original articles

Annals of Oncology

Annals of Oncology 26: 21552161, 2015

doi:10.1093/annonc/mdv317
Published online 27 July 2015

FLORENCE: a randomized, double-blind, phase III

pivotal study of febuxostat versus allopurinol for the
prevention of tumor lysis syndrome (TLS) in patients
with hematologic malignancies at intermediate to high
TLS risk

Division of Medical Oncology A, National Cancer Institute, Aviano, Italy; 2First Department of Medicine, Semmelweis University Medical School, Budapest, Hungary;
ICO-Hospital Germans Trias i Pujol, Jose Carreras Research Institute, UAB, Badalona, Spain; 4Department of Diagnostic, Clinical and Public Health Medicine, University of
Modena and Reggio Emilia, Modena, Italy; 5University Hospital Centre Zagreb and Medical School, Zagreb, Croatia; 6Department of Hematology and Oncology, Martin
Luther University Halle-Wittenberg, Halle, Germany; 7Department of Hematology, Coltea Clinical Hospital, Bucharest, Romania; 8Department of Hematology, Ryazan
Regional Clinical Hospital, Ryazan, Russia; 9Hematology Unit, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy; 10Department of Cancer
Prevention, Faculty of Public Health, Silesian Medical University in Katowice, Katowice, Poland; 11Department of Hematology, Ivano-Frankivsk Regional Clinical Hospital,
Ivano-Frankivsk, Ukraine; 12Institute for Oncology and Radiology of Serbia, Belgrade, Serbia; 13First Department of Internal Medicine Endocrinology and Hematology, Pandy
Kalman Megyei Korhaz, Gyula, Hungary; 14Department of Hematology, Hospital Universitario La Fe, Valencia, Spain; 15Department of Internal Medicine, Hematology and
Oncology, University Hospital Brno, Brno, Czech Republic; 16Hospital das Clinicas da Faculdade de Medicina de Ribeiro PretoUSP, Ribeiro Preto, Brazil; 17Department
of Clinical Research, Menarini Ricerche, Firenze, Italy
3

Received 30 April 2015; revised 3 July 2015; accepted 13 July 2015

Background: Serum uric acid (sUA) control is of key relevance in tumor lysis syndrome (TLS) prevention as it correlates
with both TLS and renal event risk. We sought to determine whether febuxostat xed dose achieves a better sUA control
than allopurinol while preserving renal function in TLS prevention.
Patients and methods: Patients with hematologic malignancies at intermediate to high TLS risk grade were randomized to receive febuxostat or allopurinol, starting 2 days before induction chemotherapy, for 79 days. Study treatment
was blinded, whereas daily dose (low/standard/high containing allopurinol 200/300/600 mg, respectively, or xed
febuxostat 120 mg) depended on the investigators choice. The co-primary end points, sUA area under curve (AUC
sUA18) and serum creatinine change, were assessed from baseline to day 8 and analyzed through analysis of covariance
with two-sided overall signicance level of 5%. Secondary end points included treatment responder rate, laboratory and
clinical TLS incidence and safety.
Results: A total of 346 patients (82.1% intermediate TLS risk; 82.7% assigned to standard dose) were randomized.
Mean AUC sUA18 was 514.0 225.71 versus 708.0 234.42 mgxh/dl (P < 0.0001) in favor of febuxostat. Mean serum
creatinine change was 0.83 26.98% and 4.92 16.70% for febuxostat and allopurinol, respectively (P = 0.0903). No
differences among secondary efcacy end points were detected. Drug-related adverse events occurred in 6.4% of
patients in both arms.
Conclusion: In the largest adult trial carried out in TLS prevention, febuxostat achieved a signicant superior sUA
control with one xed dose in comparison to allopurinol with comparable renal function preservation and safety prole.
Clinical trial registration: NCT01724528.
Key words: tumor lysis, allopurinol, febuxostat, kidney injury, hematologic malignancy

introduction
*Correspondence to: Dr Michele Spina, Division of Medical Oncology A, National Cancer
Institute, via Franco Gallini 2, Aviano (PN) 33081, Italy. Tel: +39-0434-659730; E-mail:
mspina@cro.it

Tumor lysis syndrome (TLS) is the most common treatmentrelated emergency in patients with hematologic malignancies

The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.

