstracted from a direct chart review by the authors.
Patients were grouped according to the type of systemic therapy before dCN: TMT, immunotherapy, and immunotherapy plus TMT. The primary objective was to compare OS and cancer-specific survival (CSS) in these three groups. The secondary objectives were to assess the correlation of PTS and/or metastatic tumor shrinkage (MTS) of at least 10% and the IMDC score with OS and CSS. Patients were stratified by PTS and/or MTS (MTS ≥ 10%, PTS ≥ 10%, PTS/MTS ≥ 10%, and PTS/MTS < 10%). Hazard ratios (HRs) for OS according to location of metastasis in patients with tumor shrinkage (primary, metastatic or both) of at least 10% were calculated using multivariable Cox regression analysis, after adjustment for the number of metastases.
Primary and metastatic tumor diameters were measured using cross-sectional images obtained at the time of initial diagnosis and before dCN using the validated RECIST (version 1.1) protocol [17].
Patient characteristics were summarized using frequencies (percentages) and median (interquartile range [IQR]) values for categorical and continuous variables. Categorical and continuous data were compared using the Fisher exact test and Kruskal-Wallis test, respectively. OS and CSS were defined as the time from surgery to death, and patients who were alive at the last follow-up date were censored. The Kaplan-Meier method was used to estimate survival curves, and Cox proportional hazards regression models were used to assess associations among patient characteristics, OS, and CSS. Factors with P values of up to 0.10 in the univariable model were included in the multivariable model. Next, backward elimination was used until all remaining variables had P values less than 0.05. The preoperative therapy variable was included in the multivariable model regardless of its significance in the univariable model. P values less than 0.05 were considered significant, and all statistical analyses were performed using the R computing language (version 3.6.1) [18].
3. Results
The median age of the 198 study patients with metastatic ccRCC at the time of diagnosis was 60.6 years (IQR 52.8–66.1 years). Also, 74% of the patients were male, 54% had an Eastern Cooperative Oncology Group performance score of 1 or greater, 89% had intermediate-risk IMDC score, and 55% had cN1 disease. The median time from systemic therapy to dCN was 87.9 days (IQR, 67.0–194.0 days). The most common systemic therapies used in the TMT group were sunitinib 72%, bevacizumab 25 %, and pazopanib 17%; in the IO group were nivolumab plus ipilimumab 83% and tremelimumab 17%; in the IO+TMT group was nivolumab plus bevacizumab 90%. The median overall tumor diameter reduction was 9.5 mm (IQR −0.5–21.8 mm); 31% of the patients had MTS ≥ 10%, 8% had PTS ≥ 10%, 32% had PTS/MTS ≥ 10%, and 28% had PTS/MTS < 10% (Table 1). As for pathological features, 17% of the patients had sarcomatoid differentiation, 28% had tumor thrombi, and 36% had pN1 disease (Table 1).
Table 1.
Characteristics of the study population.
