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On-target Toxicities Predictive of Survival in Metastatic Renal Cell Carcinoma (mRCC) Treated With Sunitinib: A Multicenter Retrospective Study
Journal Pre-proof ON-TARGET TOXICITIES PREDICTIVE OF SURVIVAL IN METASTATIC RENAL CELL CARCINOMA (mRCC) TREATED WITH SUNITINIB: A MULTICENTER RETROSPECTIVE STUDY Bolzacchini Elena, Pinotti Graziella, Lorenza Bertu’, Verusio Claudio, Galli Luca, Mumoli Nicola, Barbara Cecilia, Danova Marco, Bregni Marco, Artale Salvatore, Rossini Chiara, Olga Nigro, Antonuzzo Andrea, Derosa Lisa, Torchio Martina, Barzaghi Sabrina, Ricci Isabella, Suter Matteo, Ballerio Alice, Vallini Ilaria, Dentali Francesco PII:
S1558-7673(19)30307-6
DOI:
https://doi.org/10.1016/j.clgc.2019.10.003
Reference:
CLGC 1365
To appear in:
Clinical Genitourinary Cancer
Received Date: 24 April 2019 Revised Date:
23 September 2019
Accepted Date: 6 October 2019
Please cite this article as: Elena B, Graziella P, Bertu’ L, Claudio V, Luca G, Nicola M, Cecilia B, Marco D, Marco B, Salvatore A, Chiara R, Nigro O, Andrea A, Lisa D, Martina T, Sabrina B, Isabella R, Matteo S, Alice B, Ilaria V, Francesco D, ON-TARGET TOXICITIES PREDICTIVE OF SURVIVAL IN METASTATIC RENAL CELL CARCINOMA (mRCC) TREATED WITH SUNITINIB: A MULTICENTER RETROSPECTIVE STUDY, Clinical Genitourinary Cancer (2020), doi: https://doi.org/10.1016/ j.clgc.2019.10.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
ON-TARGET TOXICITIES PREDICTIVE OF SURVIVAL IN METASTATIC RENAL CELL CARCINOMA (mRCC) TREATED WITH SUNITINIB: A MULTICENTER RETROSPECTIVE STUDY
Authors Bolzacchini Elena1, Pinotti Graziella1 , Lorenza Bertu’2 , Verusio Claudio3, Galli Luca4 , Mumoli Nicola5 , Barbara Cecilia 6, Danova Marco7 , Bregni Marco8, Artale Salvatore9 , Rossini Chiara3, Olga Nigro1, Antonuzzo Andrea 4, Derosa Lisa4, Torchio Martina7, Barzaghi Sabrina9, Ricci Isabella9, Suter Matteo1, Ballerio Alice3, Vallini Ilaria1, Dentali Francesco 2
Affiliation 1 Oncologia Medica, Ospedale di Circolo, Varese 2 Dipartimento di Medicina e Chirurgia, Università degli Studi dell’Insubria di Varese 3 Oncologia Medica, Presidio Ospedaliero di Saronno 4 Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Pisa 5 Medicina Interna, Azienda USL6 Livorno - Presidio Ospedaliero di Livorno 6 Oncologia Medica, Azienda USL 6 di Livorno, Livorno 7 Medicina Interna, Ospedale di Vigevano, Azienda Socio-Sanitaria Territoriale di Pavia 8 Oncologia Medica, Ospedale di Busto Arsizio - ASST Valle Olona 9 Oncologia Medica, Azienda Ospedaliera S. Antonio Abate di Gallarate
Running title: On-target toxicities and survival for sunitinib in mRCC Key-words: mRCC, sunitinib, toxicities Word count: 1943
Corresponding Author Elena Bolzacchini M.D. U.O Oncologia Medica Ospedale di Circolo,Viale Borri 57, 21100 Varese Tel. 0039 3298597540 FAX: 0332/278673 Email: [email protected] Conflict of interest: nothing to declare on behalf of all the authors
Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors
This paper has not been published entirely previously, is not under consideration for publication elsewhere, and that, if accepted, will not be published elsewhere in the same form, in English or in any other language. The preliminary data of this study was published in abstract form at the XVIII annual meeting of the Associazione Italiana di Oncologia Medica (AIOM), Rome, Italy, 2016
Abstract Background Preliminary studies suggested that selected drug-related toxicities of sunitinib may correlate with a better prognosis. Patients and methods From January 2006 till December 2015 we retrospectively analysed data of 145 patients (pts) affected with metastatic renal cell carcinoma (mRCC) treated with sunitinib as a first-line therapy in 7 different Italian Oncology Departments. Hypertension, hypothyroidism, thrombocytopenia, neutropenia and anemia were evaluated. Overall survival (OS) and progression free survival (PFS) were calculated. OS and PFS were compared in patients who developed and who did not develop a drug-related toxicity. A multivariate analysis using the Cox’s regression model were performed. Results We evaluated 145 pts(92 males, median age 70 years); 105 pts (62.4%) experienced at least one toxicity: 66 pts (45,5%) developed hypothyroidism, 41 pts (28,3%) thrombocytopenia, 39 pts (26,9%) hypertension that required medical therapy, 22 (15.2%) anemia and 11 pts (7,6%) neutropenia. The median PFS of patients who developed hypertension was 12 month(95%CI 9-21) vs. 9 months(95% CI 7-12) in patients who did not develop toxicity, the median OS was 36 months (95%CI 22-not reached) vs. 26 months(95%CI 18-34). For neutropenia, median PFS was 17.5 (95%CI 9-65) vs. 10 (95%CI 8-12),OS median 23(95%CI 13- not reached)vs. 28 (95%CI 22-35). At the univariate and at the multivariate analysis, we observed a protective effect of hypertension and neutropenia on tumor progression(HR=0.47, IC 95% 0.28-0.78 and HR 0.26, IC 95% 0.090.76, respectively). Conclusions Many patients developed toxicities during treatment with sunitinib; hypertension and neutropenia were related to longer PFS in our cohort.
MicroAbstract: Preliminary studies suggested that drug-related toxicity of sunitinib may correlate with a better prognosis. We conducted a retrospective multicenter study regarding sunitinib-related toxicity. We evaluated 145 pts affected with metastatic renal cancer treated with sunitinib in first line therapy. At the univariate and at the multivariate analysis, we observed a protective effect of hypertension and neutropenia on tumor progression.
Text Introduction Sunitinib malate is an oral targeted tyrosine kinase inhibitor (TKI) able to inhibit members of specific receptor tyrosine kinases families such as vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), c-KIT, and RET. [1] It is associated with several well-characterized side effects, such as hypertension, hypothyroidism, neutropenia, anemia, thrombocytopenia and hand foot syndrome [2-3] Molecular mechanisms underlying these toxicities remain unclear, but they may be related to the additional effect of sunitinib on non-malignant cells that also express sunitinib targets, or to the cross-talk between different intracellular signaling pathways. [1] A number of retrospective analyses about the association between defined adverse event (AE) and clinical outcome are available in the literature. Several studies suggest that development of these on-target effects indicates effective inhibition of the corresponding receptor linked with oncogenesis. This is reflected as improved efficacy in the subgroup of patients who develop these on-target AE compared with those who do not. [4] In particular, preliminary studies regarding sunitinib-induced hypertension suggest that it correlates with a better prognosis in terms of overall survival (OS) and progression free survival (PFS) [5-9]. Other data are available regarding the favorable prognostic role of sunitinib-induced hypothyroidism [10-12] and bone marrow toxicity. [5,13] In order to confirm these preliminary findings, we retrospectively analyzed toxicities and outcomes of more than 100 consecutive patients affected by mRCC treated with sunitinib.
Methods From January 2006 till December 2017 we retrospectively collected and analysed data of 145 consecutive patients, from seven different Italian Oncology Departments (Varese, Saronno, Busto
Arsizio, Gallarate, Vigevano, Pisa, Livorno), affected by mRCC treated with sunitinib as first-line therapy. Data regarding age, gender, Eastern Oncology Cooperative Group (ECOG) performance status, body mass index (BMI), histology, previous nephrectomy, memorial Sloan-Kettering Cancer Center criteria (MSKCC score), previous radiotherapy, previous caval thrombosis and number of metastatic sites were collected. Previous hypertension and hypothyroidism were evaluated and data regarding the type and dosage of drugs were collected. Patients with mRCC received sunitinib 50 mg orally once a day in repeated 6-week cycles according to a 4/2 schedule (4 weeks of treatment followed by 2 weeks without treatment). According to the local clinical practice of participating centers, patients were monitored closely for toxicity. Dose reductions or scheduled treatment modification (2 weeks on, 1 week off) were performed based on toxicities type and grade. Adverse events were graded using the National Cancer Institute (NCI) CTCAE-Version 4.03 [14] In particular the following toxicities were evaluated: hypertension (blood pressure>140/90 mmHg or blood pressure requiring more intensive anti-hypertensive therapy than previously used), hypothyroidism (requiring hormone replacement therapy), thrombocytopenia (platelet count <100.000 109/L), neutropenia (neutrophils <500 109/L), anemia (decrease in hemoglobin≥2 g/dL). Laboratory assessments (hematology and biochemistry) were performed at baseline and before every cycle thereafter. Blood pressure and thyroid function were assessed at baseline and before every cycle. Clinical symptoms were assessed before every cycle. Specific therapy was administered in case of hypertension development. Patients previously affected by hypertension who developed uncontrolled blood pressure during sunitinib modified their anti-hypertensive therapy after consulting the anti-hypertensive local center.
