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Actas Urol Esp.

2017;41(6):347---351

Actas Urologicas Espanolas

www.elsevier.es/actasuro

EDITORIAL

Chemotherapy should not yet be considered in patients


with hormone-sensitive metastatic prostate cancer
La quimioterapia no debera todava ser considerada en los pacientes con
cncer de prstata metastsico hormonosensible

Since 2004, the docetaxel---prednisone combination has chemotherapy with docetaxel and prednisone at standard
been the standard treatment for patients with castration- doses associated with AS and 193 received AS alone.7 Only
resistant prostate cancer (CRPC).1,2 Compared with 10% had visceral metastases. After a mean follow-up of 50
mitoxantrone---prednisone, it showed an overall survival months, the docetaxel group showed a survival advantage
increase of almost 2 months, signicant improvements in of 4 months, which was not statistically signicant. In con-
pain control in 35% of patients, and a PSA 50% response in trast, increased toxicity was observed, mainly neutropenia
45%. In 32%, grade 3---4 neutropenia was observed and in 3% (32% grades 3---4), with 3% febrile neutropenia and 2% mor-
febrile neutropenia. tality. The quality of life perceived by the patient worsened
In recent years, hormone-based treatments (abi- during treatment with docetaxel, but it was similar in the
raterone acetate, enzalutamide), targeting progression- 2 groups at 12 months. Due to these observations, it was
related mechanisms involving the androgen receptor concluded that such combination was inappropriate for this
(ARTT), have demonstrated at least equivalent efcacy in type of patients. It should be noted that during the inclu-
terms of overall progression-free survival, with excellent sion period of this trial, the new ARTT were not available, so
tolerance in patients with CRPC.3---6 only 10% received abiraterone and 5% enzalutamide in the
Recently, different studies have evaluated the role of context of clinical trial.
the combination castration-chemotherapy with docetaxel in In 2014, at the 50th ASCO Congress, the results of the
metastatic patients who had not previously been castrated. CHAARTED study, published in 2015, were released. It is an
Their justication would be based on the possibility of acting American study carried out between 2006 and 2012, where
precociously on androgen-independent clones, acting more 790 patients were randomized, of which 397 received che-
effectively on cells weakened by androgenic suppression motherapy with docetaxel and prednisone at standard doses
(AS) and on greater accessibility of patients to chemother- associated with AS and 393 received AS alone.8,9 66% of the
apy, given the risk that in later stages they might not be in patients had a high volume metastatic disease dened as
a position to receive it. Against its use, one could argue a the presence of visceral metastases (about 15%) or 4 bone
possible deleterious effect on immunity in a massive apop- metastases with one or more located outside the spine or
totic induction phase, or the fact that AS takes the cells out pelvis. After a median follow-up of 29 months, there was an
of cycle making them less sensitive to chemotherapy. increase in survival of the combination group of 13.6 months,
In the year 2013, GTUG-AFU-15 was published, a Euro- limited exclusively to those with a high tumor burden. Like-
pean study with recruitment between 2004 and 2008 where wise, the time of development of resistance to castration
385 patients were randomized, of whom 192 received (11.7 vs. 20.2 months) was extended by 9 months. Some
kind of severe grade 4---5 toxicity was observed in 13% of
those treated with chemotherapy, grade 3---4 neutropenia in
Please cite this article as: Minana Lpez B. La quimioter- slightly more than 10% (compared to 30% GETUG) and febrile
apia no debera todava ser considerada en los pacientes con
neutropenia in 2%.
cncer de prstata metastsico hormonosensible. Actas Urol Esp. Such promising results required a comparison with
2017;41:347---351. GETUG-15. The observed differences could be attributed

2173-5786/ 2016 AEU. Published by Elsevier Espana, S.L.U. All rights reserved.
348 EDITORIAL

Treatment beyond progression


ADT+Docet (N=397) ADT alone (N=393)
N N

Biochemical, symptomatic, and


radiographic progression 145 174

Symptomatic or radiographic
progression 93 133

Docetaxel 49 129

Another chemotherapy
Cabazitaxel 43 29

Mitoxantrone and/or platinum 22 23

Hormone therapy

Abiraterone/ enzalutamide 92 79

Antiandrogen/ ketoconazole 87 99
Immunotherapy
Sipuleucel T 20 18
Radiotherapy 54 67

Table presented by:C.J. Sweeney en ASCO 2014


Figure 1 CHAARTED. Treatments to progression. Presented at the ASCO Annual Meeting 2014 by Christopher Sweeney.