| Patient Characteristics | N = 198 | IO (N = 24) | IO + TMT (N = 10) | TMT (N = 164) | P-value |
|---|---|---|---|---|---|
|
| |||||
| Age, y, median (IQR) | 60.62 (52.78, 66.91) | 62.05 (47.85, 67.5) | 69.37 (64.12, 73.75) | 60.29 (52.82, 66.16) | 0.02 |
| Gender, No. (%) | |||||
| Female | 51 (25.76%) | 3 (12.5%) | 2 (20%) | 46 (28.05%) | 0.26 |
| Male | 147 (74.24%) | 21 (87.5%) | 8 (80%) | 118 (71.95%) | |
| ECOG performance, binary, No. (%) | |||||
| >1 | 107 (54.04%) | 7 (29.17%) | 6 (60%) | 94 (57.32%) | 0.03 |
| 0 | 91 (45.96%) | 17 (70.83%) | 4 (40%) | 70 (42.68%) | |
| Clinical T category, No. (%) | |||||
| t1a | 7 (3.74%) | 1 (4.35%) | 0 (0.00%) | 6 (3.9%) | 0.38 |
| t1b | 34 (18.18%) | 7 (30.43%) | 0 (0.00%) | 27 (17.53%) | |
| t2a | 36 (19.25%) | 2 (8.7%) | 3 (30% ) | 31 (20.13%) | |
| t2b | 27 (14.44%) | 4 (17.39%) | 1 (10%) | 22 (14.29%) | |
| t3a | 51 (27.27%) | 6 (26.09%) | 4 (40%) | 41 (26.62%) | |
| t3b | 30 (16.04%) | 3 (13.04%) | 1 (10%) | 26 (16.88%) | |
| t3c | 2 (1.07%) | 0 (0.00%) | 1 (10%) | 1 (0.65%) | |
| Clinical N1 category, No. (%) | 109 (55.05%) | 12 (50%) | 7 (70%) | 90 (54.88%) | 0.56 |
| Median tumor diameter reduction, mm (IQR) | 9.5 (−0.5, 21.88) | 14 (2.99, 22.5) | 11.75 (4.88, 24) | 9 (−1.12, 20.88) | 0.59 |
| Tumor shrink ≥ 10%, No. (%) | |||||
| PTS/MTS < 10% | 56 ‘28%) | 5 (20.83%) | 1 (10%) | 50 (30.49%) | |
| PTS/MTS ≥ 10% | 64 (32.32%) | 10 (41.67%) | 3 (30%) | 51 (31.1%) | |
| MTS ≥ 10% | 62 (31.31%) | 8 (33.33%) | 4 (40%) | 50 (30.49%) | |
| PTS ≥ 10% | 16 (8.08%) | 1 (4.17%) | 2 (20%) | 13 (7.93%) | 0.5 |
| IMDC score, No. (%) | |||||
| Intermediate | 176 (88.88%) | 21 (87.5%) | 10 (100%) | 145 (88.41%) | |
| Poor | 22 (11.11%) | 3 (12.5%) | 0 (0.00%) | 19 (11.59%) | 0.8 |
| Pathologic T category, No. (%) | |||||
| pT1a | 3 (1.52%) | 0 (0.00%) | 0 (0.00%) | 3 (1.83%) | 0.75 |
| pT1b | 21 (10.61%) | 1 (4.17%) | 1 (10%) | 19 (11.59%) | |
| pT2a | 7 (3.54%) | 1 (4.17%) | 0 (0.00%) | 6 (3.66%) | |
| pT2b | 3 (1.52%) | 0 (0.00%) | 0 (0.00%) | 3 (1.83%) | |
| pT3a | 117 (59.09%) | 18 (75%) | 6 (60%) | 93 (56.71%) | |
| pT3b | 24 (12.12%) | 3 (12.5%) | 1 (10%) | 20 (12.2%) | |
| pT3c | 2 (1.01%) | 0 (0.00%) | 1 (10%) | 1 (0.61%) | |
| pT4 | 21 (10.61%) | 1 (4.17%) | 1 (10%) | 19 (11.59%) | |
| Grade, No. (%) | |||||
| 2 | 21 (10.71%) | 1 (4.17%) | 1 (10%) | 19 (11.73%) | 0.25 |
| 3 | 77 (39.29%) | 13 (54.17%) | 6 (60%) | 58 (35.8%) | |
| 4 | 98 (50%) | 10 (41.67%) | 3 (30%) | 85 (52.47%) | |
| Sarcomatoid differentiation,, No. (%) | 34 (17.17%) | 6 (25%) | 1 (10%) | 27 (16.46%) | 0.62 |
| Tumor thrombus, No. (%) | 56 (28.28%) | 7 (29.17%) | 6 (60%) | 43 (26.22%) | 0.09 |
| Pathologic N1 category, No. (%) | 48 (36.36%) | 4 (25%) | 3 (37.5%) | 41 (37.96%) | 0.59 |
ECOG, Easter Cooperative Oncology Group; IO, immunotherapy; PTS, primary tumor shrinkage; MTS, metastatic tumor shrinkage; IMDC, International Metastatic RCC Database Consortium; TMT, targeted molecular therapy.
