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Evidence and Clinical Relevance of Tumor Flare in Patients Who Discontinue Tyrosine Kinase Inhibitors for Treatment of Metastatic Renal Cell Carcinoma
European Urology, Volume 68, Issue 1, July 2015, Pages 154 - 160
Several tyrosine kinase inhibitors (TKIs) and one monoclonal antibody targeting the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis have been approved for the treatment of metastatic renal cell carcinoma (mRCC). Preclinical data suggest that cessation of anti-VEGF therapy may generate a tumor flare (TF) but its clinical relevance is still questionable.
This analysis investigates the occurrence of tumor flare and its prognostic role after discontinuation of anti-VEGFR TKIs in patients affected by mRCC.
Design, setting, and participants
Patients with mRCC treated with first-line sunitinib or pazopanib at standard dosages were screened. Patients included in the analysis were required to have: (1) discontinued treatment because of progression of disease or intolerable toxicity or sustained response; (2) evaluation of tumor growth rates immediately before (GR1) and after discontinuation (GR2); and (3) no treatment during evaluation of GR2.
Outcome measurements and statistical analysis
Overall survival (OS) was the main outcome. TF was calculated as the difference between the GR values (TF = GR2 – GR1). Cox proportional hazards regression was used to assess the prognostic role.
Results and limitations
Sixty-three consecutive patients were analyzed; the median duration of treatment was 9.3 mo, the median progression-free survival (PFS) was 11.1 mo, and the median OS was 41.5 mo. The reasons for treatment discontinuation were sustained response (partial response/stable disease) in 15.9%, toxicity in 22.2%, and progression of disease in 61.9% of cases. The median GR1 and GR2 were 0.16 cm/mo (interquartile range [IQR] –0.07 to 0.53) and 0.70 cm/mo (IQR 0.21–1.46), respectively (p = 0.001). In the overall population, the median TF was 0.55 cm/mo (IQR 0.08–1.22) and differed according to the reason for discontinuation: 0.15 cm/mo for response, 0.95 cm/mo for toxicity, and 1.66 cm/mo for progression. When TF was compared to other prognostic variables, Cox analysis confirmed its prognostic role (hazard ratio 1.11, 95% confidence interval 1.001–1.225; p = 0.048).
This study reports clinical evidence that TKI discontinuation results in acceleration of tumor GR and induces TF, which can negatively affect the prognosis of mRCC patients.
In this report, we looked at the outcomes for patients affected by metastatic kidney tumors who discontinued treatment with antiangiogenic agents. We found that tumor regrowth after discontinuation of therapy was related to the reason for discontinuation: regrowth was higher in patients who discontinued treatment because of disease progression, and lower in patients who discontinued treatment because of a sustained response. Moreover, we found that the higher the growth rate, the shorter the survival. We conclude that discontinuation of antiangiogenic agents may cause an increase in tumor growth rate, which is related to patient survival.
Keywords: Pazopanib, Sunitinib, Metastatic renal cell carcinoma (mRCC), Tumor flare, Growth rate, Treatment cessation, Treatment discontinuation, Tyrosine kinase inhibitors.
Renal cell carcinoma (RCC) is the sixth most common cancer diagnosis in men and the eighth most common in women in the USA, with an estimated 65 150 new cases and 13 680 deaths expected to occur in the current year  . In Europe, the incidence and mortality of RCC are estimated to be 71 739 and 31 293 cases per year, respectively  and .
The von Hippel-Lindau tumor suppressor gene has been found to be responsible for the majority of the cases of sporadic clear-cell RCC. This gene functions as a tumor suppressor, inhibiting hypoxia-inducible genes involved in angiogenesis (eg, vascular endothelial growth factor [VEGF]), cell growth, glucose uptake, and acid-base balance. Among these, VEGF and its receptor (VEGFR) are highly expressed on endothelial cells. These pathways have been found attractive as targets for molecular therapies  .
