World J Urol (2010) 28:391–398
DOI 10.1007/s00345-010-0527-5
O R I G I N A L A R T I CL E
Carboplatin plus weekly docetaxel as salvage chemotherapy
in docetaxel-resistant and castration-resistant prostate cancer
Christoph W. M. Reuter · Michael A. Morgan ·
Philipp Ivanyi · Martin Fenner · Arnold Ganser ·
Viktor Grünwald
Received: 22 December 2009 / Accepted: 23 February 2010 / Published online: 14 March 2010
© Springer-Verlag 2010
Abstract
Background There is no proven, eVective, standard sec-
ond-line chemotherapy for castration- and docetaxel-resis-
tant prostate cancer (DRPC). Recent data suggest that
carboplatin may be eVective in combination with docetaxel
in this setting; however, the optimal docetaxel/carboplatin-
based regimen is still unclear.
Aim of the study We identiWed 43 consecutive patients
with DRPC treated with carboplatin (AUC5 d1) and doce-
taxel (35 mg/m2 d1, 8, 15 q4w i.v.) as a second-line or sub-
sequent salvage chemotherapy until discontinuation of
therapy due to disease progression or unacceptable toxicity.
Results Decreased prostate-speciWc antigen (¸50% PSA)
was observed in 22/43 (51.2%, 95% CI, 35.5, 66.7%)
patients, with ¸90% reduction in 12/43 patients (27.9%).
At the time of analysis, the median follow-up time for all
patients was 10.4 months. Median progression-free survival
(PFS) for all patients was 6.5 months (95% CI 4.1, 8.9), and
median overall survival (OS) was 15.8 months (95% CI
12.1, 18.5). In PSA responders, PFS was 9.5 (95% CI 8.2,
19.0) months versus 3.3 (95% CI 2.6, 4.0) months in PSA
non-responders (P < 0.0001; hazard ratio (HR) 0.108) and
OS was 24.4 months (95% CI 19.5, 29.4) versus 7.8 (95%
CI 5.2, 10.3) months (P = 0.001; HR 0.232). Established
prognostic factors were associated with survival. This regi-
men was reasonably well tolerated, with leukopenia/neutro-
C. W. M. Reuter (&) · M. A. Morgan · P. Ivanyi ·
M. Fenner · A. Ganser · V. Grünwald
Department of Hematology, Hemostasis,
Oncology, and Stem Cell Transplantation,
Hannover Medical School, Carl-Neuberg-Str. 1,
30625 Hannover, Germany
e-mail: christophreuter@yahoo.com
penia as the most common reversible grade 3/4 toxicity
(41.9/39.5%).
Conclusion These data suggest that weekly docetaxel
plus carboplatin may be an important therapeutic second-
line treatment option for patients with DRPC.
Keywords Docetaxel · Carboplatin · Salvage
chemotherapy · Docetaxel-resistant · Castration-resistant ·
Prostate cancer
Introduction
Castration-resistant prostate cancer (CRPC) is character-
ized by substantial morbidity and mortality. Most patients
receive docetaxel-based regimens as Wrst-line chemother-
apy based on the survival advantage with a median
19.2 months overall survival (OS) for three-weekly doce-
taxel demonstrated in the TAX327 trial [1]. Patients with
CRPC who have progressive disease after Wrst-line doce-
taxel chemotherapy survive only »10–11 months and
many are symptomatic. An increasing number of these
patients receive subsequent therapies resulting in signiW-
cant PSA reduction (¸50%) in 17–24% of patients [2].
Cross-over trials demonstrated that only »6–20% of
patients respond to mitoxantrone after Wrst receiving doce-
taxel [3]. Other older drugs with activity against prostate
cancer include cyclophosphamide, doxorubicin, vincristine,
vinorelbine, and etoposide. There is little information about
the palliative beneWt, eYcacy, and tolerability of these
agents after docetaxel failure [2–6].