Downloaded from http://annonc.oxfordjournals.org/ by guest on June 28, 2016

M. Spina1*, Z. Nagy2, J. M. Ribera3, M. Federico4, I. Aurer5, K. Jordan6, G. Borsaru7, A. S. Pristupa8,

A. Bosi9, S. Grosicki10, N. L. Glushko11, D. Ristic12, J. Jakucs13, P. Montesinos14, J. Mayer15,
E. M. Rego16, S. Baldini17, S. Scartoni17, A. Capriati17, C. A. Maggi17 & C. Simonelli17, on behalf
of FLORENCE Study Group

original articles

Annals of Oncology

(HM) [1, 2]. It encompasses metabolic derangements that predispose the patient to renal insufciency, cardiac arrhythmias,
neurological complications and potentially sudden death [2, 3].
The control of serum uric acid (sUA) level plays a key role in
TLS prevention as urate triggers several mechanisms that lead to
acute kidney injury [46]. Noteworthy, TLS guidelines consider
the risk of developing TLS and renal events to be increased by
1.75- and 2.21-fold, respectively, for every mg/dl increase in
sUA [2]. The current recommendations for TLS prophylaxis
include the use of allopurinol or rasburicase in patients with
intermediate or high-risk disease for developing TLS, respectively [3]. Allopurinol is a xanthine-oxidase (XO) inhibitor widely
used to prevent cancer-related hyperuricemia for almost 50
years [7]. Though efcacious and safe, allopurinol requires 24
72 h to inhibit uric acid formation, lacks xed posology and
needs dose-adaption based on renal function [3, 8]. Rasburicase,
a recombinant form of urate oxidase, is faster and more effective
than allopurinol in controlling sUA level in cancer patients [8,
9]. However, due to cost-restrictions its availability is widely
variable throughout the European Union (EU). Febuxostat is a
potent, oral XO inhibitor approved in both the United States
and the EU for the management of chronic hyperuricemia in
gout, where it has demonstrated its superiority over allopurinol
in decreasing sUA level [10, 11]; its average cost in the EU (120
mg strength) is 0.91 Euros/tablet. Unlike allopurinol, the nonpurine structure of febuxostat prevents the inhibition of other
enzymes involved in purine and pyrimidine metabolism and
allows the inhibition of both the oxidized and reduced forms of
XO, eventually resulting into a more potent and selective activity
[12]. Febuxostat exhibits linear pharmacokinetics and the rate
and extent of absorption are not substantially affected by age and
gender. Noteworthy, no dose adjustment is necessary in patients
with mild or moderate renal impairment, nor any of the drug
drug interaction studies conducted so far provided specic dosing
recommendations [13]. In view of such prole, febuxostat was
deemed suitable for development in TLS. Here, we present the
results of the double-blind, randomized, phase III pivotal study
comparing a xed daily dose of febuxostat with allopurinol, administered at an adaptable daily dose, for TLS prevention in patients
with HM at intermediate to high TLS risk grade.

across 11 European countries and Brazil. A sample size of 340 patients was
considered adequate to achieve 80% power, to demonstrate a benet of
febuxostat versus allopurinol of 15% decrease in AUC sUA1-8 and 13% increase in the mean serum creatinine.