In recent years, several tyrosine kinase inhibitors (TKIs) and one monoclonal antibody targeting the VEGF/VEGFR axis have been approved for the treatment of metastatic RCC (mRCC), based on their advantages in clinical outcomes as demonstrated in phase 3 clinical trials , , , , , and . Among these, sunitinib and pazopanib are both suitable for frontline treatments and have recently been compared in a noninferiority phase 3 trial reporting similar outcomes, but different toxicity profiles  .
These drugs have produced efficacy mainly in terms of tumor shrinkage, stabilization of disease, and delayed time to progression following a period of clinical benefit  and . However, most patients will ultimately progress, suggesting a resistance to antiangiogenic agents, although approximately 25% of patients do not experience resistance because of treatment discontinuation because of adverse events  . Moreover, in the few patients who obtain a complete response, one of the most challenging questions is whether or not antiangiogenic treatment should be discontinued  and . Preclinical data suggest that cessation of anti-VEGF therapy may accelerate tumor growth and metastatic spread  ; this phenomenon, also called flare-up, has been reported in clinical practice during the off-period of sunitinib  , but its relevance is still questionable.
The present work sought to investigate the occurrence of tumor flare and its prognostic role after discontinuation of sunitinib or pazopanib in mRCC patients.
2. Patients and methods
Patients with mRCC treated at Institut Gustave Roussy, Villejuif, France, with first-line sunitinib or pazopanib at a standard dosage were included in this study if serial computed tomography (CT) scans were available before and after treatment discontinuation. All patients discontinued treatment for progression of disease, intolerable toxicity, or sustained response, and had CT scans performed at the time of discontinuation (t0) and before (t–1) and after discontinuation (t+1). In addition, eligible patients should not have received any active therapy from t0 to t+1. Reasons for the delay in the beginning of a new line of treatment included a wash-out period before inclusion in a second-line clinical trial, recovery from previous toxicity, and patient and/or physician decision.
Baseline characteristics were collected for each patient and prognosis was evaluated using International mRCC Database Consortium (IMDC) criteria  .
Values are expressed as median and interquartile range (IQR). The baseline was defined as the date for initiation of treatment with sunitinib or pazopanib.
We chose to evaluate the growth rate (GR) with an easy and reproducible method in clinical practice, and an Excel program for calculating this parameter is available as Supplementary File 1. For each patient, GR1 between t–1 and t0, and GR2 between t0 and t+1 were calculated. These values were calculated as the difference between the sum of the longest diameters (SLD) for targeted lesions evaluated by CT over time: GR1 = SLD0 – SLD–1/t0 – t–1 and GR2 = SLD+1 – SLD0/t+1 – t0, expressed in cm/mo. Tumor flare (TF) was defined as the difference between the GR values (TF = GR2 – GR1).
Treatment duration was calculated from the start of therapy to the time of discontinuation for any reason. Progression-free survival (PFS) was evaluated from baseline to progression of disease or death; disease progression was defined as a ≥20% increase in SLD according to RECIST v. 1.0  . Median overall survival (OS) was evaluated for different time points: OS was evaluated from baseline to death; OS0 was evaluated from treatment discontinuation (t0) to death; and OS+1 was evaluated from t+1 to death. The effect of GR1 on OS0 and of GR2 on OS0 and OS+1 was evaluated. All OS values were calculated by the Kaplan-Meier method and compared across the groups using the log-rank test.
The correlation between GR or TF and other variables was evaluated using the nonparametric Spearman rank test (rs) or the parametric Pearson test (rp) as appropriate. Differences between groups in terms of GRs or TF were evaluated by t test.
The association of TF as a continuous variable with death (OS0) was evaluated using the Cox proportional hazards model, and values were adjusted for IMDC criteria. All variables were considered significant at the level of p < 0.05. We used PASW (Predictive Analytics Software, v21; IBM SPSS, Chicago, IL, USA). European Urology guidelines for statistics were followed for the preparation of the manuscript  .
