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Enzalutamide in Patients With Castration-Resistant Prostate Cancer Progressing After Docetaxel: Retrospective Analysis of the Swiss Enzalutamide Named Patient Program
Clinical Genitourinary Cancer, In Press, Corrected Proof, Available online 23 June 2016, Available online 23 June 2016
Therapeutic options for metastatic castration-resistant prostate cancer have considerably changed in the past decade. In this retrospective analysis of patients included in the Swiss Enzalutamide Named Patent Program, we analyzed the outcome of patients based on different sequencing strategies reflecting current daily practice. We demonstrate a median overall survival of more than 3 years and different effects in regard to treatment sequences.
Enzalutamide is a second-generation androgen receptor (AR) inhibitor that binds to and blocks the AR with higher affinity than previously available AR inhibitors. High activity has been proven in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and in chemotherapy-naive patients with mCRPC. However, its activity in patients previously treated with other novel agents (for example, abiraterone and/or cabazitaxel), remains controversial.
Patients and Methods
The aim of this retrospective analysis of the Swiss Enzalutamide Named Patient Program was to evaluate clinical efficacy and safety of enzalutamide treatment in patients with mCRPC progressing after docetaxel and other lines of therapy considering different treatment sequences. We report on 44 patients treated with enzalutamide.
The median survival time from diagnosis of CPRC was 41.1 months (95% confidence interval [CI], 32.3-49.8 months). Enzalutamide was used as a second, third, fourth, fifth, sixth, or seventh-line therapy in 13%, 20%, 31%, 20%, 11%, and 2% of patients. The median duration of enzalutamide treatment was 3.0 months (range, 1-21 months). Median progression-free survival was 3.0 months (95% CI, 2.4-3.7 months). The estimated median overall survival was 6.3 months (95% CI, 4.6-8.1 months). Sixteen patients (36.4%) had a prostate-specific antigen decrease of ≥ 30%, and 11 patients (25.0%) of ≥ 50%, respectively. In multivariate analysis, the absence of previous therapy with abiraterone and a prostate-specific antigen response of ≥ 50% on enzalutamide therapy were significantly associated with overall survival on enzalutamide treatment.
Our results show that enzalutamide has modest activity in extensively pretreated patients. However, there is a subgroup of patients achieving benefit from enzalutamide therapy even after pretreatment with abiraterone.
Keywords: Abiraterone, Androgen receptor antagonist, Antihormonal drugs, PSA, Treatment sequence.
Prostate cancer is the most prevalent cancer among men in the western world and the second leading cause of male cancer death.1 Although the majority of patients with prostate cancer initially respond to medical or surgical castration, the disease usually progresses despite continuation of androgen deprivation therapy. This situation is known as castration-resistant prostate cancer (CRPC) and is almost inevitably fatal.2 Therapeutic options for metastatic CRPC (mCRPC) have considerably changed since the introduction of docetaxel in 2004.3 Four new drugs have recently been approved in Europe; a new taxane-derivative (cabazitaxel), 2 novel endocrine drugs (abiraterone, enzalutamide), and an alpha particle-emitting radionuclide (radium-223).4, 5, 6, 7, 8, and 9 Moreover, sipuleucel-T is approved in the United States and Europe.10 The approval of these new drugs has improved the outcome of patients with mCRPC. Today, we are facing several unresolved issues with the new treatment options: sequencing of available agents, possible combinations, and resistance mechanisms. Historically, the treatment landscape was divided into a pre-chemotherapy (namely pre-docetaxel) and a post-chemotherapy space based on the longstanding standard treatment with docetaxel. Most of the novel therapeutic agents have been investigated separately in both of these settings.