patients and methods

statistical analysis

This multicenter, double-blind, randomized, parallel-group, comparative

phase III pivotal study encompassed two treatment arms: febuxostat and
allopurinol, either administered orally for 79 days. The primary objective
was to compare the efcacy of febuxostat with allopurinol, in terms of sUA
level control and preservation of renal function after 7 days of treatment
starting 2 days before chemotherapy (CT) onset. The co-primary efcacy
measures were area under the concentrationtime curve over days 18 of
sUA (AUC sUA18) and change in serum creatinine level, each evaluated
from baseline (day 1) to the evaluation visit (day 8). Secondary objectives
included treatment responder rate, where treatment response was the maintenance of sUA 7.5 mg/dl (treatment failure was two or more consecutive
values of sUA missing or >7.5 mg/dl), incidence of laboratory TLS (LTLS)
and clinical TLS (CTLS) dened as per Cairo and Bishop criteria [14] and
safety. Secondary efcacy objectives were evaluated from the start of CT
(day 3) to the evaluation visit (day 8). The study was conducted in 79 sites

| Spina et al.

Patients provided fully informed, written consent before enrollment. The

study was approved by local institutional review boards and conducted in accordance with Good Clinical Practice and the Helsinki Declaration of the
World Medical Assembly. Eligible criteria included age 18 years, Eastern
Cooperative Oncology Group performance status of 03, life expectancy of
1 month, sUA level <10 mg/dl at randomization, scheduled to receive rst
cytotoxic CT cycle (regardless of the line of treatment) because of HM at
intermediate or high TLS risk as per TLS panel consensus [3], candidate to
allopurinol treatment or no access to rasburicase. Main exclusion criteria
were uncontrolled ischemic heart disease or congestive heart failure, severe
renal and/or hepatic insufciency, presence of LTLS/CTLS at randomization,
hypersensitivity to febuxostat or allopurinol (or respective excipients), treatment with any investigational drug or any urate-lowering therapy within 30
days before randomization or with mercaptopurine or azathioprine within
14 days before randomization.

study treatment and assessments

Patients stratied by TLS risk (intermediate or high) and baseline sUA levels
(7.5 or >7.5 mg/dl) were randomized to either arm at a 1 : 1 ratio, using a
randomized block design. Study treatment was blinded while daily dose
depended on investigators choice among low, standard and high containing
either allopurinol 200, 300 and 600 mg, respectively, or xed febuxostat 120
mg. CT was initiated 2 days after the rst dose of urate-lowering treatment.
Treatment duration was 79 days according to CT duration as per investigators judgment. Adequate or increased hydration up to 3 l/m2/day was recommended according to TLS prophylaxis recommendations [3]. Randomization
visit (day 1) assessments were considered as baseline; screening visit assessments, if carried out within 24 h before randomization, could be considered as
baseline and not repeated. Samples for sUA and serum creatinine levels were
collected at baseline and daily before study drug intake up to the evaluation
visit (day 8). Treatment-emergent signs and symptoms (TESSs) reports and
hematology and clinical chemistry data were collected throughout study
treatment and on day 14. Central laboratory evaluation was used for primary
efcacy measures and treatment responder rate, local laboratory evaluation was
used for LTLS and CTLS incidence.

Safety analysis was carried out for all patients who received at least one dose
of study drug. Primary and secondary efcacy analyses were carried out on
all randomized patients (intention-to-treat analysis). The two co-primary
end points were analyzed through analysis of covariance (ANCOVA) in
order to test the difference in treatment efcacy quantied by AUC sUA18
and change in serum creatinine level between treatment arms. All statistical
tests were to be two-sided with a signicance level of = 0.05. The two
ANCOVA models included the treatment and the two stratication factors
(i.e. TLS risk and sUA levels) as covariates. The treatment responder rate was
determined along with its 95% condence interval (CI). Statistical comparison of treatment responder rates was conducted through the Wilson score
CI for binomial variable and Wilson condence limits were used [15]. One
arm was considered superior to another if the lower one-sided 97.65% condence limit of the difference in response rates between two arms was >0%
(type I error rate = 4.695%). LTLS and CTLS incidence were summarized
through descriptive statistics and compared using a 2 test. For safety
assessments, descriptive statistics were used.