Before systemic therapy, the median number of metastases was two (IQR 2–4); after systemic therapy, the median number of metastasis was also two (IQR 1–3). The median follow-up time after dCN among survivors was 33.7 months (IQR 16.2–60.1 months). The majority of patients were selected for surgery because of radiographic disease stability. Systemic therapy was stopped for dCN and resumed after surgery until radiographic evidence of progression. The four most common sites of metastasis were the lung, bone, adrenal gland, and retroperitoneal space. The percentages of patients with lung and adrenal metastasis were higher among those with tumor shrinkage less than 10% than among those with tumor shrinkage of at least 10% (P = 0.001 and P = 0.01, respectively; Table 2).
Table 2.
Characteristics of the metastasis.
| Characteristic | No. (%) | P-value | |
|---|---|---|---|
| TS < 10% (n = 56) | TS > 10% (n = 142) | ||
|
| |||
| Lung metastasis | 43 (76.8) | 75 (52.82) | 0.002 |
| Bone metastasis | 16 (28.57) | 29 (20.42) | 0.26 |
| Brain metastasis | 0 | 1 (0.7) | > 0.990 |
| Pancreatic metastasis | 1 (1.79) | 6 (4.23) | 0.68 |
| Retroperitoneal adenopathy | 16 (28.57) | 30 (21.13) | 0.27 |
| Supraclavicular adenopathy | 1 (1.79) | 6 (4.23) | 0.68 |
| Mediastinal adenopathy | 11 (19.64) | 27 (19) | > 0.99 |
| Soft tissue metastasis | 3 (5.36) | 12 (8.45) | 0.56 |
| Adrenal metastasis | 18 (32.14) | 21 (14.79) | 0.01 |
| Total number of metastases before systemic therapy | |||
| 1 | 12 (21. 43) | 22 (15.49) | 0.78 |
| 2 | 20 (35.71) | 51 (35.92) | |
| 3 | 9 (16) | 27 (19) | |
| ≥ 4 | 15 (26.79) | 42 (29.58) | |
| Total number of metastases after systemic therapy | |||
| 0 | 0 | 18 (12.68) | < 0.001 |
| 1 | 6 (10.71) | 39 (27.46) | |
| 2 | 25 (44.64) | 42 (29.58) | |
| 3 | 7 (12.5) | 20 (14.08) | |
| ≥ 4 | 18 (32.14) | 23 (16.2) | |
| Staged metastasectomy | 3 (5.36) | 10 (7.04) | > 0.99 |
| Time systemic therapy started | |||
| 2005–2009 | 28 (50. 91) | 67 (48.2) | 0.7 |
| 2010–2014 | 16 (29) | 36 (25.9) | |
| 2015–2019 | 11 (20) | 36 (25.9) | |
TS, Tumor Shrinkage; ECOG, Eastern Cooperative Oncology Group.
The three types of preoperative systemic therapy produced similar responses with no statistically significant difference identified. PTS ≥ 10% occurred in 4%, 20%, and 8% of patients who received immunotherapy only, immunotherapy plus TMT, and TMT only, respectively. MTS ≥ 10% occurred in 33%, 40%, and 30% of patients who received immunotherapy only, immunotherapy plus TMT, and TMT only, respectively. PTS/MTS ≥ 10% occurred in 42%, 30%, and 31% of patients who received immunotherapy only, immunotherapy plus TMT, and TMT only, respectively. PTS/MTS < 10% occurred in 21%, 10%, and 30% of patients who received immunotherapy only, immunotherapy plus TMT, and TMT only, respectively (Table 1). The 1- and 2-year OS rates were 95.8% and 71.6%, respectively, in patients who received immunotherapy only; 90% and 77.1%, respectively, in those who received immunotherapy plus TMT; and 76.2% and 55.4%, respectively, in those who received TMT only (P = 0.8, Figure 1). In both univariable and multivariable analyses, the type of preoperative systemic therapy was not significantly associated with OS or CSS (Table 3).