Thyroid hormone replacement with levothyroxine was started after an endocrinologist consult. Treatment response was assessed by physical examination and computed tomography every 12 weeks (two cycles). All radiological assessments were evaluated by radiologists according to RECIST 1.1 criteria [15]. Progression free survival (PFS) was calculated from the start of treatment until disease progression. Overall survival (OS) was calculated from the start of treatment until death. Patients were followed-up from the beginning of therapy for metastatic disease until they died. We compared median OS and PFS of patients who developed on-target AE with the ones who did not experience the specific AE. We also evaluated if the development of at least one toxicity was predictive of survival.
Statistical analysis The variables collected were described with absolute and relative frequencies in the case of discrete variables, with mean and standard deviation for continuous ones. The percentage, the median time and the range for drug–related toxicities (hypertension, thyroid toxicity, thrombocytopenia, neutropenia and anemia) were calculated. An explorative landmark analysis was performed to take into account possible distortions due to "lead time" bias, at 6,12 and 24 weeks; disease free survival (PFS) and overall survival (OS) were evaluated using at 12 weeks’ cut-off, by the Kaplan-Meier. To study the potential role of other factors on the PFS and OS a Cox regression model (univariate and multivariate) with drug-related toxicity as time-varying covariates, was implemented and Hazard Ratios together with 95% confidence intervals were calculated. Primary analysis was conducted as considering the single drug-related toxicity “per se”; in a secondary analysis we considered all toxicities as composite variables (“at least one toxicity”).
The following variables were considered in the multivariate models: age at diagnosis, gender, histology, nephrectomy, Karnofsky index, MSKCC, previous radiotherapy, vena cava thrombosis and number of metastases. Two tailed P values < 0.05 were used to indicate statistical significance. All analysis was carried out using SAS statistical package (Version 9.4 for Windows. SAS Institute Inc. Cary NC).
Results Patients The pooled database comprehended 145 patients (97 males, 48 females) affected by mRCC treated with sunitinib as first line therapy. Median age was 63 year-old (ranging from 38 to 90); 126 patients (86.9%) had a diagnosis of mRCC with clear cell histology and 127 (87.6%) underwent nephrectomy; all of them had ECOG performance status 0-1. MSKCC score was available in almost all of the patients: it was favorable in 38 patients (28.8%), intermediate in 75 patients (56.8%), poor in 19 patients (14.4%), and missing in 13 patients; 48 patients (33.1%) had more than one metastatic site. Seventeen patients (11.7%) underwent prior radiotherapy. Sixty-four patients (44.1%) had pre-existing controlled hypertension and 10 patients (6.9%) pre-existing hypothyroidism in treatment with L-Thyroxine. Complete blood count was normal in all patients before starting treatment. Out of 145 patients, 117 progressed during sunitinib, 88 died. Median OS was 18 months (range 2-99 months), median PFS was 9 months (range 2-78 months).
Incidence of on-target AEs during treatment Baseline characteristics for patients with AEs versus patients without AEs are summarized in table 1. Significant difference between two group was observed for MSKCC distribution (favorable
34.4% AEs group vs. 15.6%, intermediate 57.0% vs. 56.4% and poor 8,6 % vs. 28.2, p=0.005). No other differences among baseline features was detected. As show in table 2, 105 patients (72.4% of the included patients) experienced at least one toxicity: 66 patients (45.5%) developed hypothyroidism (median time to onset was 4.5 months, ranging from 1.5 to 36.0 months), 41 patients (28.3%) thrombocytopenia (3.0 months, range 0-12), 39 patients (26.9%) hypertension that required medical therapy (1.5 months, range 0-18), 11 patients (7.6%) neutropenia (4.5 months, range 1.5-18.0), and 22 (15.2%) anemia (3.0 months, range 1.5-10.5). In Figure 1 and 2 Kaplan-Meier estimates of Overall Survival and Progression Free Survival by Hypertension and neutropenia, developed in the first 3 months of treatment, were graphically presented. The median PFS of patients who developed hypertension in the first 3 months was 12 month (95%CI 9-21) vs. 9 months (95%CI 7-12) in patients who did not develop toxicity, the median OS was 36 months (95%CI 22- not reached) vs. 26 months (95%CI 18-34). For neutropenia, median PFS was 17.5 (95%CI 9-65) vs. 10 (95%CI 8-12), OS median 23 (95%CI 13- not reached) vs. 28 (95%CI 22-35). At the univariate analysis, we observed a protective effect of hypertension (HR=0.64, IC 95% 0.410.99) and neutropenia (HR=0.32, IC 95% 0.13-0.80) on tumor progression; this effect was confirmed at the multivariate analysis (HR=0.47, IC 95% 0.28-0.78 and HR 0.26, IC 95% 0.090.76, respectively) (Table 3). Hypertension and neutropenia seem to improve, although not in a statistically significant way, also the OS: multivariate HR 0.77 ( 95%CI 0.43-1.38) and 0.50 (95% CI 0.18-1.43) for Hypertension and neutropenia respectively (Table 4). Regarding the development of at least one toxicity (hypertension, hypothyroidism, neutropenia, thrombocytopenia or anemia) we didn’t find a significant protective effect of developing at least one toxicity, but considering hypertension or neutropenia we found a protective effect of one of these two toxicity in terms of PFS at the univariate and at the multivariate analysis (HR=0.42 95%CI 0.26-0.69).
Discussion Sunitinib is one of the standards of care for patients affected by mRCC. [16] The most common side effects are hypertension, hypothyroidism, bone marrow toxicities and hand-foot syndrome. [2] Many previous paper explore the potential role of side effects and have assessed the potential prognostic role of on-target toxicities in mRCC patients on mechanisms controlled by nervous and hormonal factors that affect blood vessels [17]. In our multicenter study on more than 140 consecutive patients with mRCC treated with sunitinib as a first line therapy, the development of toxicities seems clinically relevant. Our results are completely in line with a larger study of 770 mRCC patients treated with sunitinib [13] and hypertension and neutropenia were considered by the authors effective biomarkers of response. Many other previous studies correlate the development of hypertension with survival. [5-8] Underlying mechanisms regarding sunitinib-induced hypertension are well described; it is known that VEGF enhance transcriptional activity of nitric oxide synthase [19] while inhibition of VEGFsignalling may bock nitric oxide production, leading to vascular constriction and promoting hypertension. [20] On the contrary, hematologic toxicity may be induced by inhibition of activated tyrosine kinases such as the KIT receptor, expressed by hematopoietic progenitor cells [21] and because sunitinib inhibits the autophosphorylation of PDGR and FLT3. [22-23] To the best of our knowledge very few data are available regarding the potential prognostic role of bone marrow toxicity. [13] Considering the underlying mechanism of sunitinib-induced hypothyroidism, several hypotheses can be considered to explain, such as a direct effect of sunitinib on sodium iodide symporter or TSH receptor [24], drug induced atrophy of the thyroid through inhibition of gland vascularity or thyroiditis [25], and reduced synthesis of thyroid hormones due to inhibition of thyroid peroxidase
activity and progressive depletion of functional reserves.[26] While all with a rationale, none of these hypotheses are clearly established as of today. Data regarding induced sunitinib thyroid toxicity are controversial; some authors [12,27] found in previous report that hypotiroidism was predictive of survival. On the contrary, Sabatier et al. [28] in a multicenter prospective study of 111 patients did not find any significant correlation between thyroid dysfunction during sunitinib therapy and PFS. In our cohort of patients the development of hypothyroidism was not associated with longer survival. Also, the best timing for evaluating thyroid function remains to be established. Wolter et al [29] suggests to evaluate it at day 1 and 28 of every cycle for the first 4 cycles; if normal every 3-4 cycles. Instead, Torino at al [30] advise to assess thyroid function on day 1 of every cycle of sunitinib treatment. In our study, some patients developed hypothyroidism even beyond the 7th cycle of therapy suggesting that periodical TSH dosage should never be ceased in patients on treatment. We did not assess the prognostic role of the hand foot syndrome (HFS) because at the time the work was conceived, there were no clear indications that the cutaneous toxicity had a prognostic role. Recently, few reports have highlighted a positive role of development of HFS too. [31-32] In our cohort, patients with favorable MSKCC score developed more toxicity and we could suppose that is related to the longer survival of this group. Potential limitations of our study included its retrospective design and the lack of a pre-specified systematic patients monitoring for the development of side effects; however all of the oncological centers involved in this study followed guidelines [18] and monitored the patients for the development of side effects very often and in particular before every cycle.
Conclusion: Clinically validated predictive biomarkers for response to antiangiogenic therapy are still lacking.
Our findings, on a large sample of consecutive patients, support the hypothesis that side effects arising from sunitinib are predictive of response in mRCC. Our results, are completely in line with the available literature regarding the positive effect of hypertension and neutropenia on PFS. On the contrary, the development of hypothyroidism was not associated with longer survival in our cohort. Larger prospective trials are needed to validate AEs as biomarkers for efficacy.
Clinical practice points:
A number of retrospective analyses suggest that development of on-target effects during sunitinib therapy (hypertension, hypothyroidism and medullary toxicities) are predictive of better survival in patients affected with metastatic kidney cancer. In a large cohort of patients, retrospectively analysed, we found that sunitinib-induced hypertension and neutropenia were predictive of longer PFS. Our results, are completely in line with the available literature regarding the positive effect of hypertension and neutropenia on PFS. On the contrary, the development of hypothyroidism was not associated with longer survival in our cohort. Larger prospective trials are needed to validate AEs as biomarkers for efficacy.