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study design

patients

original articles

Annals of Oncology

results

sUA level control

patients
From October 2012 to September 2013, 385 patients were
screened and 346 were randomized. The 173 patients allocated to
each arm received at least one dose of study medication.
Treatment arms were well balanced regarding baseline characteristics (Table 1) with the exception of median lactate dehydrogenase
(LDH) that was 24% higher in febuxostat arm (P = 0.0184).
Overall, 82.1% of study patients were at intermediate TLS risk,
87.6% had a baseline sUA level 7.5 mg/dl and 82.7% were
assigned to receive standard daily dose. All patients but one in
febuxostat arm underwent CT during the study. Owing to missing
values at baseline, one patient per arm was excluded from the analysis of AUC sUA18; for the same reason, two patients allocated
to allopurinol were excluded from that of serum creatinine change.

The mean [standard deviation (SD)] sUA AUC18 was signicantly lower for febuxostat than for allopurinol (514.0 225.71
versus 708.0 234.42 mg h/dl; P < 0.0001). Mean (SD) sUA
at baseline showed no signicant differences between febuxostat and allopurinol (5.6 1.82 versus 5.8 1.77 mg/dl;
P = 0.3008), whereas it was signicantly lower for febuxostat
from the rst 24 h of treatment throughout the whole treatment period up to the evaluation visit (P < 0.0001 at each time
point; see Figure 1).

serum creatinine change over time

Mean (SD) percent change in serum creatinine level from
baseline to day 8 showed neither any positive change over time
for febuxostat or allopurinol nor signicant differences between

Sex
Female
Male
Age (years)
Mean
SD
Median
Range
Ethnicity
Black
Caucasian
Other
LDH (U/L)b
Mean
SD
Median
Range
Type of malignancy
AL
CLL
Lymphoma
TLS risk
High
Intermediate
sUA level
7.5 mg/dl
>7.5 mg/dl
Dose levelc
High
Low
Standard

Febuxostat (%)
(N = 173)

Allopurinol (%)
(N = 173)

Overall (%)
(N = 346)

P value

65 (37.6%)
108 (62.4%)

67 (38.7%)
106 (61.3%)

132 (38.1%)a
214 (61.8%)a

0.8248

58.5
14.26
61
2087

58.3
13.27
60
2085

58.4
13.75
60
2087

0.7401

1 (0.6%)
167 (96.5%)
5 (2.9%)

0 (0%)
164 (94.8%)
9 (5.2%)

1/(0.3%)
331 (95.7%)
14 (4.0%)

0.4142

622.3
865.26
410.5
91.68727.0

500.6
503.41
331.5
118.63428.0

561.8
710.46
379.5
91.68727.0

0.0184

34 (19.7%)
80 (46.2%)
59 (34.1%)

25 (14.5%)
94 (54.3%)
54 (31.2%)

59 (17.1%)
174 (50.3%)
113 (32.6%)

0.2566

30 (17.3%)
143 (82.7%)

32 (18.5%)
141 (81.5%)

62 (17.9%)
284/(82.1%)

0.7792

151 (87.3%)
22 (12.7%)

152 (87. 9%)

21 (12.1%)

303 (87.6%)
43 (12.4%)

0.8705

26 (15.0%)
4 (2.3%)
143 (82.7%)

29 (16.8%)
1 (0.5%)
143 (82.7%)

55 (15.9%)
5 (1.4%)
286 (82.7%)

0.4498

Percentages may not add up to 100 because of rounding.

The data were missing in one and three patients in febuxostat and allopurinol arm, respectively.
c
The distribution of patients by dose level was consistently reported for either arm; however, the three dose levels were actually applied only to allopurinol,
being febuxostat fixed 120 mg daily in any dose level.
SD, standard deviation; LDH, lactate dehydrogenase; AL, acute leukemia; CLL, chronic lymphocytic leukemia; TLS, tumor lysis syndrome; sUA, serum uric
acid.
b

Volume 26 | No. 10 | October 2015

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Table 1. Baseline characteristics of all randomized patients (n = 346)