It is known that the androgen receptor (AR) signaling remains a key driver of progression during mCRPC despite adequate testosterone suppression (< 50 μg/mL) with current novel agents targeting the AR.11 Recently, 2 agents that interact with the AR signaling pathway have been investigated in large randomized phase III trials before and after chemotherapy. Abiraterone acetate is a selective cytochrome P450 17-hydroxysteroid dehydrogenase (CYP17A1) inhibitor that blocks androgen precursors synthesis, causing effective systemic and intratumoral suppression of androgen production.5 Enzalutamide is a second-generation AR inhibitor that binds to and blocks the AR with higher affinity than previously available AR inhibitors and has no known agonistic effects.12 Moreover, enzalutamide inhibits AR nuclear translocation and binding of the AR complex to the DNA.13 In randomized phase III trials in the post-chemotherapy setting, abiraterone and enzalutamide have shown to increase overall survival (OS) by 3.9 and 4.8 months, respectively.5 and 6 In the randomized phase III AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) trial, 1199 mCRPC patients previously treated with docetaxel were randomized between placebo and enzalutamide 160 mg daily. Enzalutamide prolonged OS by 4.8 months from 13.6 to 18.4 months (P < .001).6 Based on these results, abiraterone and enzalutamide have been approved by health care authorities in many countries. In Switzerland, a Named Patient Program (NPP) was installed to bridge the time gap to Swissmedic approval. At that time point, abiraterone was already approved and reimbursed in Switzerland.
Recently, several groups have reported on response rates of abiraterone in patients pretreated with enzalutamide,14 and 15 whereas other groups have reported response rates for the reverse sequence.16, 17, 18, 19, 20, and 21 In summary, all studies show a low response rate for patients pretreated with enzalutamide and undergoing treatment with abiraterone (3% to 8% with prostate-specific antigen [PSA] response decline of ≥ 50%), whereas PSA response rates of ≥ 50% in the range of 10% to 29% have been described for patients being treated with enzalutamide after pretreatment with abiraterone. But these results have to be interpreted with caution because the studies were small, retrospective, and mostly from single centers with inhomogeneous patient populations.
Here, we report the results from the Swiss Enzalutamide NPP including patients with mCRPC treated with at least one prior course of docetaxel chemotherapy. Most patients were also pretreated with abiraterone and some of them also with cabazitaxel, providing the unique opportunity to evaluate the clinical efficacy and safety of enzalutamide treatment in patients with mCRPC progressing after docetaxel chemotherapy used in different treatment sequences.
Patients and Methods
The main inclusion criteria were documented disease progression, previous treatment with docetaxel, effective surgical or medical castration, Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 3, and no comparable or satisfactory alternative therapy by the judgment of the treating physician. The number of previous therapies was not limited. Exclusion criteria of the NPP included earlier treatment with or participation in a clinical trial with enzalutamide, severe concurrent disease, inadequate bone marrow, liver, vascular, heart, and kidney functions, and prior systemic therapy or radiotherapy within 3 weeks before treatment and radionuclide treatment within 8 weeks before treatment. Patients were treated with enzalutamide 160 mg orally once daily. All patients received at least 1 dose. Treatment was supposed to be continued until disease progression, clinical deterioration, and/or unacceptable toxicities or until death.
Patient- and tumor-specific data were obtained from the patients' medical records. During enzalutamide therapy, patients had clinical follow-up visits at least every 3 weeks in the first 3 months and every 6 weeks thereafter. Imaging studies were performed at the discretion of the treating physician. Patients were followed for prostate cancer progression and survival until March 2015.
PSA response was evaluated using the Prostate Cancer Clinical Trials Working Group 2 recommendation. PSA response was defined as a decrease of ≥ 50% from baseline, and PSA progression was defined as an increase of ≥ 25% and a minimum level of 2 ng/mL confirmed by a second PSA measurement at least 3 weeks apart. PSA declines of < 30%, < 50%, and < 90% from baseline were also evaluated. Progression-free survival (PFS) was calculated from the beginning of therapy to the first date of confirmed tumor progression, death, or the date of last follow-up. Progression was defined as clinical and/or radiographic and/or biochemical (PSA) progression. OS was calculated from beginning of enzalutamide therapy to patients' death or date of last follow-up.