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Table 1. Baseline characteristics for patients with Adverse Events versus patients without Adverse Events (toxicity)
Number of patients Age,years Sex, Male Clear cell histology Papillary Nephrectomy Karnosky index,Low
N Median (IQR) n(%) n(%) n(%) n(%) n(%) Missing n
Total sample 145 63 17.0 97 66.9 126 86.9 11 7.6 127 87.6
AEs* 105 64 73 91 8 93
17.0 69.5 86.7 7.6 88.6
No AEs 40 61.4 19.5 24 60.0 35 87.5 3 7.5 35 85.0
p-value§ 0.95 0.28 0.89 0.98 0.58
29 1
20.1
18
17.1
11 1
28.2
0.14
n(%) n(%) n(%) n
38 75 19 13
28.8 56.8 14.4
32 53 8
34.4 57.0 8.6
6 22 11
15.4 56.4 28.2
0.005
History of hypertension n(%) History of hypothyroidism n(%) Missing n
64 10 1
44.1 6.9
48 7
45.7 6.7
16 3
40.0 7.5
0.54 0.99
Prior radiotherapy Metastatic site, 2 or more TVP cavale Missing
17 48 20 1
11.7 33.1 13.9
10 34 14
9.5 32.4 13.3
7 14 6
17.5 35.0 15.4
0.25 0.76 0.75
MSKCC Favorable Intermediate Poor Missing
n(%) n(%) n(%) n
*Hypertension, Thyroid toxicity, Thrombocytopenia, Neutropenia and Anaemia § Specific AEs vs None or nonspecific AEs , chi-square/Fisher exact test or Mann-Whitney U test
Table 2.Progression Free Survival - Unadjusted and adjusted Cox proportional Hazard model with time-dependent (TD) covariates
Hypertension (TD) Thyroid Toxicity (TD) Thrombocytopenia (TD) Neutropenia (TD) Anaemia (TD) Age Sex Clear cell histology Papillary Nephrectomy Karnosky index
No Yes No Yes No Yes No Yes No Yes Female Male No Yes No Yes No Yes High Low
Unadjusted HR 95%CI 1.0 Ref. 0.64 0.41-0.99 1.0 Ref. 0.82 0.54-1.26 1.0 Ref. 1.06 0.69-1.61 1.0 Ref. 0.32 0.13-0.80 1.0 Ref. 1.90 1.10-3.29 1.01 0.99-1.02 1.0 Ref. 0.64 0.43-0.95 1.0 Ref. 1.03 0.61-1.75 1.0 Ref. 0.61 0.30-1.25 1.0 Ref. 0.57 0.32-1.00 1.0 Ref. 2.02 1.27-3.23
HR 1.0 0.47
95%CI Ref. 0.28-0.78
HR
95%CI
1.0 0.75
Ref. 0.47-1.21
Adjusted HR 95%CI
1.0 1.19
HR
95%CI
1.0 0.26
Ref. 0.09-0.76
HR
95%CI
Ref. 0.80-2.89 0.92-1.02 Ref. 0.41-1.01 Ref. 0.26-1.35 Ref. 0.09-0.88 Ref. 0.34-1.25 Ref. 0.67-2.63 Ref. 0.83-2.20 1.49-7.88 Ref. 0.63-1.61 Ref. 0.46-1.98 Ref.
Ref. 0.72-1.95
0.99 1.0 0.61 1.0 0.48 1.0 0.23 1.0 0.50 1.0 1.15
0.97-1.02 Ref. 0.39-.96 Ref. 0.20-1.13 Ref. 0.07-0.71 Ref. 0.25-0.99 Ref. 0.58-2.29
0.99 1.0 0.66 1.0 0.56 1.0 0.26 1.0 0.67 1.0 1.29
0.97-1.02 Ref. 0.43-1.03 Ref. 0.24-1.30 Ref. 0.08-0.79 Ref. 0.35-1.29 Ref. 0.65-2.53
1.0 1.0 0.66 1.0 0.61 1.0 0.29 1.0 0.67 1.0 1.33
0.98-1.02 Ref. 0.42-1.02 Ref. 0.27-1.41 Ref. 0.10-0.90 Ref. 0.35-1.28 Ref. 0.67-2.63
1.00 1.0 0.67 1.0 0.66 1.0 0.26 1.0 0.76 1.0 1.15
0.98-1.02 Ref. 0.43-1.03 Ref. 0.28-1.51 Ref. 0.09-0.81 Ref. 0.39-1.46 Ref. 0.59-2.28
1.0 1.52 1.00 1.0 0.65 1.0 0.59 1.0 0.29 1.0 0.65 1.0 1.32
1.0 1.32 3.95 1.0 1.20 1.0 0.82 1.0
Ref. 0.81-2.15 1.74-8.97 Ref. 0.75-1.92 Ref. 0.39-1.70 Ref.
1.0 1.43 3.77 1.0 1.09 1.0 0.92 1.0
Ref. 0.88-2.33 1.65-8.59 Ref. 0.68-1.75 Ref. 0.44-1.89 Ref.
1.0 1.43 3.90 1.0 1.06 1.0 0.96 1.0
Ref. 0.88-2.33 1.68-9.03 Ref. 0.67-1.69 Ref. 0.46-2.00 Ref.
1.0 1.46 4.03 1.0 1.15 1.0 0.79 1.0
Ref. 0.89-2.37 1.74-9.33 Ref. 0.72-1.85 Ref. 0.37-1.67 Ref.
1.0 1.35 3.43 1.0 1.01 1.0 0.96 1.0
MSKCC Favorable Intermediate Poor History of hypertension No Yes History of hypothyroidism No Yes Prior radiotherapy No
1.0 1.38 3.30 1.0 1.10 1.0 1.07 1.0
Ref. 0.89-2.15 1.79-6.09 Ref. 0.76-1.60 Ref. 0.56-2.04 Ref.
Metastatic site, 2 or more TVP cavale
Yes No Yes No Yes
1.07 1.0 1.05 1.0 1.43
0.59-1.96 Ref. 0.71-1.54 Ref. 0.85-2.40
0.58 1.0 1.07 1.0 1.36
0.27-1.28 Ref. 0.67-1.70 Ref. 0.75-2.45
0.57 1.0 1.15 1.0 1.44
0.26-1.25 Ref. 0.73-1.81 Ref. 0.80-2.59
0.55 1.0 1.12 1.0 1.47
0.25-1.21 Ref. 0.70-1.79 Ref. 0.82-2.56
0.58 1.0 1.17 1.0 1.42
0.26-1.29 Ref. 0.74-1.87 Ref. 0.79-2.56
0.59 1.0 1.14 1.0 1.43
0.27-1.28 Ref. 0.72-1.80 Ref. 0.79-2.57
Table 3. Overall Survival - Unadjusted and adjusted Cox proportional Hazard model with time-dependent (TD) covariates
Hypertension (TD) Thyroid Toxicity (TD) Thrombocytopenia (TD) Neutropenia (TD) Anaemia (TD) Age Sex Clear cell histology Papillary Nephrectomy Karnosky index
No Yes No Yes No Yes No Yes No Yes Female Male No Yes No Yes No Yes High Low
Unadjusted HR 95%CI 1.0 Ref. 0.62 0.37-1.04 1.0 Ref. 0.98 0.63-1.52 1.0 Ref. 0.94 0.59-1.51 1.0 Ref. 0.48 0.19-1.20 1.0 Ref. 1.66 0.97-2.82 0.99 0.98-1.03 1.0 Ref. 0.99 0.63-1.56 1.0 Ref. 1.10 0.58-2.06 1.0 Ref. 0.75 0.33-1.73 1.0 Ref. 0.60 0.32-1.15 1.0 Ref. 2.42 1.48-3.97
HR 1.0 0.77
95%CI Ref. 0.43-1.38
HR
95%CI
1.0 1.23
Ref. 0.74-2.03
Adjusted HR 95%CI
1.0 1.06
HR
95%CI
1.0 0.50
Ref. 0.18-1.43
HR
95%CI
Ref. 0.66-2.57 0.98-1.03 Ref. 0.72-.00 Ref. 0.59-4.44 Ref. 0.22-2.31 Ref. 0.43-1.87 Ref. 0.82-3.51 Ref. 1.06-3.53 2.46-18.19 Ref. 0.54-1.64 Ref. 0.43-2.66 Ref. 0.18-1.16
Ref. 0.59-1.89
1.00 1.0 1.19 1.0 1.55 1.0 0.70 1.0 0.80 1.0 1.59
0.98-1.03 Ref. 0.70-2.00 Ref. 0.57-4.22 Ref. 0.22-2.22 Ref. 0.37-1.72 Ref. 0.76-3.33
1.01 1.0 1.25 1.0 1.62 1.0 0.73 1.0 0.90 1.0 1.65
0.98-1.03 Ref. 0.74-2.11 Ref. 0.61-4.33 Ref. 0.23-2.29 Ref. 0.43-1.89 Ref. 0.79-3.42
1.00 1.0 1.19 1.0 1.62 1.0 0.71 1.0 0.90 1.0 1.69
0.98-1.03 Ref. 0.71-2.01 Ref. 0.59-4.40 Ref. 0.22-2.31 Ref. 0.43-1.88 Ref. 0.81-3.52
1.00 1.0 1.23 1.0 1.73 1.0 0.70 1.0 0.95 1.0 1.61
0.98-1.03 Ref. 0.74-2.06 Ref. 0.64-4.68 Ref. 0.22-2.24 Ref. 0.45-1.98 Ref. 0.78-3.31
1.0 1.30 1.00 1.0 1.20 1.0 1.62 1.0 0.71 1.0 0.89 1.0 1.70
1.0 1.84 6.43 1.0 1.02 1.0 0.98 1.0 0.46
Ref. 1.01-3.37 2.40-17.26 Ref. 0.58-1.78 Ref. 0.39-2.43 Ref. 0.18-1.16
1.0 1.95 6.33 1.0 0.99 1.0 1.01 1.0 0.46
Ref. 1.07-3.56 2.36-16.96 Ref. 0.57-1.73 Ref. 0.40-2.51 Ref. 0.19-1.16
1.0 1.93 6.59 1.0 0.94 1.0 1.07 1.0 0.46
Ref. 1.06-3.52 2.40-18.10 Ref. 0.54-1.63 Ref. 0.43-2.66 Ref. 0.18-1.17
1.0 1.92 6.67 1.0 0.98 1.0 0.99 1.0 0.47
Ref. 1.05-3.50 2.47-18.03 Ref. 0.56-1.70 Ref. 0.39-2.47 Ref. 0.19-1.18
1.0 1.93 6.69 1.0 0.94 1.0 1.07 1.0 0.45
MSKCC Favorable Intermediate Poor History of hypertension No Yes History of hypothyroidism No Yes Prior radiotherapy No Yes
1.0 1.84 5.02 1.0 0.92 1.0 0.92 1.0 1.48
Ref. 1.05-3.21 2.47-10.24 Ref. 0.60-1.41 Ref. 0.40-2.12 Ref. 0.78-2.79
Metastatic site, 2 or more TVP cavale
No Yes No Yes
1.0 1.17 1.0 1.75
Ref. 0.76-1.82 Ref. 1.00-3.07
1.0 1.06 1.0 1.90
Ref. 0.63-1.80 Ref. 1.00-3.62
1.0 1.13 1.0 1.99
Ref. 0.67-1.91 Ref. 1.05-3.76
1.0 1.12 1.0 2.08
Ref. 0.65-1.91 Ref. 1.10.-3.91
1.0 1.10 1.0 2.00
Ref. 0.66-1.85 Ref. 1.06-3.77
1.0 1.11 1.0 2.08
Ref. 0.66-1.86 Ref. 1.07-4.07
46-18.19
Table 4. Progression Free and Overall Survival - Unadjusted and adjusted Cox proportional Hazard model with time-dependent (TD) covariates
At least one toxicity Age Sex Clear cell histology Papillary Nephrectomy Karnosky index
No Yes Female Male No Yes No Yes No Yes High Low
Progession Free Survival (a) Unadjusted Adjusted HR 95%CI HR 95%CI 1.0 Ref. 1.0 Ref. 0.82 0.55-1.22 0.67 0.43-1.05 0.99 0.98-1.03 1.00 0.97-1.02 1.0 Ref. 1.0 Ref. 0.99 0.63-1.56 0.62 0.40-0.97 1.0 Ref. 1.0 Ref. 1.10 0.58-2.06 0.57 0.25-1.31 1.0 Ref. 1.0 Ref. 0.75 0.33-1.73 0.25 0.08-0.76 1.0 Ref. 1.0 Ref. 0.60 0.32-1.15 0.64 0.33-1.24 1.0 Ref. 1.0 Ref. 2.42 1.48-3.97 1.21 0.61-2.38