Demographics and baseline characteristics

original articles

Annals of Oncology

them (0.83 26.977% versus 4.92 16.695% for febuxostat

and allopurinol, respectively; P = 0.0903). Differences in mean
(SD) serum creatinine level between febuxostat and allopurinol arm were detected neither at baseline (0.94 0.347
versus 0.94 0.266 mg/dl; P = 0.5689) nor at the evaluation
visit (0.91 0.359 versus 0.88 0.273 mg/dl for febuxostat
and allopurinol, respectively; P = 0.8881).

secondary efcacy analyses

No signicant difference was found between treatment groups
with respect to any of the secondary efcacy analysis. Treatment
responder rate was 98% (95% CI 96% to 100%) for febuxostat
and 96% (95% CI 93% to 99%) for allopurinol (P = 0.1993).
LTLS and CTLS incidence was 8.1% versus 9.2% (P = 0.8488)
and 1.7% versus 1.2% (P = 1.000) for febuxostat and allopurinol
treatment arm, respectively.

primary efcacy variables by subgroups

safety

The results of the primary efcacy analysis were fully conrmed

in subgroups of patients with different baseline characteristics in
terms of sUA level, TLS risk grade, creatinine level, performance
status score and malignant diagnosis (Table 2).

Overall, drug-related TESSs occurred only in 11 (6.4%) patients

in each arm. The only system organ classes with at least 1%
patients reporting drug-related TESSs were gastrointestinal disorders and investigations (Table 3). Severe drug-related TESSs

Mean sUA time course

8
7

AUC (mg x h/dL)

Febuxostat
Allopurinol
514.0 (225.71)
708.0 (234.42)
< 0.0001

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Treatment
Mean (SD)
P-value

mg/dL

5
4
P = 0.3008
3
2

P < 0.0001
P < 0.0001

1
0

Day 1
start treatment

Day 2

Day 3
start
chemoterapy

P < 0.0001

Day 4

Febuxostat (n = 172)

P < 0.0001

P < 0.0001

P < 0.0001

Day 6

Day 7

Day 5

P < 0.0001
Day 8
evaluation visit

Allopurinol (n = 172)

Figure 1. Mean sUA time course. Error bars indicate the standard deviation (SD) of the mean.

Table 2. Primary efficacy variables by subgroups of patients with different baseline characteristics
Baseline
characteristic

Category

sUA level

7.5 mg/dl
>7.5 mg/dl
Intermediate
High
MBC
>MBC
0
>0
AL
CLL+LYM

TLS risk
Creatinine level
ECOG PS score
Disease group

sUA AUC18 (mg h/dl)

Febuxostat

Allopurinol

Mean SD
Mean SD
Mean SD
Mean SD
Mean SD
Mean SD
Mean SD
Mean SD
Mean SD
Mean SD

672.7 217.02
992.0 169.05
709.9 223.45
698.2 286.83
610.6 191.42
822.1 228.46
682.6 216.19
720.5 242.88
649.7 260.51
717.9 229.19

472.3 190.47
850.5 208.13
506.2 224.78
551.0 230.28
432.7 204.69
624.4 206.23
539.3 254.85
501.5 209.84
491.2 248.55
519.7 220.34

P value
<0.0001
0.0313
<0.0001
0.0053
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001

Serum creatinine change (%)

Febuxostat
Mean SD
Mean SD
Mean SD
Mean SD
Mean SD
Mean SD
Mean SD
Mean SD
Mean SD
Mean SD

0.35 24.538
4.74 42.637
0.46 24.334
2.52 37.225
2.04 23.588
4.67 30.686
2.02 26.247
0.23 27.431
8.05 22.264
0.94 27.794

P value
Allopurinol
4.03 16.973
12.11 12.431
3.41 16.681
12.64 14.751
3.37 13.988
6.83 19.426
6.35 13.560
4.21 18.074
11.04 12.211
3.88 17.162

0.1245
0.4833
0.2136
0.1427
0.0524
0.0515
0.0822
0.9585
0.3243
0.0832

sUA, serum uric acid; SD, standard deviation; TLS, tumor lysis syndrome; MBC, median baseline creatinine; ECOG, Eastern Cooperative Oncology Group;
PS, performance status; AL, acute leukemia; CLL, chronic lymphocytic leukemia; LYM, lymphoma.

| Spina et al.

