Letters to the Editor
CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS Volume 29, Number 7, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/cbr.2014.1604
The Outcome of Targeted Therapies in Patients with Poor Prognosis Metastatic Renal Cell Carcinoma Jacopo Giuliani1 and Marina Marzola 2
Dear Editor:
T
he treatment of metastatic renal cell carcinoma (mRCC) has changed dramatically over the past few years. Targeted therapies (TT) have changed the therapy of mRCC: sunitinib and sorafenib as multikinase inhibitors, everolimus and temsirolimus as mammalian target of rapamycin inhibitors, and bevacizumab as an antibody against vascular endothelial growth factor in combination with interferon-alpha (IFN-alpha). Currently, the best sequence of targeted therapy in patients with mRCC has not been sufficiently defined and is based on the patient’s and physician’s decision, which may be influenced by comorbidities and toxicity profiles1; this choice is even more uncertain when it comes to patients with poor prognosis.2 The aim of this report is to evaluate the outcome of TT on clinical practice after the era of cytokine-based therapy in mRCC and focus on patients with poor prognosis. The authors retrospectively analyzed all consecutive patients with poor prognosis mRCC treated at the Clinical Oncology Unit of the University Hospital of Ferrara from June 1998 to September 2010. A univariate analysis for different prognostic–predictive variables on overall survival (OS) was estimated according to the Kaplan–Meier method with statistical significance ( p < 0.05) of differences evaluated by the log-rank test. Among the 61 mRCC patients treated in the reference period, 22 (35.5%) were poor prognosis. Ten patients (45.5%) were treated with only cytokine-based therapy (because nothing else was available at the time; INF-alpha was used in all patients), 8 patients (36.4%) were treated with TT in first line (100% sunitinib), and 4 patients (31.8%) were treated with TT in second or subsequent lines (in these cases, patients received immunotherapy first and targeted therapies at disease progression; no patients received targeted therapies first and immunotherapy at relapse or as a planned sequence of therapy). The median follow-up time was 10.75 1 2
months (range 2.1–49.9) and the median OS was 11.27 months (range 1.0–47.2). The median age was 63.0 years (range 40–79 years), 17 patients were male (77.3%) and 5 female (22.7%), and prevalent histology (18 patients) was clear cell carcinoma (81.8%); in five cases (33.3%), the Fuhrman grading was 2, in 6 patients (40.0%) was 3, and in 4 (26.7%) was 4. In 15 patients (71.4%), a nephrectomy for the primary site was performed; in nine cases (60.0%), patients were metastatic after surgery. Seven patients (31.8%) had one site of metastasis, 5 patients (22.7%) had two sites, and 10 patients (45.5%) had more than three sites at the time of diagnosis of metastatic disease. The univariate analysis for OS showed statistically significant differences for performing a nephrectomy for the primary site ( p = 0.012), the number of sites of metastases ( p = 0.017), and a high corrected serum calcium level ( p < 0.001). The general case study is summarized in Table 1. The univariate analysis for OS (Fig. 1) did not show statistically significant advantages for the use of immunotherapy in first line versus TT versus TT in second or subsequent lines ( p = 0.971). The median OS for patients treated only with immunotherapy in first line was 18.3 months (95% confidence interval: 9.8–26.8), for patients treated with immunotherapy in first line and with TT in second or subsequent lines, the OS was 16.5 months (95% confidence interval: 6.9–26.0), and for patients treated with TT in first line, the OS was 16.8 months (95% confidence interval: 12.0–24.5). These data seem to highlight how the use of TT in poor prognosis mRCC has less impact in terms of OS than other prognostic subgroups not showing significant differences compared to the pre-TT era. The authors know from the randomized phase III trial of sunitinib versus INF-alpha that the median OS was greater in the sunitinib group than in the INF-alpha group,3 and they do not dispute this much larger data, but shift the attention on the poor prognosis subgroup. In fact, the literature is very poor and there are no data from studies
Department of Oncology, ASL 21 della Regione Veneto, Legnago (VR), Italy. Clinical Oncology Unit, St. Anna University-Hospital, Ferrara, Italy.