The respective local ethics committees approved implementation of the NPP. This retrospective data collection was approved by the ethics committee of North-Western and Central Switzerland (EKNZ; 2014-151) as well as by the respective local ethics committees of participating centers.
Numerical data were described with median, mean, standard deviation, and quartiles. PFS and OS were evaluated using Kaplan-Meier estimates. The Fisher exact and χ2 tests were used to assess correlations of nominal covariate distributions and response groups. The Mann-Whitney U test was applied to compare metric variables among different subgroups. A 2-sided P < .05 was considered statistically significant. Statistical analyses were conducted using IBM SPSS Statistics software version 22 (IBM Corporation, Armonk, NY).
Between August 2012 and March 2013, 65 patients previously treated with docetaxel were enrolled in 18 different hospitals or private practices in Switzerland. For this retrospective analysis, records from 44 patients were accessible and were considered for efficacy analysis. Patient- and tumor-specific characteristics are summarized in Table 1. The median age before starting enzalutamide therapy was 70 years; 84.1% of patients had bone metastases at the time of inclusion in the NPP, 50% of patients had lymph node metastases, and 6.8% of patients had visceral metastases. Median survival time from diagnosis of CRPC was 41.1 months (95% confidence interval [CI], 32.3-49.8 months).
Patient and Treatment Characteristics
|Characteristic||Median (IQR) or No. of Patients (%)|
|Age, y||70 (64-76)|
|ECOG performance status|
|Not available||1 (2.3)|
|Not available||2 (4.6)|
|Neuroendocrine differentiation at initial diagnosis|
|Prior local therapy|
|Radical prostatectomy||21 (47.7)|
|Local irradiation||20 (45.5)|
|Primary androgen deprivation therapy|
|LHRH agonist||36 (81.8)|
|LHRH antagonist||1 (2.3)|
|Localization of metastases|
|Lymph nodes||22 (50.0)|
|PSA (μg/L)||144.7 (36.125-430.5)|
|Duration (months)||3 (1-17)|
|Duration (months)||6 (4-10)|
|Antihormonal therapy while on enzalutamide|
|LHRH agonist||35 (79.5)|
Abbreviations: ECOG = Eastern Cooperative Oncology Group; IQR = interquartile range; LHRH = luteinizing hormone-releasing hormone; PSA = prostate-specific antigen.
A total of 42 of 44 patients (95.5%) received a previous therapy with docetaxel. Two patients did not receive docetaxel as they were considered ineligible for docetaxel, and no comparable or satisfactory alternative therapy was available by judgment of the treating physician. The median time of docetaxel therapy was 3 months (range, 1-17 months). A total of 25 patients (56.8%) had a PSA response of > 30%, and 11 patients (25%) showed a radiographic partial response to docetaxel chemotherapy. Thirty-six patients (81.8%) were previously treated with abiraterone. The median duration of abiraterone therapy was 6 months (interquartile range, 4-10 months). Twenty-three patients (52.3%) showed a PSA reduction of > 30%, and 6 patients (13.7%) had a radiographic response to abiraterone treatment. Twenty-five patients (56.8%) were previously treated with cabazitaxel. The median number of cabazitaxel cycles was 6 (range, 1-10 cycles). A total of 16 patients (36.4%) received other therapies before inclusion in the enzalutamide NPP.
Enzalutamide was used as a second, third, fourth, fifth, sixth, or seventh-line therapy in 13%, 20%, 31%, 20%, 11%, and 2% of patients. A total of 35 patients (79.5%) received a luteinizing hormone-releasing hormone agonist while on enzalutamide, and 8 patients (18.2%) previously underwent orchiectomy. Nineteen patients (43.2%) received steroid drugs at the time of enzalutamide treatment initiation. The median duration of enzalutamide treatment was 3.0 months (range, 1-21 months). The dose of 160 mg was reduced in 8 patients (18.2%). At the time of analyses, 1 patient had ongoing treatment with enzalutamide.