to one or the combination of the following causes: that new ARTTs and not to chemotherapy, which would nullify its
the European study lacked the necessary sample size; that conclusions.
the population (casuistry) was different; or that, since most In the study publication, surprisingly, the survival data
patients in CHAARTED received treatment for progression correspond to December 2013 (those presented in ASCO),
with ARTT, with demonstrated efcacy in the increase of whereas the table with data of the treatments received on
survival, the arms were not balanced with regard to these progression, published in a separated appendix, are from
treatments. Indeed, CHAARTED doubles the sample size and December 2014, that is, a year later (Fig. 2), so the dif-
the type of patients included is different from GETUG, ference could have been masked.9 No less surprising, if
with a higher presence of visceral involvement and high- we compare both tables, is the fact that, having almost
burden metastatic disease (52% GETUG vs 66% CHAARTED), doubled the number of patients with clinical---radiological
which translates into the lower survival observed in the progression (from 93 to 180) between 2013 and 2014, only
group treated with AS (54 months in GETUG vs 44 months 13 patients out of the 87 (15%) who progressed in 2014
in CHAARTED), so the rst 2 hypotheses could justify the have received treatments with abiraterone or enzalutamide,
observed differences. something completely outside the usual clinical practice
However, according to the results presented by the (Fig. 3). Therefore, it is urgent to clarify these discordances
authors, and although in the publication they indicate that so that this study is taken into account, given the severe
the differences were detected already before having these implications that derive from it.
treatments, the patients of the experimental group seem to This is of particular importance if we take into account
have received at progression more ARTT than the arm that the observation in GETUG-15 of a decrease in the benecial
receives only AS, as it can be seen in the table presented effect of long-term chemotherapy that the authors consider
at ASCO (Fig. 1). If, as usual in clinical practice, progression a possible justication for the absence of observed benet in
for clinical or radiological reasons is considered as treat- overall survival, despite the good initial clinical---biological
ment criterion, 92 out of 93 (98%) of the experimental group responses (PSA).7 In addition, subsequent sub-analyses per-
would have received abiraterone or enzalutamide treatment formed on the GETUG study, applying the CHAARTED tumor
on progression, compared to only 79 of 133 (59%) in the AS burden, do not show any survival benet, nor in the high-
monotherapy arm, a difference of 39%. If we consider all burden group.10
those who progress, including those who do it due to PSA, 92 In December 2015, the STAMPEDE study, a multi-arm and
of 145 (63%) receive treatment with abiraterone or enzalu- stage design study was published, one of which includes the
tamide on progression compared to 79 of 174 (45%), resulting addition of docetaxel to AS in patients with high-risk and
in a difference of 18%. If these data presented in ASCO are metastatic tumors with the same objectives as the previous
true, the observed benet could also be attributed to the ones.11 Focusing on the last subgroup, between 2005 and
EDITORIAL 349

Treatment beyond progresssion


ADT+Docet (N=397) ADT alone (N=393)
N N
Serological progression/ clinical
238 287
progression

Clinical progression 180 228

Docetaxel 54 137

Another chemotherapy
Cabazitaxel 57 37

Mitoxantrone and/or platinum 29 27

Hormone therapy

Abiraterone/ enzalutamide 105 104

Antiandrogen/ ketoconazole 80 91
Immunotherapy
Sipuleucel T 22 19
Radiotherapy 69 79
This set of data represents the number of patients that had progressed and the treatment
given on 23rd December 2014, while the survival data represent the data of 23rd
December 2013.

Figure 2 CHAARTED. Treatment to progression.


Source: Sweeney et al.9

Comparison tables ASCO 2014 - N Engl J Med 2015


ADT+Docet (N=397) ADT alone (N=393) ADT+Docet (N=397) ADT alone (N=393)
N N N N
Biochemical, symptomatic, and Serological progression/ clinical
radiographic progression 145 174 238 287
progression
Symptomatic or radiographic
progression 93 133 Clinical progression 180 228

Docetaxel 49 129 Docetaxel 54 137


Another chemotherapy Another chemotherapy
Cabazitaxel 43 29 Cabazitaxel 57 37
Mitoxantrone and/or platinum 22 23 Mitoxantrone and/or platinum 29 27
Hormone therapy Hormone therapy

Abiraterone/ enzalutamide 92 79 Abiraterone/ enzalutamide 105 104

Antiandrogen/ ketoconazole 87 99 Antiandrogen/ ketoconazole 80 91


Immunotherapy
Immunotherapy
Sipuleucel T 20 18
Sipuleucel T 22 19
Radiotherapy 54 67
Radiotherapy 69 79
Table presented by: C.J. Sweeney en ASCO 2014 N Engl J Med (ref. 9)

December data 2013 December data 2014

Figure 3 CHAARTED. Disagreements between the tables presented at ASCO Annual Meeting 2014 and published in the New England
Journal of Medicine.

2013, 2962 mostly British and Swiss patients were random- or without zoledronate, showed a survival benet limited to
ized, of whom 1184 received standard treatment (AS), 592 metastatic patients (slightly more than 350 in each group),
AS and docetaxel and 593 AS with zoledronate and doce- being 15 months (HR: 0.76) with docetaxel and 10 months
taxel. Overall and free from failure survival dened as the (HR: 0.79) with docetaxel and zoledronate. Compared to
presence of any of the following was assessed: biochemical CHAARTED, a lower proportion of patients (34%) received
progression (PSA > 50% nadir), local or radiological progres- ARTT on progression, suggesting more regular recruitment
sion, or death from prostate cancer. With a median follow-up from the onset, with a balanced distribution between the
of 43 months, patients treated with AS and docetaxel, with 2 groups. No subanalysis has been reported by subgroups
350 EDITORIAL

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EDITORIAL 351

prostate cancer treated with docetaxel and prednisone in and B. Minana Lpez
out of clinical trials. Ann Oncol. 2013;24:2972---7. Hospital General Universitario Morales Meseguer,
16. Zheng HR, Wen F, Wu YF, Wheeler JR, Li Q. Cost-effectiveness Universidad Catlica San Antonio, UCAM, Murcia, Spain
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E-mail addresses: bminana@ucam.edu,
sensitive prostate cancer treated with androgen-deprivation
bernardino.minana@gmail.com
therapy from a Chinese perspective. Eur J Cancer Care (Engl).
2016;May, http://dx.doi.org/10.1111/ecc.12505 [Epub ahead
of print].