Overall, 63 patients were included in the final analysis. Their main baseline characteristics are reported in Table 1 . The majority of patients (89%) received sunitinib, while 11% received pazopanib. At the time of analysis, 59 patients had tumor progression and 30 had died, with a median OS of 41.5 mo (95% confidence interval [CI] 28.7–54.2). A total of 33% of patients were in the IMDC good prognostic group and 67% in the intermediate group, with median OS of 67.2 mo (95% CI 25.8–109) and 28.6 mo (95% CI 10.0–47.3), respectively (p = 0.03). The median duration of treatment was 9.3 mo and the median PFS was 11.1 mo (95% CI 8.7–13.4).
|Median age (yr)||57.1|
|Time from nephrectomy <1 yr||62|
|ECOG score 0||78|
|ECOG score 1||22|
|Hb < LLN||12|
|LDH > ULN||5|
|PLT > ULN||2|
|Neu > ULN||2|
|Corrected calcium > ULN||1.7|
|Sites of disease >2||24|
|IMDC prognostic group|
|Type of therapy|
ECOG = Eastern Cooperative Oncology Group; Hb = hemoglobin; IMDC = International Metastatic Renal Cell Carcinoma Database Consortium; LDH = lactate dehydrogenase; LLN = lower limit of normal; Neu = tumor-associated antigen; PLT = platelets; ULN = upper limit of normal.
The reasons for treatment discontinuation were sustained response (partial response/stable disease) in 16%, toxicity in 22%, and disease progression in 62% of cases. The median time from t–1 to t0 was 3.0 mo, and the median time from t0 to t+1 was 2.1 mo. Overall, the median GR1 and GR2 were 0.16 cm/mo (IQR –0.07 to 0.53) and 0.70 cm/mo (IQR 0.21–1.46), respectively (p = 0.001); no relationship was found between GR1 and GR2 (rp = –0.12; p = 0.3). The median GR1 and GR2 according to reason for discontinuation are reported in Table 2 and Figure 1 . In patients with papillary histology, all discontinued because of disease progression and the median GR1 and GR2 were 0.5 cm/mo and 1.1 cm/mo, respectively.
|Reason for discontinuation||Growth rate (cm/mo)||t test|
|Before discontinuation||After discontinuation||(p value)|
|t test (p value)||0.001||0.097|
The median values of GR1 and GR2 were able to predict patient prognosis. Patients with GR1 less than the median had OS0 of 51.6 mo, compared to 12.3 mo for patients with GR1 greater than or equal to the median (p < 0.001; Fig. 2 A). Similarly, patients with GR2 less than the median had OS0 of 51.6 mo, compared to 15.1 mo for patients with GR2 greater than or equal to the median (p = 0.03; Fig. 2 B). We performed a further analysis in which the impact of GR2 on OS+1 was evaluated; we found that patients with GR2 less than the median value had median OS+1 of 49.0 mo, compared to 13.2 mo for patients with GR2 greater than or equal to the median (p = 0.045).
In the overall population, the median TF was 0.55 cm/mo (IQR 0.08–1.22). According to the reason for discontinuation, the median TF was 0.15 cm/mo (IQR –0.14 to 0.56), 0.95 cm/mo (IQR 0.24–2.01), and 1.66 cm/mo (IQR 0.08–1.7) in patients who discontinued treatment because of response, toxicity, or progression, respectively. No relationship was found between the time from nephrectomy to the diagnosis of metastatic disease (<1 yr vs ≥1 yr) and TF (rs = 0.30; p = 0.8).