PSA information following initiation of enzalutamide therapy was available in 43 patients (Figure 1). Among these 43 patients, 25 (56.8%) had a PSA decline, and 18 patients (40.9%) showed PSA progression. Sixteen patients (36.4%) had a PSA decrease of ≥ 30%, and 11 patients (25.0%) of ≥ 50%, respectively. Eighteen patients (41.9%) showed radiographic and biochemical progression, and 38 patients (88.4%) had PSA progression only. Overall, the estimated median PFS was 3.0 months (95% CI, 2.4-3.7 months) (Figure 2A). The estimated median OS was 6.3 months (95% CI, 4.6-8.1 months); the respective Kaplan-Meier curve is shown in Figure 2B. Fifty percent of patients received at least 1 further treatment line for mCRPC (Table 2).
Waterfall Plot of Best Prostate-Specific Antigen (PSA) Response to Enzalutamide Treatment. Results Are Presented as Percentage Change From Baseline PSA Value. *Abiraterone Pretreatment
A, Kaplan-Meier Progression-Free Survival Curve for Enzalutamide Patients (n = 44); B, Kaplan-Meier Overall Survival Curve for Enzalutamide Patients (n = 44)
Outcome Parameters of Enzalutamide Therapy and Subsequent Therapies
|Outcome Variable||Median (IQR) or No. of Patients (%)|
|Duration of enzalutamide treatment (months)||3 (2-8)|
|≥30%, <50%||7 (15.9)|
|Not available||1 (2.3)|
|Not available||18 (40.9)|
|PFS median, 95% CI (mos)||3.0 (2.4-3.7)|
|OS median, 95% CI (mos)||6.3 (4.6-8.1)|
|PSA progression||38 (86.4)|
|Radiographic progression||18 (40.9)|
|Therapies after enzalutamide||22 (50)|
Abbreviations: CI = Confidence interval; CR = complete remission; IQR = interquartile range; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial remission; PSA = prostate-specific antigen; SD = stable disease.
Uni- and Multivariate Analysis
In univariate analysis, the number of previous therapies showed a significant influence on PSA response to enzalutamide (Table 3). A higher number of previous treatment lines was associated with an inferior rate of patients showing a PSA response of ≥ 50% (χ2 test; P = .034). Among the different medical treatment options used before enzalutamide, only therapy with abiraterone was significantly associated with PSA response to enzalutamide. Patients pretreated with abiraterone achieved a PSA response of ≥ 50% less often (Fisher exact test; P = .017). However, response to other previous therapies did not predict the response to enzalutamide (Table 4).
Activity of Enzalutamide in Relation to Tumor- and Patient-Specific Characteristics
|Variable||PSA Response <50% (No., %)||PSA Response ≥50% (No., %)||P Value|
|6||2 (4.6)||2 (4.6)|
|7||10 (22.7)||2 (4.6)|
|8||6 (13.6)||1 (2.3)|
|9||13 (29.6)||4 (9.1)|
|Localization of metastases|
|Lymph node||16 (36.4)||6 (13.6)||1.0b|
|Bone||27 (61.4)||10 (22.7)||1.0b|
|Visceral||2 (4.6)||1 (2.3)||1.0b|
|Second||3 (6.8)||3 (6.8)|
|Third||6 (13.6)||3 (6.8)|
|Fourth||13 (29.6)||2 (4.6)|
|Sixth||1 (2.3)||3 (6.8)|
|Combination with steroids||.17b|
|No||16 (36.4)||8 (18.2)|
|Yes||16 (36.4)||3 (6.8)|
|Response to prior docetaxel||1.0b|
|<50% PSA reduction||13 (29.6)||4 (9.1)|
|≥50% PSA reduction||14 (31.8)||5 (11.4)|
|No||3 (6.8)||5 (11.4)|
|Yes||29 (65.9)||6 (13.6)|
|Response to prior abiraterone||1.0b|
|<50% PSA reduction||12 (27.3)||2 (4.6)|
|≥50% PSA reduction||15 (34.1)||3 (6.8)|
|No||8 (18.2)||5 (11.4)|
|Yes||19 (43.2)||6 (13.6)|
|Overall survival (median, mos)||6.1||Not reached||.001c|
a χ2 test.