Overall Survival (a) Unadjusted Adjusted HR 95%CI HR 95%CI 1.0 Ref. 1.0 Ref. 0.87 0.54-1.41 1.23 0.71-2.11 1.01 0.98-1.03 1.00 0.98-1.03 1.0 Ref. 1.0 Ref. 1.25 0.74-2.11 1.21 0.73-2.03 1.0 Ref. 1.0 Ref. 1.62 0.61-4.33 1.60 0.59-4.35 1.0 Ref. 1.0 Ref. 0.73 0.23-2.29 0.73 0.22-2.42 1.0 Ref. 1.0 Ref. 0.90 0.43-1.89 0.89 0.43-1.84 1.0 Ref. 1.0 Ref. 1.65 0.79-3.42 1.74 0.84-3.60
Progession Free Survival (b) Unadjusted Adjusted HR 95%CI HR 95%CI 1.0 Ref. 1.0 Ref. 0.59 0.39-0.90 0.42 0.26-0.69 1.00 0.98-1.03 1.00 0.97-1.02 1.0 Ref. 1.0 Ref. 1.23 0.74-2.06 0.59 0.38-0.93 1.0 Ref. 1.0 Ref. 1.73 0.64-4.68 0.49 0.21-1.15 1.0 Ref. 1.0 Ref. 0.70 0.22-2.24 0.21 0.07-0.65 1.0 Ref. 1.0 Ref. 0.95 0.45-1.98 0.49 0.25-0.98 1.0 Ref. 1.0 Ref. 1.61 0.78-3.31 1.07 0.54-2.13
Overall Survival (b) Unadjusted Adjusted HR 95%CI HR 95%CI 1.0 Ref. 1.0 Ref. 0.64 0.40-1.03 0.77 0.44-1.34 1.00 0.98-1.03 1.00 0.98-1.03 1.0 Ref. 1.0 Ref. 1.23 0.74-2.06 1.20 0.71-2.01 1.0 Ref. 1.0 Ref. 1.73 0.64-4.68 1.61 0.59-4.38 1.0 Ref. 1.0 Ref. 0.70 0.22-2.24 0.69 0.22-2.22 1.0 Ref. 1.0 Ref. 0.95 0.45-1.98 0.83 0.39-1.78 1.0 Ref. 1.0 Ref. 1.61 0.78-3.31 1.61 0.77-3.36
1.0 1.84 5.02 1.0 0.92 1.0 0.92 1.0 1.48 1.0 1.17 1.0 1.75
1.0 1.95 6.33 1.0 0.99 1.0 1.01 1.0 0.46 1.0 1.13 1.0 1.99
1.0 1.92 6.67 1.0 0.98 1.0 0.99 1.0 0.47 1.0 1.10 1.0 2.00
1.0 1.92 6.67 1.0 0.98 1.0 0.99 1.0 0.47 1.0 1.10 1.0 2.00
MSKCC Favorable Intermediate Poor History of hypertension No Yes History of hypothyroidism No Yes Prior radiotherapy No Yes Metastatic site, 2 or more No Yes TVP cavale No Yes
Ref. 1.05-3.21 2.47-10.24 Ref. 0.60-1.41 Ref. 0.40-2.12 Ref. 0.78-2.79 Ref. 0.76-1.82 Ref. 1.00-3.07
1.0 1.40 3.58 1.0 1.08 1.0 0.91 1.0 0.58 1.0 1.19 1.0 1.43
a: At least one toxicity (any) b: At least one toxicity between Hypertension and Neutropenia
Ref. 0.86-2.28 1.57-8,17 Ref. 0.68-1.72 Ref. 0.44-1.87 Ref. 0.26-1.27 Ref. 0.75-1.88 Ref. 0.80-2.57
Ref. 1.07-3.56 2.36-16.96 Ref. 0.57-1.73 Ref. 0.40-2.51 Ref. 0.19-1.16 Ref. 0.67-1.91 Ref. 1.05-3.76
1.0 2.00 7.21 1.0 0.92 1.0 1.08 1.0 0.45 1.0 1.13 1.0 2.09
Ref. 1.09-3.67 2.62-19.84 Ref. 0.53-1.60 Ref. 0.43-2.70 Ref. 0.18-1.14 Ref. 0.67-1.89 Ref. 1.11-3.93
Ref. 1.05-3.50 2.47-18.03 Ref. 0.56-1.70 Ref. 0.39-2.47 Ref. 0.19-1.18 Ref. 0.66-1.85 Ref. 1.06-3.77
1.0 1.37 4.21 1.0 1.18 1.0 0.77 1.0 0.56 1.0 1.03 1.0 1.32
Ref. 0.84-2.24 1.85-9.56 Ref. 0.74-1.89 Ref. 0.37-1.61 Ref. 0.26-1.23 Ref. 0.65-1.66 Ref. 0.73-2.39
Ref. 1.05-3.50 2.47-18.03 Ref. 0.56-1.70 Ref. 0.39-2.47 Ref. 0.19-1.18 Ref. 0.66-1.85 Ref. 1.06-3.77
1.0 1.88 6.62 1.0 0.98 1.0 1.00 1.0 0.45 1.0 1.06 1.0 1.97
Ref. 1.03-3.45 2.47-17.78 Ref. 0.56-1.71 Ref. 0.40-2.51 Ref. 0.18-1.13 Ref. 0.63-1.80 Ref. 1.04-3.74
2.47-17.78
S1558-7673(19)30307-6
DOI:
https://doi.org/10.1016/j.clgc.2019.10.003
Reference:
CLGC 1365
To appear in:
Clinical Genitourinary Cancer
Received Date: 24 April 2019 Revised Date:
23 September 2019
Accepted Date: 6 October 2019
Please cite this article as: Elena B, Graziella P, Bertu’ L, Claudio V, Luca G, Nicola M, Cecilia B, Marco D, Marco B, Salvatore A, Chiara R, Nigro O, Andrea A, Lisa D, Martina T, Sabrina B, Isabella R, Matteo S, Alice B, Ilaria V, Francesco D, ON-TARGET TOXICITIES PREDICTIVE OF SURVIVAL IN METASTATIC RENAL CELL CARCINOMA (mRCC) TREATED WITH SUNITINIB: A MULTICENTER RETROSPECTIVE STUDY, Clinical Genitourinary Cancer (2020), doi: https://doi.org/10.1016/ j.clgc.2019.10.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
ON-TARGET TOXICITIES PREDICTIVE OF SURVIVAL IN METASTATIC RENAL CELL CARCINOMA (mRCC) TREATED WITH SUNITINIB: A MULTICENTER RETROSPECTIVE STUDY
Authors Bolzacchini Elena1, Pinotti Graziella1 , Lorenza Bertu’2 , Verusio Claudio3, Galli Luca4 , Mumoli Nicola5 , Barbara Cecilia 6, Danova Marco7 , Bregni Marco8, Artale Salvatore9 , Rossini Chiara3, Olga Nigro1, Antonuzzo Andrea 4, Derosa Lisa4, Torchio Martina7, Barzaghi Sabrina9, Ricci Isabella9, Suter Matteo1, Ballerio Alice3, Vallini Ilaria1, Dentali Francesco 2
Affiliation 1 Oncologia Medica, Ospedale di Circolo, Varese 2 Dipartimento di Medicina e Chirurgia, Università degli Studi dell’Insubria di Varese 3 Oncologia Medica, Presidio Ospedaliero di Saronno 4 Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Pisa 5 Medicina Interna, Azienda USL6 Livorno - Presidio Ospedaliero di Livorno 6 Oncologia Medica, Azienda USL 6 di Livorno, Livorno 7 Medicina Interna, Ospedale di Vigevano, Azienda Socio-Sanitaria Territoriale di Pavia 8 Oncologia Medica, Ospedale di Busto Arsizio - ASST Valle Olona 9 Oncologia Medica, Azienda Ospedaliera S. Antonio Abate di Gallarate
Running title: On-target toxicities and survival for sunitinib in mRCC Key-words: mRCC, sunitinib, toxicities Word count: 1943
Corresponding Author Elena Bolzacchini M.D. U.O Oncologia Medica Ospedale di Circolo,Viale Borri 57, 21100 Varese Tel. 0039 3298597540 FAX: 0332/278673 Email: [email protected] Conflict of interest: nothing to declare on behalf of all the authors
Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors
This paper has not been published entirely previously, is not under consideration for publication elsewhere, and that, if accepted, will not be published elsewhere in the same form, in English or in any other language. The preliminary data of this study was published in abstract form at the XVIII annual meeting of the Associazione Italiana di Oncologia Medica (AIOM), Rome, Italy, 2016
Abstract Background Preliminary studies suggested that selected drug-related toxicities of sunitinib may correlate with a better prognosis. Patients and methods From January 2006 till December 2015 we retrospectively analysed data of 145 patients (pts) affected with metastatic renal cell carcinoma (mRCC) treated with sunitinib as a first-line therapy in 7 different Italian Oncology Departments. Hypertension, hypothyroidism, thrombocytopenia, neutropenia and anemia were evaluated. Overall survival (OS) and progression free survival (PFS) were calculated. OS and PFS were compared in patients who developed and who did not develop a drug-related toxicity. A multivariate analysis using the Cox’s regression model were performed. Results We evaluated 145 pts(92 males, median age 70 years); 105 pts (62.4%) experienced at least one toxicity: 66 pts (45,5%) developed hypothyroidism, 41 pts (28,3%) thrombocytopenia, 39 pts (26,9%) hypertension that required medical therapy, 22 (15.2%) anemia and 11 pts (7,6%) neutropenia. The median PFS of patients who developed hypertension was 12 month(95%CI 9-21) vs. 9 months(95% CI 7-12) in patients who did not develop toxicity, the median OS was 36 months (95%CI 22-not reached) vs. 26 months(95%CI 18-34). For neutropenia, median PFS was 17.5 (95%CI 9-65) vs. 10 (95%CI 8-12),OS median 23(95%CI 13- not reached)vs. 28 (95%CI 22-35). At the univariate and at the multivariate analysis, we observed a protective effect of hypertension and neutropenia on tumor progression(HR=0.47, IC 95% 0.28-0.78 and HR 0.26, IC 95% 0.090.76, respectively). Conclusions Many patients developed toxicities during treatment with sunitinib; hypertension and neutropenia were related to longer PFS in our cohort.
