Re: Prednisone Plus Cabazitaxel or Mitoxantrone for Metastatic Castration-Resistant Prostate Cancer Progressing After Docetaxel Treatment: A Randomized Open-Label Trial

Article (PDF Available)inThe Lancet 376(9747):1147-54 · October 2010with1,539 Reads
DOI: 10.1016/S0140-6736(10)61389-X · Source: PubMed
Abstract
Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment. We undertook an open-label randomised phase 3 trial in men with metastatic castration-resistant prostate cancer who had received previous hormone therapy, but whose disease had progressed during or after treatment with a docetaxel-containing regimen. Participants were treated with 10 mg oral prednisone daily, and were randomly assigned to receive either 12 mg/m(2) mitoxantrone intravenously over 15-30 min or 25 mg/m(2) cabazitaxel intravenously over 1 h every 3 weeks. The random allocation schedule was computer-generated; patients and treating physicians were not masked to treatment allocation, but the study team was masked to the data analysis. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, NCT00417079. 755 men were allocated to treatment groups (377 mitoxantrone, 378 cabazitaxel) and were included in the intention-to-treat analysis. At the cutoff for the final analysis (Sept 25, 2009), median survival was 15·1 months (95% CI 14·1-16·3) in the cabazitaxel group and 12·7 months (11·6-13·7) in the mitoxantrone group. The hazard ratio for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0·70 (95% CI 0·59-0·83, p<0·0001). Median progression-free survival was 2·8 months (95% CI 2·4-3·0) in the cabazitaxel group and 1·4 months (1·4-1·7) in the mitoxantrone group (HR 0·74, 0·64-0·86, p<0·0001). The most common clinically significant grade 3 or higher adverse events were neutropenia (cabazitaxel, 303 [82%] patients vs mitoxantrone, 215 [58%]) and diarrhoea (23 [6%] vs one [<1%]). 28 (8%) patients in the cabazitaxel group and five (1%) in the mitoxantrone group had febrile neutropenia. Treatment with cabazitaxel plus prednisone has important clinical antitumour activity, improving overall survival in patients with metastatic castration-resistant prostate cancer whose disease has progressed during or after docetaxel-based therapy. Sanofi-Aventis.
Re: Prednisone Plus Cabazitaxel or Mitoxantrone for
Metastat ic Castration-Resistant Prostate Cancer Pro-
gressing After Docetaxel Treatment : A Randomized
Open-Label Trial
de Bono JS, Oudard S, Ozguroglu M, et al;
TROPIC Investigators
Lancet 2010;376:1147–54
Experts’ summary:
The TROPIC study is a randomized phase 3 trial comparing
efficacy and safety of cabazitaxel plus prednisone and mito-
xantrone plus prednisone in 755 patients with castration-
resistant prostate cancer (CRPC) with progressive disease after
docetaxel-based chemotherapy. Between January 2007 and
October 2008, 377 patients were treated with 12 mg/m
2
mitoxantrone and 378 patients were treated with 25 mg/m
2
cabazitaxel. Regarding overall survival (OS; primary end
point), cabazitaxel was superior to mitoxantrone with 15.1
mo in the cabazitaxel group compared with 12.7 mo in the
mitoxantrone group—a 30% reduction in relative risk of death
(hazard ratio [HR]: 0.70; p < 0.0001).
A statistically significant advantage concerning
progression-free survival can be determined and was twice
as long with cabazitaxel versus mitoxantrone (2.8 mo vs 1.4
mo; HR: 0.74; p < 0.0001). The prostate-specific antigen and
tumor response rates were also significantly higher in the
cabazitaxel group. The most frequent side effects were
hematologic, with 8% febrile neutropenia in the cabazitaxel
group and 1% in the mitoxantrone group.
In conclusion, cabazitaxel has proven antitumor activity
in patients with CRPC with progressive disease after
docetaxel therapy. This results in a significant improvement
in OS in these patients.
Experts’ comments:
Based on the results of the TAX 327 and Southwest Oncology
Group SWOG-S9916 studies, which revealed for the first time
a survival benefit of 2 mo in patients with hormone-refractory
prostate cancer, docetaxel-based chemotherapy is the stan-
dard of care for these patients [1,2]. Patients who progress
with this therapy have the possibility of palliative treatment
with mitoxantrone.
Studies to date with mitoxantrone merely showed
improvement of quality of life and symptoms but failed to
prove a survival benefit [3]. The results of this study, which
already resulted in an approval by the US Food and Drug
Administration, are very promising and offer a therapeutic
option to affected patients. Regarding the side effects of
cabazitaxel, one should carefully note that neutropenia is the
primary dose-limiting factor, and a relevant proportion of
patients had grade 3 diarrhea. It is necessary to have
strategies for acute and preventive treatment, particularly
for these two side effects. Furthermore, patients must be
appropriately informed.