b Fisher exact test.
c Log-rank test.
Abbreviation: PSA = Prostate-specific antigen.
Multivariate Analysis of Factors Potentially Influencing Outcome of Enzalutamide Therapy
|Factor||Hazard Ratio||95% CI||P Value|
|Enzalutamide treatment line||0.868||0.501-1.502||.613|
|PSA response ≥50%||0.232||0.073-0.738||.013|
Abbreviation: PSA = Prostate-specific antigen.
Patients with any PSA decline under to enzalutamide showed a significantly improved median OS (Figure 3A). This finding was confirmed in patients with a PSA decrease of ≥ 30% (Figure 3B) and ≥ 50% (Figure 3C). Patients with a PSA response of < 50% had a median OS of 6.1 months, whereas in patients with a PSA response of > 50%, the median OS was not reached. Patients pretreated with abiraterone showed a significantly inferior survival compared with patients without previous abiraterone therapy (Figure 4). The median OS was 6.1 months for patients pretreated with abiraterone, whereas it was not reached for patients without previous abiraterone therapy.
A, Kaplan-Meier Survival Curves for Patients Treated With Enzalutamide, Dichotomized According to a Decline or Stabilization of the Prostate Specific Antigen (PSA) (Green Line) or Progressing PSA (Blue Line); B, Kaplan-Meier Survival Curves for Patients Treated With Enzalutamide, Dichotomized According to a PSA Response Greater or Equal than (Green Line) or Lower than (Blue Line) 30%; C, Kaplan-Meier Survival Curves for Patients Treated With Enzalutamide, Dichotomized According to a PSA Response Greater or Equal than (Green Line) or Lower than (Blue Line) 50%
Kaplan-Meier Survival Curves for Patients Previously Treated With Abiraterone (Green Line) and Patients Without Abiraterone Pretreatment (Blue Line)
In multivariate analysis, the absence of previous therapy with abiraterone and a PSA response of ≥ 50% on enzalutamide therapy were significantly associated with OS. Patients not previously treated with abiraterone and those having a PSA response of ≥ 50% on enzalutamide showed a significantly better survival. The number of previous treatment lines was not independently associated with survival in this analysis.
Response to Treatment After Enzalutamide Therapy
Twenty-two patients (50%) received further systemic therapies after failure of enzalutamide. Five patients were treated with abiraterone after progression on enzalutamide. None of these patients showed a PSA response, 1 patient showed PSA stabilization, and all other patients showed PSA progression.
In this retrospective analysis of the Swiss Enzalutamide NPP, we were able to collect comprehensive clinical data including sequential PSA values from 44 unselected patients included in this program. Compared with the pivotal AFFIRM study6 of enzalutamide in the post-docetaxel setting with a 54% PSA response rate of ≥ 50% and a median PFS and OS time of 8.3 and 18.4 months, respectively, results for patients in later lines of therapy are clearly inferior. However, our patients had a more advanced disease setting compared with those in the AFFIRM trial. This is shown by a higher number of previous therapies, a poorer ECOG PS, and higher PSA levels at baseline.6 In addition, the majority of patients in the NPP were pretreated with abiraterone.