MicroAbstract: Preliminary studies suggested that drug-related toxicity of sunitinib may correlate with a better prognosis. We conducted a retrospective multicenter study regarding sunitinib-related toxicity. We evaluated 145 pts affected with metastatic renal cancer treated with sunitinib in first line therapy. At the univariate and at the multivariate analysis, we observed a protective effect of hypertension and neutropenia on tumor progression.
Text Introduction Sunitinib malate is an oral targeted tyrosine kinase inhibitor (TKI) able to inhibit members of specific receptor tyrosine kinases families such as vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), c-KIT, and RET. [1] It is associated with several well-characterized side effects, such as hypertension, hypothyroidism, neutropenia, anemia, thrombocytopenia and hand foot syndrome [2-3] Molecular mechanisms underlying these toxicities remain unclear, but they may be related to the additional effect of sunitinib on non-malignant cells that also express sunitinib targets, or to the cross-talk between different intracellular signaling pathways. [1] A number of retrospective analyses about the association between defined adverse event (AE) and clinical outcome are available in the literature. Several studies suggest that development of these on-target effects indicates effective inhibition of the corresponding receptor linked with oncogenesis. This is reflected as improved efficacy in the subgroup of patients who develop these on-target AE compared with those who do not. [4] In particular, preliminary studies regarding sunitinib-induced hypertension suggest that it correlates with a better prognosis in terms of overall survival (OS) and progression free survival (PFS) [5-9]. Other data are available regarding the favorable prognostic role of sunitinib-induced hypothyroidism [10-12] and bone marrow toxicity. [5,13] In order to confirm these preliminary findings, we retrospectively analyzed toxicities and outcomes of more than 100 consecutive patients affected by mRCC treated with sunitinib.
Methods From January 2006 till December 2017 we retrospectively collected and analysed data of 145 consecutive patients, from seven different Italian Oncology Departments (Varese, Saronno, Busto
Arsizio, Gallarate, Vigevano, Pisa, Livorno), affected by mRCC treated with sunitinib as first-line therapy. Data regarding age, gender, Eastern Oncology Cooperative Group (ECOG) performance status, body mass index (BMI), histology, previous nephrectomy, memorial Sloan-Kettering Cancer Center criteria (MSKCC score), previous radiotherapy, previous caval thrombosis and number of metastatic sites were collected. Previous hypertension and hypothyroidism were evaluated and data regarding the type and dosage of drugs were collected. Patients with mRCC received sunitinib 50 mg orally once a day in repeated 6-week cycles according to a 4/2 schedule (4 weeks of treatment followed by 2 weeks without treatment). According to the local clinical practice of participating centers, patients were monitored closely for toxicity. Dose reductions or scheduled treatment modification (2 weeks on, 1 week off) were performed based on toxicities type and grade. Adverse events were graded using the National Cancer Institute (NCI) CTCAE-Version 4.03 [14] In particular the following toxicities were evaluated: hypertension (blood pressure>140/90 mmHg or blood pressure requiring more intensive anti-hypertensive therapy than previously used), hypothyroidism (requiring hormone replacement therapy), thrombocytopenia (platelet count <100.000 109/L), neutropenia (neutrophils <500 109/L), anemia (decrease in hemoglobin≥2 g/dL). Laboratory assessments (hematology and biochemistry) were performed at baseline and before every cycle thereafter. Blood pressure and thyroid function were assessed at baseline and before every cycle. Clinical symptoms were assessed before every cycle. Specific therapy was administered in case of hypertension development. Patients previously affected by hypertension who developed uncontrolled blood pressure during sunitinib modified their anti-hypertensive therapy after consulting the anti-hypertensive local center.
Thyroid hormone replacement with levothyroxine was started after an endocrinologist consult. Treatment response was assessed by physical examination and computed tomography every 12 weeks (two cycles). All radiological assessments were evaluated by radiologists according to RECIST 1.1 criteria [15]. Progression free survival (PFS) was calculated from the start of treatment until disease progression. Overall survival (OS) was calculated from the start of treatment until death. Patients were followed-up from the beginning of therapy for metastatic disease until they died. We compared median OS and PFS of patients who developed on-target AE with the ones who did not experience the specific AE. We also evaluated if the development of at least one toxicity was predictive of survival.
Statistical analysis The variables collected were described with absolute and relative frequencies in the case of discrete variables, with mean and standard deviation for continuous ones. The percentage, the median time and the range for drug–related toxicities (hypertension, thyroid toxicity, thrombocytopenia, neutropenia and anemia) were calculated. An explorative landmark analysis was performed to take into account possible distortions due to "lead time" bias, at 6,12 and 24 weeks; disease free survival (PFS) and overall survival (OS) were evaluated using at 12 weeks’ cut-off, by the Kaplan-Meier. To study the potential role of other factors on the PFS and OS a Cox regression model (univariate and multivariate) with drug-related toxicity as time-varying covariates, was implemented and Hazard Ratios together with 95% confidence intervals were calculated. Primary analysis was conducted as considering the single drug-related toxicity “per se”; in a secondary analysis we considered all toxicities as composite variables (“at least one toxicity”).
The following variables were considered in the multivariate models: age at diagnosis, gender, histology, nephrectomy, Karnofsky index, MSKCC, previous radiotherapy, vena cava thrombosis and number of metastases. Two tailed P values < 0.05 were used to indicate statistical significance. All analysis was carried out using SAS statistical package (Version 9.4 for Windows. SAS Institute Inc. Cary NC).