3.1. Multivariate analysis
To test its prognostic role in survival, TF was estimated from the time of treatment discontinuation (OS0). Under univariate analysis, increasing TF, as continuous variable, was found to be a negative prognostic factor, with a hazard ratio (HR) of 1.13 (95% CI 1.02–1.24; p = 0.02); similarly, baseline IMDC prognostic classification remained a prognostic factor even after treatment discontinuation (HR = 2.90, 95% CI 1.19–7.19; p = 0.02). When TF was adjusted for IMDC criteria, it retained its negative prognostic role (HR = 1.11, 95% CI 1.00–1.23; p = 0.048; Table 3 ).
|HR||95% confidence interval|
|IMDC prognostic group||2.73||1.09–6.82||0.03|
Rapid vascular regrowth in tumors after reversal of VEGF inhibition has been described by several authors in preclinical experiments in tumor cultures  and , but to our knowledge there is no report on the rate or extent of vascular regrowth in tumors after withdrawal of antiangiogenic therapy and its prognostic role in vivo.
This study reports the first clinical evidence that discontinuation of sunitinib or pazopanib results in acceleration of tumor GR, and thus negatively affects the prognosis of mRCC patients. Moreover, the lack of correlation between GR1 and GR2 suggests the impossibility of predicting tumor growth after treatment discontinuation. However, we found that the reason for treatment discontinuation may predict the magnitude of GR2. This evidence suggests that inhibition of VEGFR might be a useful strategy to decrease GR and avoid TF, even in tumors that have progressed under anti-VEGFR treatment.
In the medical literature, other evidence is available regarding continued inhibition of angiogenesis. Two phase 3 trials  and  have revealed that patients affected by metastatic colorectal cancer who were previously treated with chemotherapy and an anti-VEGF monoclonal antibody (bevacizumab) had a better outcome if inhibition of angiogenesis was maintained. In the VELOUR study, patients received chemotherapy with or without a soluble decoy receptor molecule composed of the critical ligand-binding domains of human VEGFR-1 and -2 fused with the Fc portion of immunoglobulin G. Patients treated in the experimental arm experienced an increase in median PFS (6.9 vs 4.7 mo; p < 0.001) and OS (13.5 vs 12.1 mo; p = 0.003)  . Similarly, maintenance of bevacizumab in the ML18147 study resulted in an increase in median PFS (5.7 vs 4.1 mo; p < 0.001) and OS (11.2 vs 9.8 mo; p = 0.006) compared to the placebo group  .
In addition, continuation of angiogenesis inhibition in mRCC is supported by clinical evidence that switching to another VEGF inhibitor in mRCC may increase OS in patients previously treated with sunitinib  . If a sequence of two antiangiogenic therapies is proven to be clinically feasible, it would be interesting to speculate whether an agent with higher inhibitory potency or with a greater spectrum of inhibition would be better. Both strategies have been tested in clinical practice with ambiguous results. First, the AXIS trial, which compared the more potent axitinib to sorafenib, reported longer disease control for axitinib without a significant improvement in OS  . Second, the GOLD trial, which compared the VEGFR/fibroblast growth factor receptor inhibitor dovitinib to sorafenib, did not reveal better patient outcome  , suggesting that the best sequence is not yet easy to determine in clinical practice.
It is interesting to analyze patients who discontinued treatment because of a sustained response in our study. These patients had the longest TF, the lowest GR1, and a nonsignificant increase in GR2 after discontinuation. Clinically, it is debatable whether treatment should be continued or not in such cases. Albiges et al  performed a large retrospective study of mRCC patients who achieved a complete response with anti-VEGFR therapy, with or without the aid of local procedures. In patients treated with medical therapy alone, the rate of tumor relapse was higher when anti-VEGFR therapy was discontinued immediately after a response (44%) when compared to patients who continued the treatment for a few months (33%) or patients who continued treatment (13%). Similarly, in patients who reached a complete response with medical therapy plus local procedures, the rates of relapse were 52%, 50%, and 33%, respectively. On the basis of these results, the authors recommended therapy cessation when a complete response occurs, since rechallenge is generally efficient if relapse is observed  . A drug holiday has been discussed for patients who discontinue treatment because of a sustained response. Some reports suggest that this strategy is useful in selected patients  and . It will be of interest to determine prospectively whether TF is predictive of drug holiday duration.