The OS of patients in our analysis, with 41.1 months from the time of diagnosis of CRPC, is substantially longer than in recently published prospective randomized trials. The COU-AA-302 (Cougar-Abiraterone Acetate-302) study compared abiraterone acetate with placebo in previously untreated patients with mCRPC and showed a median OS of 34.7 months in the abiraterone group. A total of 67% of these patients received a further treatment line, 16% enzalutamide.7 The PREVAIL trial investigated enzalutamide in chemotherapy-naive patients with mCRPC and showed a median OS of 32.4 months.8 Only 40% of patients in the enzalutamide arm received a subsequent antineoplastic therapy. Our results indicate that the use of several lines of therapy may be beneficial for patients with mCRPC. However, it has to be acknowledged that patient populations included in the COU-AA-302 and the PREVAIL trial are different from the patients included in our retrospective trial. A potential lead-time bias in our retrospective data collection cannot be ruled out. However, the unselected patient population included in the Swiss Enzalutamide NPP probably more accurately reflects patients presenting in daily clinical practice. Although response rates for enzalutamide are modest in later lines compared with the pivotal AFFIRM study, there seems to be a subgroup of patients obtaining a clinical benefit from enzalutamide also in a later line setting.
In our analysis, most patients were pretreated with docetaxel (95.5%) and abiraterone (81.8%). The response rates to enzalutamide in this patient cohort are comparable to those presented by other authors analyzing the activity of enzalutamide in heavily pretreated patients.16, 17, 18, 19, 20, and 21 In our analysis, enzalutamide was used in different lines of therapy; the majority of patients received enzalutamide as third, fourth, or fifth line therapy. The number of previous therapies was associated with the response to enzalutamide in the univariate analysis of our patient cohort. However, in the multivariate analysis, the treatment line was not a statistically significant parameter for patient outcome with enzalutamide. Previous therapy with abiraterone was an independent negative prognostic factor for enzalutamide therapy in the multivariate analysis.
The largest analysis on enzalutamide therapy in abiraterone pretreated patients to date reported on patients treated in 4 European compassionate use programs of enzalutamide.20 A total of 137 patients pretreated with docetaxel and abiraterone were included. Forty-five (38%) and 22 (18%) patients showed a PSA response of ≥ 30% or ≥ 50%, respectively. This population was less heterogeneous than the one we present here, as all patients treated with enzalutamide had the same previous treatment lines (docetaxel and abiraterone). Despite the higher number of precedent therapies in our patients, response rates and median time on treatment were very comparable. Only median OS was longer (8.2 vs. 6.3 months). As shown in our analysis, PSA response to enzalutamide is a useful and reliable prognostic factor for treatment outcome. Patients with a PSA decrease of ≥ 30% and ≥ 50% showed a significantly longer OS. This analysis is the first to suggest the role of PSA response as an independent factor for treatment outcome in enzalutamide-treated patients using a multivariate analysis. Patients with a PSA decline of ≥ 50% had a reduction of their risk of death of 77% (hazard ratio, 0.232). Also, patients with a PSA response of ≥ 30% had a significantly prolonged survival compared with non-responders. An association between tumor response and OS has been shown for docetaxel,22 and 23 but has, to date, not been shown for the novel antihormonal therapies. We show that 56.8% of patients had a PSA response to enzalutamide even in later lines of their therapy, with 25% of patients having a PSA response of ≥ 50%. The first trial that ever reported on the effect of enzalutamide in abiraterone-pretreated patients included 35 patients from the German compassionate use program.16 All patients were pretreated with docetaxel and abiraterone. Response rates were similar to our cohort, with an overall PSA response rate of 51.4% and a PSA decline of ≥ 50% in 28.6%. Contrary to our analysis, Schrader and colleagues reported Gleason score as a predictor for PSA response to enzalutamide.16 Concordant to our findings and other analyses, the response to previous antihormonal therapy or chemotherapy did not predict the response to enzalutamide.