The role of cabazitaxel cannot yet be clearly defined. In
2010, the results of two additional important studies
became available [4,5]. The Impact study is a phase 3 trial
in which 512 patients randomly received either an
autologous active cellular immunotherapy (sipuleucel-T)
or placebo. The use of sipuleucel-T resulted in a 4.1-mo
improvement in OS [4]. Another milestone in the treatment
of patients with CRPC is abiraterone. A phase 3 study,
presented at the 2010 European Society for Medical
Oncology Congress, revealed an improvement of 4 mo in
median survival for patients treated with this substance [5].
Because the results are comparable regarding OS with
these three substances, the duration and timing of
hormonal therapy and chemotherapy will become more
complex. Additionally, the effects on digestibility and
quality of life are crucial criteria that will influence the
palliative management of prostate cancer.
Conflicts of interest: The authors have nothing to disclose.
References
[1] Petrylak DP, et al. N Engl J Med 2004;351:1513–20.
[2] Tannock IF, et al. N Engl J Med 2004;351:1502–12.
[3] Tannock IF, et al. J Clin Oncol 1996;14:1756–64.
[4] Kantoff PW, et al. N Engl J Med 2010;363:411–22.
[5] De Bono J, et al. Abiraterone acetat improves survival in metastatic
castration-resistant prostate cancer: Phase III results. Paper pre-
sented at: 35th European Society for Medical Oncology Congress;
8–12 October 2010; Milan, Italy.
Dieter Jocham
*
, Martin Sommerauer
Universita
¨
tsklinikum, Schleswig-Holstein, Campus Lu
¨
beck,
Ratzeburger Allee 160 , D-23538 Lu
¨
beck, Germany
*Corresponding author.
E-mail address: Prof.Jocham.MUL@t-online.de (D. Jocham)
DOI: 10.1016/j.eururo.2011.01.022
RE: Mortality Results From the Go
¨
teborg Randomised
Population-Based Prostate-Cancer Screening Trial
Hugosson J, Carlsson S, Aus G, et al.
Lancet Oncol 2010;11:725–32
Expert’s summary:
After 14 yr of median follow-up, the Go
¨
teborg randomized
population-based study of screening for prostate cancer (PCa)
demonstrated a significant mortality reduction of 44% in the
screening group compared with the control group in the
intention-to-screen analysis. This translated into a relative
risk reduction of 56% for those men who were in fact screened
after adjustment for noncompliance (25% in the screening
group).
The percentage of high-risk or advanced disease in the
control group was 32% ([126 + 87] / [718 57]), which was
higher than in the screening group (13%) and lower than
nonattendees in the screening arm (52%). The number of
EUROPEAN UROLOGY 59 (2011) 657–661
659
men needed to screen (NNS) was low at 293. The number of
men needed to treat (NNT) amounted to 12 and was very
low, despite the high percentage of patients who were
under active surveillance. This percentage was higher at
27.6% (314 of 1138) in the screening group compared with
21.2% (152 of 718) in the control group.
Details of outcome in relation to birth cohort may be
relevant for the development of optimal screening systems.
The authors demonstrated that the crude mortality rate of
PCa in attendees in the screening group was lowest at 0.36%
compared with 0.72% in nonattendees in the screening
group and 0.78% in the control group. Considering the
mortality rate in attendees in the screening groups stratified
by birth cohorts, attendees between 60 and 64 yr of age at
study entry showed a higher crude mortality rate at 0.92%
than 0.25% and 0.06% in those aged 55–59 yr and 50–54 yr,
respectively. Furthermore, among 27 men who participated
in the screening group and who died due to PCa, 13 (48%)
were screened for the first time. Of those 13 cases, 12 men
(92%) were between 60 and 64 yr old at study entry. At least
some of those men might have had the possibility of being
cured by timely and appropriate treatments if they had
started screening at 50 yr of age.
Expert’s comments:
The efficacy of cancer screening for individuals should be
evaluated as the probability of mortality reduction through-
out the whole life. The Swedish study contributes heavily to
determining the effectiveness of prostate-specific antigen
(PSA) screening by adding level 1 evidence to the first inten-
tion-to-screen analysis of the European Randomized Study of
Screening for Prostate Cancer (ERSPC) [1], in which the Swed-
ish study is a partner and which showed a significant mortali-
ty reduction for the first time after 9 yr of follow-up.