Results Patients The pooled database comprehended 145 patients (97 males, 48 females) affected by mRCC treated with sunitinib as first line therapy. Median age was 63 year-old (ranging from 38 to 90); 126 patients (86.9%) had a diagnosis of mRCC with clear cell histology and 127 (87.6%) underwent nephrectomy; all of them had ECOG performance status 0-1. MSKCC score was available in almost all of the patients: it was favorable in 38 patients (28.8%), intermediate in 75 patients (56.8%), poor in 19 patients (14.4%), and missing in 13 patients; 48 patients (33.1%) had more than one metastatic site. Seventeen patients (11.7%) underwent prior radiotherapy. Sixty-four patients (44.1%) had pre-existing controlled hypertension and 10 patients (6.9%) pre-existing hypothyroidism in treatment with L-Thyroxine. Complete blood count was normal in all patients before starting treatment. Out of 145 patients, 117 progressed during sunitinib, 88 died. Median OS was 18 months (range 2-99 months), median PFS was 9 months (range 2-78 months).
Incidence of on-target AEs during treatment Baseline characteristics for patients with AEs versus patients without AEs are summarized in table 1. Significant difference between two group was observed for MSKCC distribution (favorable
34.4% AEs group vs. 15.6%, intermediate 57.0% vs. 56.4% and poor 8,6 % vs. 28.2, p=0.005). No other differences among baseline features was detected. As show in table 2, 105 patients (72.4% of the included patients) experienced at least one toxicity: 66 patients (45.5%) developed hypothyroidism (median time to onset was 4.5 months, ranging from 1.5 to 36.0 months), 41 patients (28.3%) thrombocytopenia (3.0 months, range 0-12), 39 patients (26.9%) hypertension that required medical therapy (1.5 months, range 0-18), 11 patients (7.6%) neutropenia (4.5 months, range 1.5-18.0), and 22 (15.2%) anemia (3.0 months, range 1.5-10.5). In Figure 1 and 2 Kaplan-Meier estimates of Overall Survival and Progression Free Survival by Hypertension and neutropenia, developed in the first 3 months of treatment, were graphically presented. The median PFS of patients who developed hypertension in the first 3 months was 12 month (95%CI 9-21) vs. 9 months (95%CI 7-12) in patients who did not develop toxicity, the median OS was 36 months (95%CI 22- not reached) vs. 26 months (95%CI 18-34). For neutropenia, median PFS was 17.5 (95%CI 9-65) vs. 10 (95%CI 8-12), OS median 23 (95%CI 13- not reached) vs. 28 (95%CI 22-35). At the univariate analysis, we observed a protective effect of hypertension (HR=0.64, IC 95% 0.410.99) and neutropenia (HR=0.32, IC 95% 0.13-0.80) on tumor progression; this effect was confirmed at the multivariate analysis (HR=0.47, IC 95% 0.28-0.78 and HR 0.26, IC 95% 0.090.76, respectively) (Table 3). Hypertension and neutropenia seem to improve, although not in a statistically significant way, also the OS: multivariate HR 0.77 ( 95%CI 0.43-1.38) and 0.50 (95% CI 0.18-1.43) for Hypertension and neutropenia respectively (Table 4). Regarding the development of at least one toxicity (hypertension, hypothyroidism, neutropenia, thrombocytopenia or anemia) we didn’t find a significant protective effect of developing at least one toxicity, but considering hypertension or neutropenia we found a protective effect of one of these two toxicity in terms of PFS at the univariate and at the multivariate analysis (HR=0.42 95%CI 0.26-0.69).
Discussion Sunitinib is one of the standards of care for patients affected by mRCC. [16] The most common side effects are hypertension, hypothyroidism, bone marrow toxicities and hand-foot syndrome. [2] Many previous paper explore the potential role of side effects and have assessed the potential prognostic role of on-target toxicities in mRCC patients on mechanisms controlled by nervous and hormonal factors that affect blood vessels [17]. In our multicenter study on more than 140 consecutive patients with mRCC treated with sunitinib as a first line therapy, the development of toxicities seems clinically relevant. Our results are completely in line with a larger study of 770 mRCC patients treated with sunitinib [13] and hypertension and neutropenia were considered by the authors effective biomarkers of response. Many other previous studies correlate the development of hypertension with survival. [5-8] Underlying mechanisms regarding sunitinib-induced hypertension are well described; it is known that VEGF enhance transcriptional activity of nitric oxide synthase [19] while inhibition of VEGFsignalling may bock nitric oxide production, leading to vascular constriction and promoting hypertension. [20] On the contrary, hematologic toxicity may be induced by inhibition of activated tyrosine kinases such as the KIT receptor, expressed by hematopoietic progenitor cells [21] and because sunitinib inhibits the autophosphorylation of PDGR and FLT3. [22-23] To the best of our knowledge very few data are available regarding the potential prognostic role of bone marrow toxicity. [13] Considering the underlying mechanism of sunitinib-induced hypothyroidism, several hypotheses can be considered to explain, such as a direct effect of sunitinib on sodium iodide symporter or TSH receptor [24], drug induced atrophy of the thyroid through inhibition of gland vascularity or thyroiditis [25], and reduced synthesis of thyroid hormones due to inhibition of thyroid peroxidase
activity and progressive depletion of functional reserves.[26] While all with a rationale, none of these hypotheses are clearly established as of today. Data regarding induced sunitinib thyroid toxicity are controversial; some authors [12,27] found in previous report that hypotiroidism was predictive of survival. On the contrary, Sabatier et al. [28] in a multicenter prospective study of 111 patients did not find any significant correlation between thyroid dysfunction during sunitinib therapy and PFS. In our cohort of patients the development of hypothyroidism was not associated with longer survival. Also, the best timing for evaluating thyroid function remains to be established. Wolter et al [29] suggests to evaluate it at day 1 and 28 of every cycle for the first 4 cycles; if normal every 3-4 cycles. Instead, Torino at al [30] advise to assess thyroid function on day 1 of every cycle of sunitinib treatment. In our study, some patients developed hypothyroidism even beyond the 7th cycle of therapy suggesting that periodical TSH dosage should never be ceased in patients on treatment. We did not assess the prognostic role of the hand foot syndrome (HFS) because at the time the work was conceived, there were no clear indications that the cutaneous toxicity had a prognostic role. Recently, few reports have highlighted a positive role of development of HFS too. [31-32] In our cohort, patients with favorable MSKCC score developed more toxicity and we could suppose that is related to the longer survival of this group. Potential limitations of our study included its retrospective design and the lack of a pre-specified systematic patients monitoring for the development of side effects; however all of the oncological centers involved in this study followed guidelines [18] and monitored the patients for the development of side effects very often and in particular before every cycle.
Conclusion: Clinically validated predictive biomarkers for response to antiangiogenic therapy are still lacking.
Our findings, on a large sample of consecutive patients, support the hypothesis that side effects arising from sunitinib are predictive of response in mRCC. Our results, are completely in line with the available literature regarding the positive effect of hypertension and neutropenia on PFS. On the contrary, the development of hypothyroidism was not associated with longer survival in our cohort. Larger prospective trials are needed to validate AEs as biomarkers for efficacy.
Clinical practice points:
A number of retrospective analyses suggest that development of on-target effects during sunitinib therapy (hypertension, hypothyroidism and medullary toxicities) are predictive of better survival in patients affected with metastatic kidney cancer. In a large cohort of patients, retrospectively analysed, we found that sunitinib-induced hypertension and neutropenia were predictive of longer PFS. Our results, are completely in line with the available literature regarding the positive effect of hypertension and neutropenia on PFS. On the contrary, the development of hypothyroidism was not associated with longer survival in our cohort. Larger prospective trials are needed to validate AEs as biomarkers for efficacy.
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19. Hood JD, Meininger CJ, Ziche M, Granger HJ. VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. Am J Physiol. 1998 Mar;274(3 Pt 2):H1054-8 20. Sane DC, Anton L, Brosnihan KB. Angiogenic growth factors and hypertension. Angiogenesis. 2004;7(3):193-201. Review. 21. Brandt J, Briddell RA, Srour EF, Leemhuis TB, Hoffman R. Role of c-kit ligand in the expansion of human hematopoietic progenitor cells. Blood. 1992 Feb 1;79(3):634-41. 22.Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and plateletderived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003 Jan;9(1):327-37. 23. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and plateletderived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003 May;2(5):471-8. 24. Mannavola D, Coco P, Vannucchi G, Bertuelli R, Carletto M, Casali PG, Beck-Peccoz P, Fugazzola L (2007) A novel tyrosinekinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab 92:3531–3534. 25. Wong E, Rosen LS, Mulay M, Vanvugt A, Dinolfo M, Tomoda C, Sugawara M,Hershman JM. Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid. 2007 Apr;17(4):351-5. 26. Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, Morgan JA, Dychter SS, Larsen PR, Demetri GD, Alexander EK (2006) Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 145:660– 664. 27. Clemons J, Gao D, Naam M, Breaker K, Garfield D, Flaig TW. Thyroid dysfunction in patients treated with sunitinib or sorafenib. Clin Genitourin Cancer. 2012 Dec;10(4):225-31.