Fig. 1.
Kaplan-Meier OS curves in patients who received systemic therapy with immunotherapy, immunotherapy plus TMT, or TMT followed by cytoreductive nephrectomy. IO, immunotherapy; OS, overall survival; PTS, primary tumor shrinkage; TMT, targeted molecular therapy.
Table 3.
Univariable and multivariable Cox regression analysis of overall and cancer-specific survival.
| Characteristic | Univariable HR for OS | P | Multivariable HR for OS | P | Univariable HR for CSS | P | Multivariable HR for CSS | P-value |
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Age | 0.99 (0.98–1.01) | 0.47 | 0.99 (0.98–1.01) | 0.38 | ||||
| Gender | ||||||||
| Female vs. male | 0.87 (0.59–1.27) | 0.46 | 0.86 (0.58–1.26) | 0.44 | ||||
| Pathologic T category | ||||||||
| T1b vs. T1a | 0.58 (0.17–1.98) | 0.38 | 0.58 0.17–1.97) | 0.38 | ||||
| T2a vs. T1a | 0.16 (0.04−0.74) | 0.02 | 0.16 (0.03−0.73) | 0.02 | ||||
| T2b vs. T1a | 0.19 (0.03−1.17) | 0.07 | 0.19 (0.03−1.15) | 0.07 | ||||
| T3a vs. T1a | 0.28 (0.09−0.9) | 0.03 | 0.27 (0.09−0.88) | 0.03 | ||||
| T3b vs. T1a | 0.37 (0.11−1.27) | 0.11 | 0.33 (0.1−1.14) | 0.08 | ||||
| T3c vs. T1a | 0.22 (0.02−2.13) | 0.19 | 0.22 (0.02−2.13) 0.32 | 0.19 | ||||
| T4 vs. T1a | 0.32 (0.09−1.12) | 0.08 | 0.32 (0.09−1.12) | 0.07 | ||||
| Pathologic T category | ||||||||
| pT3-pT4 vs. pT1-t2 | 0.74 (0.49−1.13) | 0.16 | 0.72 (0.48−1.1) | 0.13 | ||||
| Tumor thrombus | 0.9 (0.63−1.3) | 0.58 | 0.87 (0.6−1.25) | 0.45 | ||||
| Sarcomatoid differentiation, | 1.17 (0.77−1.76) | 0.46 | 1.2 (0.791.81) | 0.4 | ||||
| Mean diameter reduction | 0.98 (0.97−0.99) | < 0.001 | 0.98 (0.97−0.99) | < 0.001 | ||||
| ECOG performance score | 1.19 (0.86−1.64) | 0.3 | 1.18 (0.85−1.64) | 0.33 | ||||
| Total number of metastases before TX | ||||||||
| ≥ 4 vs. 1 | 1.22 (0.75−2) | 0.42 | 1.27 (0.78−2.09) | 0.34 | ||||
| 2 vs. 1 | 1.03 (0.65−1.63) | 0.9 | 1.03 (0.65−1.64) | 0.90 | ||||
| 3 vs. 1 | 1.02 (0.59−1.76) | 0.95 | 1.06 (0.61−1.84) | 0.83 | ||||
| Total number of metastases after TX | ||||||||
| ≥ 4 vs. 0 | 1.94 (0.99−3.81) | 0.05 | 2.13 (1.06−4.26) | 0.03 | ||||
| 1 vs. 0 | 1.58 (0.82−3.03) | 0.17 | 1.68 (0.85−3.31) | 0.13 | ||||
| 2 vs. 0 | 1.44 (0.76−2.71) | 0.26 | 1.54 (0.8−2.98) | 0.20 | ||||
| 3 vs. 0 | 1.76 (0.85−3.62) | 0.13 | 1.92 (0.91−4.04) | 0.09 | ||||
| Tumor shrinkage ≥ 10% | ||||||||
| PTS/MTS ≥ 10% | 0.46 (0.31−0.69) | <0.001 | 0.44 (0.29−0.67) | <0.001 | 0.46 (0.3−0.69) | <0.001 | 0.44 (0.29−0.67) | <0.001 |
| MTS ≥ 10% | 0.51 (0.34−0.77) | <0.001 | 0.48 (0.32−0.73) | <0.001 | 0.51 (0.34−0.77) | <0.001 | 0.48 (0.32−0.73) | <0.001 |