Volume 26 | No. 10 | October 2015

original articles

Annals of Oncology

Table 3. Drug-related TESSs

Drug-related TESSsa
SOC
Blood and lymphatic system
disorders
Cardiac disorders

Gastrointestinal disorders

General disorders and administration

site conditions
Hepatobiliary disorders

Metabolism and nutrition disorders

Musculoskeletal and connective tissue

disorders
Psychiatric disorders
Skin and subcutaneous tissue
disorders
Vascular disorders

Percent of patients with TESS(s)

Febuxostat (N = 173)
Allopurinol (N = 173)

Overall (N = 346)

Overall
Thrombocytopenia
Overall
Bundle branch block left
Sinus tachycardia
Overall
Upper abdominal pain
Diarrhea
Nausea
Vomiting
Overall
Peripheral edema
Overall
Cholestasis
Hepatotoxicity
Overall
ALT increased
AST increased
Blood urea increased
Blood uric acid decreased
GGT increased
QRS axis abnormal
pH urine increased
Overall
Decreased appetite
Diabetes mellitus
Overall
Muscular weakness
Overall
Insomnia
Overall
Hyperhidrosis
Pruritus
Overall
Hemorrhage

0
0
1.2
0.6
0.6
1.7
0.6
1.2
0.6
0
0
0
0
0
0
1.7
0
0
0
1.7
0
0
0
0.6
0.6
0
0.6
0.6
0
0
0.6
0.6
0
0.6
0.6

0.3
0.3
0.6
0.3
0.3
1.7
0.6
0.9
0.6
0.3
0.3
0.3
0.3
0.3
0.3
2.3
0.3
0.3
0.3
0.9
0.3
0.3
0.3
0.6
0.3
0.3
0.3
0.3
0.3
0.3
0.9
0.3
0.6
0.3
0.3

0.6
0.6
0
0
0
1.7
0.6
0.6
0.6b
0.6
0.6
0.6
0.6
0.6b
0.6b
2.9
0.6
0.6
0.6
0
0.6
0.6
0.6
0.6
0
0.6
0
0
0.6
0.6
1.2
0
1.2
0
0

One patient may experience multiple TESSs.

Severe in intensity
TESSs, treatment-emergent signs and symptoms; SOC, system organ class; PT, preferred term; ALT, alanine aminotransferase; AST, aspartate
aminotransferase; GGT, -glutamyltransferase.

occurred in two patients, both allocated to allopurinol. No drugrelated serious TESSs or deaths occurred. The most common
TESSs across treatment arms, regardless of causality, pertained to
the blood and lymphatic system (neutropenia, anemia, leukopenia,
thrombocytopenia, febrile neutropenia), to the gastrointestinal
system (nausea, diarrhea, constipation, vomiting), to investigations
(platelet count decreased) and to the general disorders and administration site conditions (mucosal inammation, pyrexia), reecting the known common toxicities of concomitant CT. The most
common serious TESSs across treatment groups, regardless of
causality, were pneumonia (1.2%2.9%) and febrile neutropenia
(0.6%1.7%). One patient in the febuxostat arm discontinued
study treatment because of TESSs, namely hematuria and septic

Volume 26 | No. 10 | October 2015

shock with a consecutive fatal outcome, which were unrelated to

the study drug.

discussion
The sUA control is a key element in the prevention of TLS and
renal events because the risk for TLS and renal events increases
by 1.75- and 2.21-fold for every mg/dl increase in sUA, respectively [2]. Up to now allopurinol, which needs dose-adaption
based on kidney function and rasburicase are the two available
agents in the TLS prophylaxis. This large, phase III, registration
study was designed to demonstrate the superiority of a xed
daily dose of febuxostat over allopurinol, administered at an

doi:10.1093/annonc/mdv317 |

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Investigations

PT

original articles

| Spina et al.