28. Sabatier R, Eymard JC, Walz J, Deville JL, Narbonne H, Boher JM, Salem N,Marcy M, Brunelle S, Viens P, Bladou F, Gravis G. Could thyroid dysfunction influence outcome in sunitinibtreated metastatic renal cell carcinoma? Ann Oncol. 2012 Mar;23(3):714-21. 39. Wolter P, Stefan C, Decallonne B, Dumez H, Bex M, Carmeliet P, SchöVski P (2008) The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation. Br J Cancer 99:448–454. 30. Torino F, Corsello SM, Longo R, Barnabei A, Gasparini G. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol. 2009 Apr;6(4):219-28. 31. Kucharz J, Budnik M, Dumnicka P, Pastuszczak M, Kuśnierz-Cabala B, Demkow T, Popko K, Wiechno P. Hand-Foot Syndrome and Progression-Free Survival in Patients Treated with Sunitinib for Metastatic Clear Cell Renal Cell Carcinoma. Adv Exp Med Biol. 2019;1133:35-40. 32. Abd Ghafar NK, Alip A, Ong TA, Yap NY, Saad M. Efficacy, safety, and prognostic indicators of first-line sunitinib in patients with metastatic renal cell carcinoma: A single center experience. J Cancer Res Ther. 2018 Oct-Dec;14(6):1303-1311
Table 1. Baseline characteristics for patients with Adverse Events versus patients without Adverse Events (toxicity)
Number of patients Age,years Sex, Male Clear cell histology Papillary Nephrectomy Karnosky index,Low
N Median (IQR) n(%) n(%) n(%) n(%) n(%) Missing n
Total sample 145 63 17.0 97 66.9 126 86.9 11 7.6 127 87.6
AEs* 105 64 73 91 8 93
17.0 69.5 86.7 7.6 88.6
No AEs 40 61.4 19.5 24 60.0 35 87.5 3 7.5 35 85.0
p-value§ 0.95 0.28 0.89 0.98 0.58
29 1
20.1
18
17.1
11 1
28.2
0.14
n(%) n(%) n(%) n
38 75 19 13
28.8 56.8 14.4
32 53 8
34.4 57.0 8.6
6 22 11
15.4 56.4 28.2
0.005
History of hypertension n(%) History of hypothyroidism n(%) Missing n
64 10 1
44.1 6.9
48 7
45.7 6.7
16 3
40.0 7.5
0.54 0.99
Prior radiotherapy Metastatic site, 2 or more TVP cavale Missing
17 48 20 1
11.7 33.1 13.9
10 34 14
9.5 32.4 13.3
7 14 6
17.5 35.0 15.4
0.25 0.76 0.75
MSKCC Favorable Intermediate Poor Missing
n(%) n(%) n(%) n
*Hypertension, Thyroid toxicity, Thrombocytopenia, Neutropenia and Anaemia § Specific AEs vs None or nonspecific AEs , chi-square/Fisher exact test or Mann-Whitney U test
Table 2.Progression Free Survival - Unadjusted and adjusted Cox proportional Hazard model with time-dependent (TD) covariates
Hypertension (TD) Thyroid Toxicity (TD) Thrombocytopenia (TD) Neutropenia (TD) Anaemia (TD) Age Sex Clear cell histology Papillary Nephrectomy Karnosky index
No Yes No Yes No Yes No Yes No Yes Female Male No Yes No Yes No Yes High Low
Unadjusted HR 95%CI 1.0 Ref. 0.64 0.41-0.99 1.0 Ref. 0.82 0.54-1.26 1.0 Ref. 1.06 0.69-1.61 1.0 Ref. 0.32 0.13-0.80 1.0 Ref. 1.90 1.10-3.29 1.01 0.99-1.02 1.0 Ref. 0.64 0.43-0.95 1.0 Ref. 1.03 0.61-1.75 1.0 Ref. 0.61 0.30-1.25 1.0 Ref. 0.57 0.32-1.00 1.0 Ref. 2.02 1.27-3.23
HR 1.0 0.47
95%CI Ref. 0.28-0.78
HR
95%CI
1.0 0.75
Ref. 0.47-1.21
Adjusted HR 95%CI
1.0 1.19
HR
95%CI
1.0 0.26
Ref. 0.09-0.76
HR
95%CI
Ref. 0.80-2.89 0.92-1.02 Ref. 0.41-1.01 Ref. 0.26-1.35 Ref. 0.09-0.88 Ref. 0.34-1.25 Ref. 0.67-2.63 Ref. 0.83-2.20 1.49-7.88 Ref. 0.63-1.61 Ref. 0.46-1.98 Ref.
Ref. 0.72-1.95
0.99 1.0 0.61 1.0 0.48 1.0 0.23 1.0 0.50 1.0 1.15
0.97-1.02 Ref. 0.39-.96 Ref. 0.20-1.13 Ref. 0.07-0.71 Ref. 0.25-0.99 Ref. 0.58-2.29
0.99 1.0 0.66 1.0 0.56 1.0 0.26 1.0 0.67 1.0 1.29
0.97-1.02 Ref. 0.43-1.03 Ref. 0.24-1.30 Ref. 0.08-0.79 Ref. 0.35-1.29 Ref. 0.65-2.53
1.0 1.0 0.66 1.0 0.61 1.0 0.29 1.0 0.67 1.0 1.33
0.98-1.02 Ref. 0.42-1.02 Ref. 0.27-1.41 Ref. 0.10-0.90 Ref. 0.35-1.28 Ref. 0.67-2.63
1.00 1.0 0.67 1.0 0.66 1.0 0.26 1.0 0.76 1.0 1.15
0.98-1.02 Ref. 0.43-1.03 Ref. 0.28-1.51 Ref. 0.09-0.81 Ref. 0.39-1.46 Ref. 0.59-2.28
1.0 1.52 1.00 1.0 0.65 1.0 0.59 1.0 0.29 1.0 0.65 1.0 1.32
1.0 1.32 3.95 1.0 1.20 1.0 0.82 1.0
Ref. 0.81-2.15 1.74-8.97 Ref. 0.75-1.92 Ref. 0.39-1.70 Ref.
1.0 1.43 3.77 1.0 1.09 1.0 0.92 1.0
Ref. 0.88-2.33 1.65-8.59 Ref. 0.68-1.75 Ref. 0.44-1.89 Ref.
1.0 1.43 3.90 1.0 1.06 1.0 0.96 1.0
Ref. 0.88-2.33 1.68-9.03 Ref. 0.67-1.69 Ref. 0.46-2.00 Ref.
1.0 1.46 4.03 1.0 1.15 1.0 0.79 1.0
Ref. 0.89-2.37 1.74-9.33 Ref. 0.72-1.85 Ref. 0.37-1.67 Ref.
1.0 1.35 3.43 1.0 1.01 1.0 0.96 1.0
MSKCC Favorable Intermediate Poor History of hypertension No Yes History of hypothyroidism No Yes Prior radiotherapy No
1.0 1.38 3.30 1.0 1.10 1.0 1.07 1.0
Ref. 0.89-2.15 1.79-6.09 Ref. 0.76-1.60 Ref. 0.56-2.04 Ref.