Inferior antitumor activity of abiraterone following docetaxel and enzalutamide has also been reported when compared with the COU-AA-301 trial investigating abiraterone in docetaxel-pretreated patients.14, 15, and 24 In our analysis, only 5 patients received abiraterone after therapy with enzalutamide, 3 of them as fifth or later line therapy. Only 1 patient had a stabilization of his PSA value; the other 4 patients showed PSA progression as best response. These results confirm previous findings of limited efficacy of abiraterone after enzalutamide with PSA response rates below 10% in 2 retrospective analyses.14 and 15
Our study has several limitations. The retrospective design, the small sample size, and the broad heterogeneity of the patient population are the most relevant factors. With regard to response rates on enzalutamide therapy, it has to be acknowledged that 43.2% of patients had concurrent therapy with a corticosteroid when starting enzalutamide treatment. Various trials have shown that single-agent corticosteroids lead to response in patients with mCRPC.25 and 26 However, in the absence of data from larger prospective trials, the knowledge that can be gained from retrospective analyses might nevertheless give important insights in treatment options and activity of drugs.
In conclusion, our results show that enzalutamide has modest activity in extensively pretreated patients. Compared with the pivotal phase III AFFIRM trial, responses and outcome parameters were clearly inferior. However, there seems to be a subgroup of patients achieving benefit from enzalutamide therapy even after pretreatment with abiraterone, and the sequenced use of the newer antihormonal agents is a treatment option for patients with mCRPC. PSA response of ≥ 50% was the most reliable prognostic factor in this NPP cohort, characterizing patients having long-term benefit of enzalutamide. For the definition of an optimal treatment sequence in men with mCRPC, prospective trials need to be designed based on hypotheses generated by retrospective analyses.
Clinical Practice Points
- With the approval of novel therapies for patients with mCRPC, the survival of these patients has substantially improved. In our unselected patient population, we can show a median OS of more than 3 years.
- Enzalutamide is an active drug for patients with mCRPC. However, the activity is influenced by previous therapies and is significantly smaller in patients pretreated with abiraterone.
- PSA response to enzalutamide is a reliable prognostic factor to predict long-term benefit.
Dominik Berthold is a consultant for Astellas; Richard Cathomas is a consultant for Astellas, Bayer, Janssen-Cillag, and Sanofi; Silke Gillesson is a consultant for Astellas and has received honoraries for invited lectures from Astellas; Sacha Rothschild is a consultant for Astellas, Bayer, and Sanofi, and has received honoraries for invited lectures from Astellas and research support from Astellas and Sanofi. All other authors state that they have no conflicts of interest.
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1 Department of Medical Oncology, University Hospital Basel, Basel, Switzerland
2 Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
3 Department of Medical Oncology, University Hospital Lausanne, CHUV, Lausanne, Switzerland
4 Department of Medical Oncology, Cantonal Hospital Chur, Chur, Switzerland
5 Department of Medical Oncology, Cantonal Hospital St Gallen, St Gallen, Switzerland
6 Medical Oncology Practice, Biel, Switzerland
7 Department of Medical Oncology, Cantonal Hospital Luzern, Luzern, Switzerland
8 Department of Medical Oncology, Bürgerspital Solothurn, Solothurn, Switzerland
9 Department of Medical Oncology, Cantonal Hospital Olten, Olten, Switzerland
10 Department of Medical Oncology, Cantonal Hospital Aarau, Aarau, Switzerland
11 Department of Medical Oncology, Triemlispital Zürich, Zürich, Switzerland
12 Onkologie Länggasse, Bern, Switzerland
13 Medical Oncology Practice, Winterthur, Switzerland
14 Department of Medical Oncology, Waidspital Zürich, Zürich, Switzerland
∗ Address for correspondence: Sacha I. Rothschild, MD, PhD, University Hospital Basel, Medical Oncology, Petersgraben 4, 4031 Basel, Switzerland
F.S. and S.R. contributed equally to this work as last authors.
© 2016 Elsevier Inc., All rights reserved.