Address correspondence to: Jacopo Giuliani; Department of Oncology, ASL 21 della Regione Veneto, Via Gianella, Legnago (VR); Gianella Street, 1, 1-37045, Italy E-mail: [email protected]
298
TARGETED THERAPIES AND POOR PROGNOSIS MRCC
299
Table 1. General Case Study and Univariate Analysis for Prognostic–Predictive Factors Variable Sex Histology Fuhrman grading system
pT
Status postsurgery for primary site No. of sites of metastases Bone metastases Lung metastases Liver metastases CNS metastases Anemia LDH level PS ECOG Corrected serum calcium level Initial diagnosis to therapy
Value
N (%)
Male Female Clear cell carcinoma Other histology G1-G2 G3 G4 Missing pT1 pT2 pT3 pT4 Missing NED Alive with metastasis 1 2 ‡3 Yes No Yes No Yes No Yes No Yes No Low ( £ 1.5 · upper limit of normal) High ( > 1.5 · upper limit of normal) 0 1 2 Low ( £ 10 mg/dL) High ( > 10 mg/dL) < 1 year ‡ 1 year
17 5 18 4 5 6 4 7 6 3 5 1 7 6 9 7 5 10 15 7 8 14 5 17 3 19 20 2 17 5 3 6 13 1 21 19 3
(77.3%) (22.7%) (81.8%) (18.2%) (33.3%) (40.0%) (26.7%) (31.8%) (40.0%) (20.0%) (33.3%) (6.7%) (31.8%) (40.0%) (60.0%) (31.8%) (22.7%) (45.5%) (68.2%) (31.8%) (36.4%) (63.6%) (22.7%) (77.3%) (13.6%) (86.4%) (90.9%) (9.1%) (77.3%) (22.7%) (13.6%) (27.3%) (59.1%) (4.5%) (95.5%) (86.4%) (13.6%)
Median OS (months)
p
16.46 28.76 18.11 18.41 30.58 18.72 14.29
0.422
28.28 11.67 23.54 11.28
0.210
19.76 22.93 24.49 22.07 10.00 15.02 25.22 17.74 18.51 15.73 19.27 11.74 19.31 17.21 24.98 20.52 11.26 36.31 19.47 12.54 1.00 10.07 18.98 14.84
0.903
0.831 0.328
0.017 0.264 0.701 0.647 0.355 0.364 0.124 0.198 < 0.001 0.543
Bold type indicates statistically significant values. N, number of patients; pT, pathological size or direct extent of the primary tumor (TNM staging system); LDH, lactate dehydrogenase; OS, overall survival.
FIG. 1. Univariate analysis for overall survival (OS) considering the different types of therapy.
focused on poor prognosis mRCC that are able to demonstrate a clear benefit by the advent of TT. Other retrospective studies have also emphasized the potential significance of utilizing immunotherapy in the initial treatment of mRCC to optimize treatment options and, in particular, considering IL-2 as the initial therapy in any patients with mRCC, who are medically fit for such therapy.4 The findings of this study partially agree with the data of this retrospective study; in fact, the conclusions focus on poor prognosis mRCC patients. Based on experience, these types of patients seem to benefit from the use of TT less than the other mRCC prognostic categories. The authors also know both the limits of a retrospective experience; on the contrary, reports like the above, although the analysis of not a selected case study, are able to evaluate treatment patterns in a real-world clinical practice. In addition, the identification of biological markers
300
predicting the response to TT might be useful. Clinical trials are needed. Disclosure Statement
There are no existing financial conflicts. References 1. Sonpavde G, Choueiri TK, Escudier B, et al. Sequencing of agents for metastatic renal cell carcinoma: Can we customize therapy? Eur Urol 2012;61:307.
GIULIANI AND MARZOLA
2. Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;22: 454. 3. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115. 4. Dillman RO, Barth NM, VanderMolen LA, et al. Should high-dose interleukin-2 still be the preferred treatment for patients with metastatic renal cell cancer? Cancer Biother Radiopharm 2011;26:273.
CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS Volume 29, Number 7, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/cbr.2014.1604
The Outcome of Targeted Therapies in Patients with Poor Prognosis Metastatic Renal Cell Carcinoma Jacopo Giuliani1 and Marina Marzola 2
Dear Editor:
T
he treatment of metastatic renal cell carcinoma (mRCC) has changed dramatically over the past few years. Targeted therapies (TT) have changed the therapy of mRCC: sunitinib and sorafenib as multikinase inhibitors, everolimus and temsirolimus as mammalian target of rapamycin inhibitors, and bevacizumab as an antibody against vascular endothelial growth factor in combination with interferon-alpha (IFN-alpha). Currently, the best sequence of targeted therapy in patients with mRCC has not been sufficiently defined and is based on the patient’s and physician’s decision, which may be influenced by comorbidities and toxicity profiles1; this choice is even more uncertain when it comes to patients with poor prognosis.2 The aim of this report is to evaluate the outcome of TT on clinical practice after the era of cytokine-based therapy in mRCC and focus on patients with poor prognosis. The authors retrospectively analyzed all consecutive patients with poor prognosis mRCC treated at the Clinical Oncology Unit of the University Hospital of Ferrara from June 1998 to September 2010. A univariate analysis for different prognostic–predictive variables on overall survival (OS) was estimated according to the Kaplan–Meier method with statistical significance ( p < 0.05) of differences evaluated by the log-rank test. Among the 61 mRCC patients treated in the reference period, 22 (35.5%) were poor prognosis. Ten patients (45.5%) were treated with only cytokine-based therapy (because nothing else was available at the time; INF-alpha was used in all patients), 8 patients (36.4%) were treated with TT in first line (100% sunitinib), and 4 patients (31.8%) were treated with TT in second or subsequent lines (in these cases, patients received immunotherapy first and targeted therapies at disease progression; no patients received targeted therapies first and immunotherapy at relapse or as a planned sequence of therapy). The median follow-up time was 10.75 1 2
months (range 2.1–49.9) and the median OS was 11.27 months (range 1.0–47.2). The median age was 63.0 years (range 40–79 years), 17 patients were male (77.3%) and 5 female (22.7%), and prevalent histology (18 patients) was clear cell carcinoma (81.8%); in five cases (33.3%), the Fuhrman grading was 2, in 6 patients (40.0%) was 3, and in 4 (26.7%) was 4. In 15 patients (71.4%), a nephrectomy for the primary site was performed; in nine cases (60.0%), patients were metastatic after surgery. Seven patients (31.8%) had one site of metastasis, 5 patients (22.7%) had two sites, and 10 patients (45.5%) had more than three sites at the time of diagnosis of metastatic disease. The univariate analysis for OS showed statistically significant differences for performing a nephrectomy for the primary site ( p = 0.012), the number of sites of metastases ( p = 0.017), and a high corrected serum calcium level ( p < 0.001). The general case study is summarized in Table 1. The univariate analysis for OS (Fig. 1) did not show statistically significant advantages for the use of immunotherapy in first line versus TT versus TT in second or subsequent lines ( p = 0.971). The median OS for patients treated only with immunotherapy in first line was 18.3 months (95% confidence interval: 9.8–26.8), for patients treated with immunotherapy in first line and with TT in second or subsequent lines, the OS was 16.5 months (95% confidence interval: 6.9–26.0), and for patients treated with TT in first line, the OS was 16.8 months (95% confidence interval: 12.0–24.5). These data seem to highlight how the use of TT in poor prognosis mRCC has less impact in terms of OS than other prognostic subgroups not showing significant differences compared to the pre-TT era. The authors know from the randomized phase III trial of sunitinib versus INF-alpha that the median OS was greater in the sunitinib group than in the INF-alpha group,3 and they do not dispute this much larger data, but shift the attention on the poor prognosis subgroup. In fact, the literature is very poor and there are no data from studies
Department of Oncology, ASL 21 della Regione Veneto, Legnago (VR), Italy. Clinical Oncology Unit, St. Anna University-Hospital, Ferrara, Italy.