| PTS ≥ 10% | 0.47 (0.23−0.95) | <0.03 | 0.48 (0.23−0.98) | 0.04 | 0.48 (0.23−0.97) | 0.04 | 0.49 (0.24−1) | 0.05 |
| IMDC score | ||||||||
| Intermediate vs. poor | 0.61 (0.38−1) | 0.05 | 0.55 (0.34–0.9) | 0.02 | 0.64 (0.3−1.04) | 0.07 | 0.57 (0.34−0.95) | 0.03 |
| Preop Therapy | ||||||||
| IO vs. TMT | 0.93 (0.47–1.84) | 0.83 | 0.84 (0.42−1.67) | 0.62 | 0.96 (0.48−1.91) | 0.91 | 0.87 (0.44−1.74) | 0.69 |
| IO + TMT vs. TMT | 0.71 (0.22–2.25) | 0.56 | 0.95 (0.3–3.04) | 0.93 | 0.73 (0.23−2.31) | 0.59 | 0.97 (0.3–3.1) | 0.95 |
CSS, cancer-specific survival; ECOG, Eastern Cooperative Oncology Group; IO, immunotherapy; PTS, Primary Tumor Shrinkage; MTS, metastatic Tumor Shrinkage; IMDC, International Metastatic RCC Database Consortium; OS, overall survival; TMT, targeted molecular therapy; TX, treatment.
We stratified survival outcomes by site of tumor shrinkage (primary, metastatic, or both). Patients with PTS ≥ 10% had a median OS of 48 months (95% CI 18.3 months-not evaluable), those with MTS ≥ 10% had a median OS of 35.9 months (95% CI 25.3–62.1 months), those with PTS/MTS ≥ 10% had a median OS of 44.4 months (95% CI 37.4–61.9 months), and those with PTS/MTS < 10% had a median OS of 16.2 months (95% CI 11.5–24.3 months). Independent of the type of preoperative systemic therapy, patients with tumor shrinkage of at least 10% (PTS ≥ 10%, MTS ≥ 10%, and PTS/MTS ≥ 10%) had better OS outcomes compared to patients with PTS/MTS < 10% (P < 0.01, Figure 2).
Fig. 2.
Kaplan-Meier OS curves in patients with MTS ≥ 10%, PTS ≥ 10%, PTS/MTS ≥ 10%, and PTS/MTS < 10% after systemic therapy followed by cytoreductive nephrectomy. MTS, metastatic tumor shrinkage; OS, overall survival; PTS, primary tumor shrinkage.
PTS ≥ 10% was significantly associated with better OS outcomes in both univariable (HR 0.47 [95% CI 0.23–0.95]; P=0.03) and multivariable (HR 0.48 [95% CI 0.23–0.98]; P = 0.04) analysis. MTS ≥ 10% was significantly associated with better OS outcomes in both univariable (HR 0.51 [95% CI 0.34–0.77]; P=0.001) and multivariable (HR 0.48 [95% C, 0.32–0.73]; P < 0.001) analysis. PTS/MTS ≥ 10% was significantly associated with better OS outcomes in both univariable (HR 0.46 [95% CI 0.31–0.69]; P < 0.001) and multivariable (HR 0.44 [95% C, 0.29–0.67]; P < 0.001) analysis (Table 3). Furthermore, MTS ≥ 10% and PTS/MTS ≥ 10% were significantly associated with better CSS outcomes in both univariable and multivariable analysis, but PTS ≥ 10% was significantly associated with better CSS outcomes in only the univariable analysis (Table 3).