In terms of the drawbacks of screening for PCa, the ERSPC
showed an increased risk of overdetection and overtreat-
ment by intensive screening exposure and invasive
treatment strategies. An NNT of 48 and an NNS of 1410
were reported, according to this interim analysis of the
study; however, the drawbacks of PSA screening might be
overestimated because of the short follow-up duration. At
the same time, we should also consider the likelihood of
underdetection of significant PCa and delay in the
appropriate treatment timing in the nonscreening cohort.
In the Swedish study, there was a 1.6-fold difference in the
number of men with PCa diagnosed in the screening cohort
and the control cohorts during 14 yr of follow-up. On the
one hand, there may be some bias between the screening
cohort and the control group in terms of increased risk of
overdetection and overtreatment in the screening cohort.
On the other hand, the outcomes of the control cohort are
likely to differ in terms of an increased risk of missing
clinically significant cancer and missing the chance of cure
by appropriate treatment strategies compared with the
screening cohort.
Although the both cohorts had completely inverse
potential drawbacks, from my current perspective as a
clinician, it would be possible to reduce the risk of
overdetection by using already available nomogram-based
risk calculators like the Prostate Risk Indicator [2].
Furthermore, the impact of overtreatment has been reduced
and will decrease further in the current ongoing prospective
clinical study by applying active surveillance. The negative
impact on quality of life has also decreased and will
decrease further by the continuing development of mini-
mally invasive treatment strategies. In contrast, by applying
active surveillance and focal treatments, many urologists
are afraid that they ineffectively treat more advanced life-
threatening disease by delaying early detection and
aggressive treatment, as is seen in the not-screened cohort
and in the nonattendees in the screening cohort. The NNS
and the NNT shown in the Swedish study were not high
compared with the other cancer screening program and
may be acceptable for many men who are at risk of
developing PCa. However, the NNT cannot estimate how
large the drawbacks of the cancer screening would be
because NNT is simply estimated with the assumption that
any stage of PCa is equal.
The treatment duration and quality-adjusted life-years
of metastatic PCa patients are different from those with
localized PCa. Increasing the number of patients with
advanced-stage PCa might cause a lot of socioeconomic
damage, not only to individuals but also to the community,
because of loss of quality of life, high treatment cost, loss of
activity as a result of long-term treatment, and severe
adverse effects caused by some treatments [3]. A treatment
for metastatic PCa and a treatment for localized PCa should
not be handled as the same entity from a clinical
perspective. In fact, the number of patients with high-risk
and advanced PCa in the control group of the Swedish study
was 2.5 times higher than that in the screening group.
Before introducing screening for cancer to the community,
it should be investigated whether introducing cancer
screening in the community improves quality-adjusted
life-years compared to routine medical care without cancer
screening. From a socioeconomic point of view, it may be
important to estimate the incremental cost-effectiveness
ratio (ICER) in the screening group. The ICER is the total
social cost of introducing a long-term cancer screening
system divided by the total social benefit from improved
quality-adjusted life-years due to intervention.
Regarding PSA screening, our mission must focus on
establishing an optimal screening system that minimizes
overdetection, overtreatment, and socioeconomic damage
and maximizes screening effects in terms of mortality
reduction and avoiding development of metastatic PCa.
Conflicts of interest: The author has nothing to disclose.
References
[1] Schro
¨
der FH, Hugosson J, Roobol MJ, et al. Screening and prostate-
cancer mortality in a randomized European study. N Engl J Med
2009;360:1320–8.
[2] Roobol MJ, Kerkhof M, Schro
¨
der FH, et al. Prostate cancer mortality
reduction by prostate-specific antigen–based screening adjusted for
nonattendance and contamination in the European Randomised
EUROPEAN UROLOGY 59 (2011) 657–661
660
Study of Screening for Prostate Cancer (ERSPC). Eur Urol 2009;56:
584–91.