intermediate to high TLS risk. Allopurinol is an efcacious, safe

and cost-effective drug that so far has been the only oral agent
approved to prevent cancer-related hyperuricemia and actually
is the only TLS prophylaxis available in several European countries. However, based on the results of this trial, febuxostat has
been recently approved in the EU for the prevention and treatment of hyperuricemia in adult patients undergoing CT for HM
at intermediate to high TLS risk [20], and may indeed represent
a valid option in the TLS prophylaxis armamentarium, especially for patients in need of a fast sUA reduction.

acknowledgements
The authors acknowledge the patients (and their families) who
participated in the FLORENCE study as well as all the investigators and their staff. They also acknowledge that the top-line
results of this trial were presented in part at the following meetings: 50th Annual Meeting of the American Society of Clinical
Oncology, Chicago, IL, 30 May3 June 2014. 19th Annual Meeting
of the European Hematology Association, Milan, Italy, 1215
June 2014. MASCC/ISOO 2014 International Symposium on
Supportive Care in Cancer, Miami, FL, 2628 June 2014.

funding
This study was funded by Menarini Ricerche SpA, Firenze, Italy
(no grant number).

disclosure
MS has served on speakers bureau for Mundipharma, Pzer,
Roche, Takeda and Teva and has served as an advisor/consultant
for Menarini Ricerche. ZN has served as an advisor/consultant for
Menarini Ricerche. JMR has served as an advisor/consultant for
Menarini Ricerche. MF has served as an advisor/consultant
for Menarini Ricerche. IA has received honoraria from Amgen,
Inc., Johnson & Johnson, Roche and Takeda, has served as an
advisor/consultant for Celgene and Menarini Ricerche, has
received research funding from Celgene, Pzer, Roche and
Spectrum Pharmaceuticals and has received travel/accommodation/expenses from Takeda. KJ has served as an advisor/consultant
for Menarini Ricerche and has received travel/accommodation/
expenses from Menarini Ricerche. GB has served as an advisor/
consultant for Menarini Ricerche. AB has served on speakers
bureau for Amgen, Inc., Gilead, GlaxoSmithKline, Sandoz and
Teva, has served as an advisor/consultant for Italfarmaco,
Mundipharma and Sandoz, has received research funding from
Italfarmaco and Teva and has received travel/accommodation/
expenses from Alexion Pharmaceuticals and Jannsen. SG has
served as an advisor/consultant for Menarini Ricerche. NLG
has served as an advisor/consultant for Menarini Ricerche. JM
has served as an advisor/consultant for Bristol-Myers Squibb,
Menarini Ricerche and Novartis, has received honoraria from
Bristol-Myers Squibb and Novartis, has received research
funding from Bristol-Myers Squibb, Novartis and Roche and
has received travel/accommodation/expenses from BristolMyers Squibb, Novartis and Roche. SB, SS, AC, CAM and CS
are employed by Menarini Ricerche. All remaining authors have
declared no conict of interest.

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adaptable daily dose, in patients with HM at risk for TLS.