Address correspondence to: Jacopo Giuliani; Department of Oncology, ASL 21 della Regione Veneto, Via Gianella, Legnago (VR); Gianella Street, 1, 1-37045, Italy E-mail: [email protected]
298
TARGETED THERAPIES AND POOR PROGNOSIS MRCC
299
Table 1. General Case Study and Univariate Analysis for Prognostic–Predictive Factors Variable Sex Histology Fuhrman grading system
pT
Status postsurgery for primary site No. of sites of metastases Bone metastases Lung metastases Liver metastases CNS metastases Anemia LDH level PS ECOG Corrected serum calcium level Initial diagnosis to therapy
Value
N (%)
Male Female Clear cell carcinoma Other histology G1-G2 G3 G4 Missing pT1 pT2 pT3 pT4 Missing NED Alive with metastasis 1 2 ‡3 Yes No Yes No Yes No Yes No Yes No Low ( £ 1.5 · upper limit of normal) High ( > 1.5 · upper limit of normal) 0 1 2 Low ( £ 10 mg/dL) High ( > 10 mg/dL) < 1 year ‡ 1 year
17 5 18 4 5 6 4 7 6 3 5 1 7 6 9 7 5 10 15 7 8 14 5 17 3 19 20 2 17 5 3 6 13 1 21 19 3
(77.3%) (22.7%) (81.8%) (18.2%) (33.3%) (40.0%) (26.7%) (31.8%) (40.0%) (20.0%) (33.3%) (6.7%) (31.8%) (40.0%) (60.0%) (31.8%) (22.7%) (45.5%) (68.2%) (31.8%) (36.4%) (63.6%) (22.7%) (77.3%) (13.6%) (86.4%) (90.9%) (9.1%) (77.3%) (22.7%) (13.6%) (27.3%) (59.1%) (4.5%) (95.5%) (86.4%) (13.6%)
Median OS (months)
p
16.46 28.76 18.11 18.41 30.58 18.72 14.29
0.422
28.28 11.67 23.54 11.28
0.210
19.76 22.93 24.49 22.07 10.00 15.02 25.22 17.74 18.51 15.73 19.27 11.74 19.31 17.21 24.98 20.52 11.26 36.31 19.47 12.54 1.00 10.07 18.98 14.84
0.903
0.831 0.328
0.017 0.264 0.701 0.647 0.355 0.364 0.124 0.198 < 0.001 0.543
Bold type indicates statistically significant values. N, number of patients; pT, pathological size or direct extent of the primary tumor (TNM staging system); LDH, lactate dehydrogenase; OS, overall survival.
FIG. 1. Univariate analysis for overall survival (OS) considering the different types of therapy.
focused on poor prognosis mRCC that are able to demonstrate a clear benefit by the advent of TT. Other retrospective studies have also emphasized the potential significance of utilizing immunotherapy in the initial treatment of mRCC to optimize treatment options and, in particular, considering IL-2 as the initial therapy in any patients with mRCC, who are medically fit for such therapy.4 The findings of this study partially agree with the data of this retrospective study; in fact, the conclusions focus on poor prognosis mRCC patients. Based on experience, these types of patients seem to benefit from the use of TT less than the other mRCC prognostic categories. The authors also know both the limits of a retrospective experience; on the contrary, reports like the above, although the analysis of not a selected case study, are able to evaluate treatment patterns in a real-world clinical practice. In addition, the identification of biological markers
300
predicting the response to TT might be useful. Clinical trials are needed. Disclosure Statement
There are no existing financial conflicts. References 1. Sonpavde G, Choueiri TK, Escudier B, et al. Sequencing of agents for metastatic renal cell carcinoma: Can we customize therapy? Eur Urol 2012;61:307.
GIULIANI AND MARZOLA
2. Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;22: 454. 3. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115. 4. Dillman RO, Barth NM, VanderMolen LA, et al. Should high-dose interleukin-2 still be the preferred treatment for patients with metastatic renal cell cancer? Cancer Biother Radiopharm 2011;26:273.