Patients with intermediate-risk IMDC scores had better OS outcomes compared to patients in the poor-risk group (Figure 3). Median OS was 34.8 months (95% CI 25.3–44.4 months) in the intermediate-risk group and 15.7 months (95% CI 13.3–62.1 months) in the poor-risk group (P = 0.046). In univariable and multivariable analyses, intermediate-risk was significantly associated with better OS outcomes and CSS (Table 3).
Fig. 3.
Kaplan-Meier OS curves in patients with intermediate and poor risk by International Metastatic Database Consortium score at initial presentation. OS, overall survival.
Before systemic therapy, the total number of metastases was similar between patients with tumor shrinkage of at least 10% and those with tumor shrinkage less than 10% (P = 0.9, Table 1). After systemic therapy, the total number of metastases was significantly lower in those with tumor shrinkage of at least 10% (P < 0.001), of whom 13% had no evidence of metastasis and 27% had only one metastasis. We found no significant differences in OS in patients with tumor shrinkage of at least 10% when stratified by the number of metastases (P = 0.49 Figure 4). The median OS time stratified by the number of metastases after systemic therapy in patients with tumor shrinkage of at least 10% was as follows: no metastases, 53.3 months (95% CI 34.6 months-not evaluable); one metastasis, 33.1 months (95% CI 19–60.1 months); two metastases, 54.6 months (95% CI 40.0–62.1 months); three metastases, 22.5 months (95% CI 15.8 months-not evaluable); four or more metastases, 77.3 months (95% CI 36.6 months-not evaluable). In a secondary analysis of OS according to the location of metastases in patients with tumor shrinkage of at least 10% with adjustment for the number of metastases, we found that no specific metastatic locations were associated with OS (Table 4).
Fig. 4.
Kaplan-Meier OS curves in patients who had tumor shrinkage of at least 10% stratified by total number of metastases after systemic therapy. OS, overall survival.
Table 4.
Survival analysis by site of metastatic lesion(s) in patients with tumor shrinkage of at least 10% adjusted for number of metastasis after systemic treatment.
| Metastatic site | OS time, months, median (95% CI) | Adjusted HR (95% CI) | P-value |
|---|---|---|---|
|
| |||
| Lung | 40.0 (33.1–57.7) | 1.03 (0.65–1.64) | 0.91 |
| Bone | 26.1 (18.3–70.3) | 1.05 (0.62–1.76) | 0.86 |
| Brain | 39.4 (NE-NE) | 1.33 (0.17–10.3) | 0.79 |
| Pancreas | 56.2 (54.6-NE) | 0.63 (0.15–2.62) | 0.53 |
| Retroperitoneal adenopathy | 36.5 (16.0–73.3) | 1.44 (0.85–2.44) | 0.18 |
| Supraclavicular adenopathy | 108 (52.0-NE) | 0.45 (0.1–2.04) | 0.3 |
| Mediastinum | 71.9 (36.6-NE) | 0.64 (0.32–1.3) | 0.22 |
| Soft tissue | 54.6 (30.5-NE) | 0.77 (0.34–1.74) | 0.52 |
NE, not evaluable; OS, overall survival.
4. Discussion
The treatment of metastatic ccRCC has evolved substantially with the recent development of new systemic therapies. Immunotherapy alone or in combination with TMT has been associated with better OS, objective responses, and complete responses than has TMT alone [15, 16]. Recent studies demonstrated a median OS of 46 months in appropriately selected patients with metastatic ccRCC who received sunitinib followed by dCN [8]. The median OS in our series ranged from 28 to 36 months, depending on the type of preoperative treatment.
Multiple randomized trials showed that treatment of metastatic ccRCC with nivolumab and ipilimumab (immunotherapy) or pembrolizumab and axitinib (immunotherapy plus TMT) was associated with better OS than was TMT alone [15, 16]. The present study demonstrated a similar trend in the immunotherapy and immunotherapy plus TMT groups, with better OS most evident during the first year of treatment. The lack of a statistical difference in OS among the three treatment groups may have been due to the small number of patients and shorter follow-up among those who received immunotherapy. Patients who received immunotherapy had better performance status before surgery than patients who received combination therapy or TMT alone. While performance status is one of the factors commonly used in patient selection for surgery, it was not associated with better survival in our study. Future studies with larger cohorts and longer follow-up may demonstrate better survival outcomes among patients who receive preoperative immunotherapy.