Metastatic site, 2 or more TVP cavale
Yes No Yes No Yes
1.07 1.0 1.05 1.0 1.43
0.59-1.96 Ref. 0.71-1.54 Ref. 0.85-2.40
0.58 1.0 1.07 1.0 1.36
0.27-1.28 Ref. 0.67-1.70 Ref. 0.75-2.45
0.57 1.0 1.15 1.0 1.44
0.26-1.25 Ref. 0.73-1.81 Ref. 0.80-2.59
0.55 1.0 1.12 1.0 1.47
0.25-1.21 Ref. 0.70-1.79 Ref. 0.82-2.56
0.58 1.0 1.17 1.0 1.42
0.26-1.29 Ref. 0.74-1.87 Ref. 0.79-2.56
0.59 1.0 1.14 1.0 1.43
0.27-1.28 Ref. 0.72-1.80 Ref. 0.79-2.57
Table 3. Overall Survival - Unadjusted and adjusted Cox proportional Hazard model with time-dependent (TD) covariates
Hypertension (TD) Thyroid Toxicity (TD) Thrombocytopenia (TD) Neutropenia (TD) Anaemia (TD) Age Sex Clear cell histology Papillary Nephrectomy Karnosky index
No Yes No Yes No Yes No Yes No Yes Female Male No Yes No Yes No Yes High Low
Unadjusted HR 95%CI 1.0 Ref. 0.62 0.37-1.04 1.0 Ref. 0.98 0.63-1.52 1.0 Ref. 0.94 0.59-1.51 1.0 Ref. 0.48 0.19-1.20 1.0 Ref. 1.66 0.97-2.82 0.99 0.98-1.03 1.0 Ref. 0.99 0.63-1.56 1.0 Ref. 1.10 0.58-2.06 1.0 Ref. 0.75 0.33-1.73 1.0 Ref. 0.60 0.32-1.15 1.0 Ref. 2.42 1.48-3.97
HR 1.0 0.77
95%CI Ref. 0.43-1.38
HR
95%CI
1.0 1.23
Ref. 0.74-2.03
Adjusted HR 95%CI
1.0 1.06
HR
95%CI
1.0 0.50
Ref. 0.18-1.43
HR
95%CI
Ref. 0.66-2.57 0.98-1.03 Ref. 0.72-.00 Ref. 0.59-4.44 Ref. 0.22-2.31 Ref. 0.43-1.87 Ref. 0.82-3.51 Ref. 1.06-3.53 2.46-18.19 Ref. 0.54-1.64 Ref. 0.43-2.66 Ref. 0.18-1.16
Ref. 0.59-1.89
1.00 1.0 1.19 1.0 1.55 1.0 0.70 1.0 0.80 1.0 1.59
0.98-1.03 Ref. 0.70-2.00 Ref. 0.57-4.22 Ref. 0.22-2.22 Ref. 0.37-1.72 Ref. 0.76-3.33
1.01 1.0 1.25 1.0 1.62 1.0 0.73 1.0 0.90 1.0 1.65
0.98-1.03 Ref. 0.74-2.11 Ref. 0.61-4.33 Ref. 0.23-2.29 Ref. 0.43-1.89 Ref. 0.79-3.42
1.00 1.0 1.19 1.0 1.62 1.0 0.71 1.0 0.90 1.0 1.69
0.98-1.03 Ref. 0.71-2.01 Ref. 0.59-4.40 Ref. 0.22-2.31 Ref. 0.43-1.88 Ref. 0.81-3.52
1.00 1.0 1.23 1.0 1.73 1.0 0.70 1.0 0.95 1.0 1.61
0.98-1.03 Ref. 0.74-2.06 Ref. 0.64-4.68 Ref. 0.22-2.24 Ref. 0.45-1.98 Ref. 0.78-3.31
1.0 1.30 1.00 1.0 1.20 1.0 1.62 1.0 0.71 1.0 0.89 1.0 1.70
1.0 1.84 6.43 1.0 1.02 1.0 0.98 1.0 0.46
Ref. 1.01-3.37 2.40-17.26 Ref. 0.58-1.78 Ref. 0.39-2.43 Ref. 0.18-1.16
1.0 1.95 6.33 1.0 0.99 1.0 1.01 1.0 0.46
Ref. 1.07-3.56 2.36-16.96 Ref. 0.57-1.73 Ref. 0.40-2.51 Ref. 0.19-1.16
1.0 1.93 6.59 1.0 0.94 1.0 1.07 1.0 0.46
Ref. 1.06-3.52 2.40-18.10 Ref. 0.54-1.63 Ref. 0.43-2.66 Ref. 0.18-1.17
1.0 1.92 6.67 1.0 0.98 1.0 0.99 1.0 0.47
Ref. 1.05-3.50 2.47-18.03 Ref. 0.56-1.70 Ref. 0.39-2.47 Ref. 0.19-1.18
1.0 1.93 6.69 1.0 0.94 1.0 1.07 1.0 0.45
MSKCC Favorable Intermediate Poor History of hypertension No Yes History of hypothyroidism No Yes Prior radiotherapy No Yes
1.0 1.84 5.02 1.0 0.92 1.0 0.92 1.0 1.48
Ref. 1.05-3.21 2.47-10.24 Ref. 0.60-1.41 Ref. 0.40-2.12 Ref. 0.78-2.79
Metastatic site, 2 or more TVP cavale
No Yes No Yes
1.0 1.17 1.0 1.75
Ref. 0.76-1.82 Ref. 1.00-3.07
1.0 1.06 1.0 1.90
Ref. 0.63-1.80 Ref. 1.00-3.62
1.0 1.13 1.0 1.99
Ref. 0.67-1.91 Ref. 1.05-3.76
1.0 1.12 1.0 2.08
Ref. 0.65-1.91 Ref. 1.10.-3.91
1.0 1.10 1.0 2.00
Ref. 0.66-1.85 Ref. 1.06-3.77
1.0 1.11 1.0 2.08
Ref. 0.66-1.86 Ref. 1.07-4.07
46-18.19
Table 4. Progression Free and Overall Survival - Unadjusted and adjusted Cox proportional Hazard model with time-dependent (TD) covariates
At least one toxicity Age Sex Clear cell histology Papillary Nephrectomy Karnosky index
No Yes Female Male No Yes No Yes No Yes High Low
Progession Free Survival (a) Unadjusted Adjusted HR 95%CI HR 95%CI 1.0 Ref. 1.0 Ref. 0.82 0.55-1.22 0.67 0.43-1.05 0.99 0.98-1.03 1.00 0.97-1.02 1.0 Ref. 1.0 Ref. 0.99 0.63-1.56 0.62 0.40-0.97 1.0 Ref. 1.0 Ref. 1.10 0.58-2.06 0.57 0.25-1.31 1.0 Ref. 1.0 Ref. 0.75 0.33-1.73 0.25 0.08-0.76 1.0 Ref. 1.0 Ref. 0.60 0.32-1.15 0.64 0.33-1.24 1.0 Ref. 1.0 Ref. 2.42 1.48-3.97 1.21 0.61-2.38
Overall Survival (a) Unadjusted Adjusted HR 95%CI HR 95%CI 1.0 Ref. 1.0 Ref. 0.87 0.54-1.41 1.23 0.71-2.11 1.01 0.98-1.03 1.00 0.98-1.03 1.0 Ref. 1.0 Ref. 1.25 0.74-2.11 1.21 0.73-2.03 1.0 Ref. 1.0 Ref. 1.62 0.61-4.33 1.60 0.59-4.35 1.0 Ref. 1.0 Ref. 0.73 0.23-2.29 0.73 0.22-2.42 1.0 Ref. 1.0 Ref. 0.90 0.43-1.89 0.89 0.43-1.84 1.0 Ref. 1.0 Ref. 1.65 0.79-3.42 1.74 0.84-3.60
Progession Free Survival (b) Unadjusted Adjusted HR 95%CI HR 95%CI 1.0 Ref. 1.0 Ref. 0.59 0.39-0.90 0.42 0.26-0.69 1.00 0.98-1.03 1.00 0.97-1.02 1.0 Ref. 1.0 Ref. 1.23 0.74-2.06 0.59 0.38-0.93 1.0 Ref. 1.0 Ref. 1.73 0.64-4.68 0.49 0.21-1.15 1.0 Ref. 1.0 Ref. 0.70 0.22-2.24 0.21 0.07-0.65 1.0 Ref. 1.0 Ref. 0.95 0.45-1.98 0.49 0.25-0.98 1.0 Ref. 1.0 Ref. 1.61 0.78-3.31 1.07 0.54-2.13
Overall Survival (b) Unadjusted Adjusted HR 95%CI HR 95%CI 1.0 Ref. 1.0 Ref. 0.64 0.40-1.03 0.77 0.44-1.34 1.00 0.98-1.03 1.00 0.98-1.03 1.0 Ref. 1.0 Ref. 1.23 0.74-2.06 1.20 0.71-2.01 1.0 Ref. 1.0 Ref. 1.73 0.64-4.68 1.61 0.59-4.38 1.0 Ref. 1.0 Ref. 0.70 0.22-2.24 0.69 0.22-2.22 1.0 Ref. 1.0 Ref. 0.95 0.45-1.98 0.83 0.39-1.78 1.0 Ref. 1.0 Ref. 1.61 0.78-3.31 1.61 0.77-3.36
1.0 1.84 5.02 1.0 0.92 1.0 0.92 1.0 1.48 1.0 1.17 1.0 1.75
1.0 1.95 6.33 1.0 0.99 1.0 1.01 1.0 0.46 1.0 1.13 1.0 1.99
1.0 1.92 6.67 1.0 0.98 1.0 0.99 1.0 0.47 1.0 1.10 1.0 2.00
1.0 1.92 6.67 1.0 0.98 1.0 0.99 1.0 0.47 1.0 1.10 1.0 2.00
MSKCC Favorable Intermediate Poor History of hypertension No Yes History of hypothyroidism No Yes Prior radiotherapy No Yes Metastatic site, 2 or more No Yes TVP cavale No Yes
Ref. 1.05-3.21 2.47-10.24 Ref. 0.60-1.41 Ref. 0.40-2.12 Ref. 0.78-2.79 Ref. 0.76-1.82 Ref. 1.00-3.07
1.0 1.40 3.58 1.0 1.08 1.0 0.91 1.0 0.58 1.0 1.19 1.0 1.43
a: At least one toxicity (any) b: At least one toxicity between Hypertension and Neutropenia
Ref. 0.86-2.28 1.57-8,17 Ref. 0.68-1.72 Ref. 0.44-1.87 Ref. 0.26-1.27 Ref. 0.75-1.88 Ref. 0.80-2.57
Ref. 1.07-3.56 2.36-16.96 Ref. 0.57-1.73 Ref. 0.40-2.51 Ref. 0.19-1.16 Ref. 0.67-1.91 Ref. 1.05-3.76
1.0 2.00 7.21 1.0 0.92 1.0 1.08 1.0 0.45 1.0 1.13 1.0 2.09
Ref. 1.09-3.67 2.62-19.84 Ref. 0.53-1.60 Ref. 0.43-2.70 Ref. 0.18-1.14 Ref. 0.67-1.89 Ref. 1.11-3.93
Ref. 1.05-3.50 2.47-18.03 Ref. 0.56-1.70 Ref. 0.39-2.47 Ref. 0.19-1.18 Ref. 0.66-1.85 Ref. 1.06-3.77
1.0 1.37 4.21 1.0 1.18 1.0 0.77 1.0 0.56 1.0 1.03 1.0 1.32
Ref. 0.84-2.24 1.85-9.56 Ref. 0.74-1.89 Ref. 0.37-1.61 Ref. 0.26-1.23 Ref. 0.65-1.66 Ref. 0.73-2.39
Ref. 1.05-3.50 2.47-18.03 Ref. 0.56-1.70 Ref. 0.39-2.47 Ref. 0.19-1.18 Ref. 0.66-1.85 Ref. 1.06-3.77
1.0 1.88 6.62 1.0 0.98 1.0 1.00 1.0 0.45 1.0 1.06 1.0 1.97
Ref. 1.03-3.45 2.47-17.78 Ref. 0.56-1.71 Ref. 0.40-2.51 Ref. 0.18-1.13 Ref. 0.63-1.80 Ref. 1.04-3.74
2.47-17.78