[3] Naito S, Kakehi Y, Ito K, et al., the Committee for Establishment of the
Guidelines on Screening for Prostate Cancer and Japanese Urological
Association. Updated Japanese Urological Association Guidelines on
prostate-specific antigen-based screening for prostate cancer in
2010. Int J Urol 2010;17:830–8.
Kazuto Ito
Gunma University Graduate School of Medicin e,
Department of Urology, Maebashi, Gunma, Japan
E-mail address: kzito@med.gunma-u.ac.jp
DOI: 10.1016/j.eururo.2011.01.023
EUROPEAN UROLOGY 59 (2011) 657–661
661
    • "However, under prolonged androgen deprivation, prostate cancer finally becomes refractory to hormonal manipulation and is then defined as castration-resistant prostate cancer (CRPC) [3, 4]. Recently, possible therapeutic strategies for CRPC have been increasing [5][6][7][8] . Novel therapies including enzalutamide , abiraterone acetate, cabazitaxel, sipuleucel-T, and radium 223 have been approved for therapy of CRPC patients. "
    Article · Dec 2016
    • "During the past 10 years significant progress has been achieved in treatment of metastatic castration resistant prostate cancer (mCRPC). Several drugs with potential to extend overall survival (OS) have been approved, some of which harbor fairly little toxicity123456789. Amongst these Abiraterone acetate is available in preand post-chemotherapy setting and has become a broadly accepted standard of care. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Significant progress in treatment of metastatic castration resistant prostate cancer (mCRPC) has been made. Biomarkers to tailor therapy are scarce. To facilitate decision-making we evaluated dynamic changes of alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and prostate specific antigen (PSA) under therapy with Abiraterone. Methods Men with bone mCRPC (bmCRPC) on Abiraterone 12/2009-01/2014 were analyzed. Dynamic ALP-, LDH- and PSA-changes were analyzed as predictors of best clinical benefit and overall survival (OS) with logistic-regression, Cox-regression and Kaplan-Meier-analysis. Results Thirty-nine pre- and 45 post-chemotherapy patients with a median follow up of 14.0 months were analyzed. ALP-Bouncing can be observed very early during therapy with Abiraterone. ALP-Bouncing is defined as rapidly rising ALP-levels independent of baseline ALP during the first 2–4 weeks of Abiraterone-therapy with subsequent equally marked decline to pretreatment levels or better within 8 weeks of therapy, preceding potentially delayed PSA-decline. In univariate analysis failure of PSA-reduction ≥50 % and failure of ALP-Bouncing were the strongest predictors of progressive disease (p = 0.003 and 0.021). Rising ALP at 12 weeks, no PSA-reduction ≥50 % and no ALP-Bouncing were strongest predictors of poor OS, (all p < 0.001). Kaplan-Meier-analysis showed worse OS for rising ALP at 12 weeks, no PSA-reduction ≥50 % and no ALP-Bouncing (p < 0.001). In subgroup-analysis of oligosymptomatic patients all parameters remained significant predictors of poor OS, with no PSA-reduction ≥50 % and rising ALP at 12 weeks being the strongest (p < 0.001). In multivariate analysis PSA-reduction ≥50 % remained an independent predictor of OS for the whole cohort and for the oligosymptomatic subgroup (both p = 0.014). No patient with ALP-Bouncing had PD for best clinical benefit. Patients with rising ALP at 12 weeks had no further benefit of Abiraterone. Conclusions Dynamic changes of ALP, LDH and PSA during Abiraterone-therapy are associated with best clinical benefit and OS in bmCRPC. ALP-Bouncing occurring earlier than PSA-changes as well as prior to equivocal imaging results and rising ALP at 12 weeks under Abiraterone may help to decide whether to discontinue Abiraterone. An external validation of these findings on a prospective cohort is planned. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2260-y) contains supplementary material, which is available to authorized users.
    Full-text · Article · Dec 2016
    • "Resistance to chemotherapy remains a major challenge in the management of CRPC and other cancers. Recently, cabazitaxel, a semi-synthetic derivative of a natural taxoid, was shown to improve survival in docetaxel-recurrent mCRPC (de Bono et al, 2010). However, the benefit in overall survival is modest (median 2.4 months) at the cost of additional adverse effects. "
    [Show abstract] [Hide abstract] ABSTRACT: Clusterin (CLU) is a stress-activated molecular chaperone that confers treatment resistance to taxanes when highly expressed. While CLU inhibition potentiates activity of taxanes and other anti-cancer therapies in preclinical models, progression to treatment-resistant disease still occurs implicating additional compensatory survival mechanisms. Taxanes are believed to selectively target cells in mitosis, a complex mechanism controlled in part by balancing antagonistic roles of Cdc25C and Wee1 in mitosis progression. Our data indicate that CLU silencing induces a constitutive activation of Cdc25C, which delays mitotic exit and hence sensitizes cancer cells to mitotic-targeting agents such as taxanes. Unchecked Cdc25C activation leads to mitotic catastrophe and cell death unless cells up-regulate protective mechanisms mediated through the cell cycle regulators Wee1 and Cdk1. In this study, we show that CLU silencing induces a constitutive activation of Cdc25C via the phosphatase PP2A leading to relief of negative feedback inhibition and activation of Wee1-Cdk1 to promote survival and limit therapeutic efficacy. Simultaneous inhibition of CLU-regulated cell cycle effector Wee1 may improve synergistic responses of biologically rational combinatorial regimens using taxanes and CLU inhibitors.
    Full-text · Article · May 2016
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