Febuxostat proved to be signicantly superior over allopurinol
in controlling sUA level throughout the whole treatment period
(P < 0.0001). The higher efcacy of febuxostat in reducing the
sUA exposure was moreover conrmed in subgroups of patients
with different baseline sUA level, TLS risk grade, creatinine
level, performance status and malignant disease (Table 2). In
addition, since the rst 24 h of treatment, febuxostat achieved a
signicantly higher sUA reduction at each time point compared
with allopurinol (Figure 1). Noteworthy, although TLS risk categories were balanced between treatment arms following the
stratication procedure, the febuxostat-treated population had a
higher pretreatment LDH level (P = 0.0184) which might reect
a greater malignant disease burden and consequently enhance
sUA increase soon after CT. Despite this, as previously mentioned febuxostat demonstrated its superiority over allopurinol
since the rst 24 h of treatment and this could be relevant for
patients in urgent need of CT when rasburicase is unavailable.
The serum creatinine percent change throughout the treatment
period demonstrated that both treatments were able to prevent
creatinine increase over time. In a previous study on pediatric
patients with HM, allopurinol led to an 11% increase in serum
creatinine but that study enrolled only patients at high TLS risk
[9]. Conversely, in our study, the majority of patients were at
intermediate risk. By starting the XO inhibition 2 days before
CT onset in such a population, both treatments were able to
prevent creatinine increase, with the advantage of a xed daily
dose for febuxostat. Treatment responder rate was high and
comparable between the two treatments. Of note, our study
dened treatment failure as two or more consecutive values of
sUA missing or >7.5 mg/dl. Cortes et al. found an 11% treatment failure rate due to hyperuricemia following allopurinol in
patients at TLS risk, but in that study a single sUA value >7.5
mg/dl was sufcient to determine treatment failure [8]. Overall,
the incidence of LTLS and CTLS was small and comparable
between treatment arms. In the study of Cortes et al., rasburicase
achieved a lower LTLS incidence and a comparable CTLS incidence in respect of allopurinol alone, but 90% of patients were
at high TLS risk grade. Interestingly, similarly to our study, all
randomized trials of rasburicase published to date (two of which
compared it with allopurinol) adopted a reduction in sUA exposure rather than in TLS incidence as the primary end point
[8, 9, 1619]. Indeed, adequate hydration and allopurinol
provide an effective benchmark for TLS prophylaxis, thus determining the need to use this recognized surrogate end point to
design feasible trials in this setting. The present study encompassed a wide variability of HM, in terms of both type and line
of treatment, as well as of CT regimens. In addition, increased
hydration was recommended, but not systematically recorded
among concomitant medications. On the one hand, such topics,
moreover shared with previous randomized trials in TLS
prophylaxis [8, 9], are acknowledged as limitations to results interpretation, though partially contained by the one-to-one randomization ratio. On the other hand, they also reect the actual
clinical practice, thus adding at the same time some value to
these trials. In conclusion, in this study, febuxostat 120 mg xed
daily dose demonstrated to be well tolerated and rapidly more
effective than allopurinol in reducing sUA level, with a comparable prevention of creatinine increase over time in patients at

Annals of Oncology

original articles

Annals of Oncology

references

Annals of Oncology 26: 21612168, 2015

doi:10.1093/annonc/mdv330
Published online 28 July 2015

Has racial difference in cause-specic death improved

in older patients with late-stage breast cancer?
J. Ning1, S. Peng1, N. Ueno2, Y. Xu3, Y. Shih3, M. Karuturi2, S. Giordano2,3 & Y. Shen1*
1
Department of Biostatistics; 2Department of Breast Medical Oncology; 3Department of Health Services Research, The University of Texas MD Anderson
Cancer Center, Houston, USA

Received 18 May 2015; revised 23 July 2015; accepted 24 July 2015

Background: Research on temporal mortality trends for stage IV breast cancer is limited, especially among older
patients by race. We evaluated factors associated with overall, breast cancer-specic and other-cause mortalities using
contemporary population data.
Patients and methods: Using the Surveillance, Epidemiology, and End ResultsMedicare linked data, we identied
older women (66 years) with stage IV breast cancer diagnosed in 20022009. Overall mortality was estimated by the
KaplanMeier method, compared by log-rank tests, and modeled by Cox models. Competing risk analysis was used to
evaluate breast cancer-specic and other-cause mortalities.
Results: The median overall survival time for non-Hispanic blacks improved from 8.6 months in 20022003 to 9.9
months in 20072009, whereas that for non-Hispanic whites improved from 12.1 to 14.8 months. In the multivariate
*Correspondence to: Dr Yu Shen, Department of Biostatistics, The University of Texas
MD Anderson Cancer Center, 1400 Pressler St, Unit 1411, Houston, TX 77030, USA.
Tel: +01-713-794-4159; E-mail: yshen@mdanderson.org

The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.

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