Researchers have made multiple efforts to identify prognostic factors associated with OS in patients who received TMT followed by dCN [10]. Tumor burden and tumor shrinkage have been associated with OS in patients given preoperative TMT [19]. PTS of at least 10% within 60 days after initiation of treatment and MTS of at least 10% have been associated with better OS outcomes [11–13]. In these studies, patients with all histological subtypes were included, and in one study [13], 24% of the patients had unknown or unclassified tumor histology. In the present analysis, we included only patients with ccRCC to limit the heterogeneity of tumor response to preoperative systemic therapy and OS. Patients with primary ccRCC and tumor shrinkage of at least 10% after systemic therapy followed by dCN had a median OS ranging from 35.9 to 48 months depending on the type of tumor shrinkage (primary, metastatic, or both). The other factor associated with better survival outcomes in our study was the IMDC. Although a patient’s IMDC score could change during treatment, the IMDC score at presentation represents a predictor of survival, with patients in the intermediate-risk group having favorable outcomes compared to patients in the poor-risk group.
In our study, the number of metastases in patients with tumor shrinkage of at least 10% after systemic therapy was considerably lower than that in patients with tumor shrinkage less than 10%. Despite this result, OS outcomes in patients with tumor shrinkage of at least 10% were similar independent of the number of metastases. Although the number of metastases may affect OS, our data suggest that metastatic tumor volume response to systemic therapy is a better predictor of survival. Prior studies showed that the location of metastasis could impact survival [20]. In the present analysis, specific metastatic sites in patients with tumor shrinkage of at least 10% were not associated with OS. These findings suggest that the biological response to systemic therapy should be used for the appropriate selection of patients who may benefit from dCN. In contrast, the location and the number of metastasis after therapy did not impact overall survival.
The role of dCN in patients with stable radiologically detected metastatic ccRCC must be better defined. In the present study, the mean OS in patients with tumor shrinkage less than 10% was 16.2 months, suggesting a potential benefit in well-selected patients. Further studies are needed to characterize other prognostic factors in this population.
Our study has limitations. It was a retrospective study performed in a single tertiary cancer center. While TMT is an option in metastatic ccRCC, monotherapy with TMT is not the current standard of care in most situations. Measuring the longest dimensions of primary and metastatic tumors may not be the optimal way to characterize tumor response with different therapies. Further studies measuring tumor volume in three dimensions and using other characteristics, such as tumor necrosis on cross-sectional images, may enable the identification of additional prognostic factors associated with survival of patients with metastatic ccRCC after systemic therapy. PDL-1 status has been associated with survival outcomes in patients who received immunotherapy [15]. In our study however, immunotherapy was only given to 17.2% of patients, limiting the utility of inclusion of such biomarkers in our analysis. As the number of patients who received immunotherapy followed by cytoreductive nephrectomy increases, further studies are warranted to identify potential biomarkers to improve patient selection.
5. Conclusions
In patients with metastatic ccRCC, preoperative immunotherapy, TMT, and immunotherapy combined with TMT resulted in comparable tumor responses. Tumor shrinkage of at least 10% after preoperative therapy was associated with better OS outcomes in patients who underwent dCN independent of the number and locations of metastases.
Highlights:
Tumor diameter response of ≥10% was associated with better overall survival.
Intermediate-risk IMDC scores at initial presentation had better overall survival.
In tumor shrinkage of ≥10%, number of metastasis was not associated with survival.
In tumor shrinkage of ≥10%, metastasis location was not associated with survival.
Acknowledgments
Editorial support was provided by Bryan Tutt, Scientific Editor, Research Medical Library, MD Anderson Cancer Center.
Funding:
The Biostatistics Resource Group is supported in part by the National Institutes of Health through M. D. Anderson’s Cancer Center Support Grant CA016672.
Footnotes
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