A recent study analyzed the molecular heterogeneity of mRCC  ; our study confirms such clinical heterogeneity by reporting that TF is an independent prognostic factor. Similarly, Powles et al  reported that in a cohort of 62 patients enrolled in three studies investigating sunitinib or pazopanib for untreated mRCC prior to a planned nephrectomy, factors such as baseline MSKCC prognostic score did not predispose patients to disease progression during a planned period of treatment discontinuation. This work, in agreement with our study, confirms the prognostic role of GR evaluated immediately after treatment discontinuation  .
This aspect, as well as the predictive role of GR2, has already been evaluated by our group. In a previous study, we reported that the increase of GR2 was specific for sorafenib, but not for everolimus, suggesting a close relationship between anti-VEGFR agents and TF  . Similarly, Griffioen et al  reported a significant increase in the number of proliferating endothelial cells after discontinuation of sunitinib, but not bevacizumab, in mRCC patients, suggesting a close relationship between the mechanism of action of drugs and TF.
The biology of TF has not been investigated in detail, although preclinical and clinical studies have revealed an increase in circulating VEGF levels during treatment with a VEGFR inhibitor, with a concomitant decrease in VEGFR2 and its soluble form. On the contrary, during the off period of therapy, VEGF decreases with increasing VEGFR in endothelial cells over a few days , , and . This change in serum markers suggests that TF may represent a type of feedback in which interruption of VEGFR inhibition, due to treatment discontinuation, may elicit an increase in functioning receptors on endothelial cells in a manner characterized by increasing levels of VEGF. Although fascinating, this hypothesis is extremely simplistic because it does not account for several other factors, such as pericytes and tumor cells, that play a role in angiogenesis.
Our study has a number of limitations. First and foremost is its retrospective nature; even if patients were all treated in one centre, several baseline characteristics other than IMDC classification may have a role in prognosis and cannot be included in multivariate analysis. Second, as there is no standard for GR evaluation, we chose a simple and consistent formula, although several others have been reported in the literature  and . Another limitation that may affect our work is related to the time since observation of reported events was begun. Vikers et al  also investigated this bias in prostate cancer. Here we estimated GRs just before (GR1) and after (GR2) treatment discontinuation (t0), but OS was calculated from t0 until before all GR2 data were available. This choice was based on the idea that TF is a continuous phenomenon that starts immediately after discontinuation of antiangiogenic therapy; therefore, the use of another time point may mask the effect of TF on prognosis and underestimate OS.
Despite the limitations noted, our study reveals clinical evidence of TF in patients who discontinue VEGFR inhibitor treatment. The prognostic significance of TF was more evident in patients who discontinued treatment because of disease progression or toxicity. The impact of this evidence in clinical practice needs to be tested in further studies to evaluate if discontinuation or maintenance of VEGFR inhibitor therapy is the best approach for responder patients.
Author contributions: Roberto Iacovelli had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Escudier.
Acquisition of data: Iacovelli, Massari.
Analysis and interpretation of data: Escudier, Iacovelli, Massari.
Drafting of the manuscript: Iacovelli, Albiges, Massari, Loriot, Massard, Escudier.
Critical revision of the manuscript for important intellectual content: Escudier, Albiges, Fizazi.
Statistical analysis: Iacovelli.
Obtaining funding: None.
Administrative, technical, or material support: None.
Other (specify): None.
Financial disclosures: Roberto Iacovelli certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
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a Medical Oncology Department, Institut Gustave Roussy, Villejuif, France
b Department of Radiology, Oncology and Human Pathology, Sapienza University of Rome, Rome, Italy
c Department of Medical Oncology, University of Verona, Verona, Italy
⁎ Corresponding author. Department of Radiology, Oncology and Human Pathology, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy. Tel. +39 064 9970408; Fax: +39 064 463686.
© 2014 European Association of Urology, Published by Elsevier B.V.