Newer drugs currently evaluated for second-line treat-
ment, including the epothilones ixabepilone and patupilone,
pemetrexed, trabectedin, and the oral multikinase inhibitors
sorafenib and sunitinib, appear to have only modest activity
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as second-line treatment in patients with taxane-resistant
CRPC [7–13]. As no second-line agents for patients with
taxane-resistant CRPC are currently approved, salvage che-
motherapy remains an unmet clinical need.
Historically, platinum chemotherapy drugs such as car-
boplatin, oxaliplatin, and satraplatin have been considered
inactive in CRPC [14]. One rationale for using platinum-
based chemotherapy in the management of CRPC is pro-
vided by the potential role of neuroendocrine diVerentiation
during disease progression [14]. Recent data suggest that
carboplatin plus docetaxel is eYcacious in the second-line
therapy of patients with taxane-resistant CRPC [17–21].
However, three-weekly combination of docetaxel plus car-
boplatin (q3w) resulted in modest additional activity and
high withdrawal rates, suggesting that the optimal DC ther-
apy regimen is still unclear [17, 18]. Here, we report our
experience using carboplatin (AUC5 on d1) in combination
with weekly docetaxel (35 mg/m2 on d1, 8, (15), intrave-
nously iv q4w) as second-line salvage therapy in 43
patients with docetaxel-resistant CRPC.
Patients and methods
Patient selection
Patients had a histologically documented adenocarcinoma
of the prostate with a median Gleason sum of 9 and with
evidence of disease progression while receiving palliative
chemotherapy with at least three cycles docetaxel for cas-
tration-resistant disease to exclude PSA Xare as a bias
source in the selection of patients. Disease progression
under docetaxel chemotherapy (e.g., docetaxel failure/resis-
tance) was deWned according to the Prostate Cancer Work-
ing Group (PCWG2 2007) criteria as: (1) two consecutive
PSA increases of ¸25% and ¸2 g/l above the nadir and/or
(2) progression of measurable disease (RECIST) and/or (3)
appearance of 2 or more new bone lesions [22].
Treatment plan
Since February 2005, 43 consecutive docetaxel-resistant
(DR)PC patients were continuously treated with at least
two cycles of carboplatin AUC5 iv for 30 min on day 1
every 4 weeks (q4w), docetaxel at a dose of 35 mg/m2 iv
for 1 h each on days 1, 8, (15) plus prednisone 2 £ 5 mg/
PO daily after receiving informed consent until disease
progression or occurrence of intolerable adverse eVects.
Standard dexamethasone premedication was used, and
androgen-deprivation therapy with luteinizing hormone-
releasing hormone analog was maintained throughout
treatment. Granulocyte colony-stimulating factor was not
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World J Urol (2010) 28:391–398
routinely used. This retrospective analysis was approved by
the institutional review board of Hannover Medical School.
Evaluations
The pretreatment evaluations included medical history,
physical examination, complete blood cell count, chemistry
proWle, serum PSA level, bone scan, and computed tomog-
raphy. Patients were evaluated for response according to
the PCWG2 and RECIST recommendations by imaging
studies every three cycles (12 weeks). Appearance of two
or more new lesions or disappearance of lesions in bone
scans was deWned as disease progression or improvement,
respectively [22]. PSA levels were measured every 1–3
weeks and post-treatment changes were deWned on the
basis of the degree of change from baseline. Use of pain
medications was monitored by clinician interview. Toxicity
was graded according to the Common Terminology Criteria
for Adverse Events v3.0 (CTCAE).
Statistical analysis
Descriptive statistics (median and range) were used to char-
acterize the population. Binomial conWdence intervals (CIs)
were calculated for PSA response rates (RR). Logistic
regression was used to investigate the associations of
patient and disease characteristics with PSA response. PFS
was calculated as the time from start of DC treatment to the
time of either disease progression (PSA or radiographic
progression, whichever came Wrst) or death. The remaining
patients who did not experience progression or death were
censored at the date they last were known alive. OS was
deWned as the time from start of DC treatment to death or
was censored at the date last known alive. OS and PFS dis-
tributions were estimated by the Kaplan–Meier method,
and comparisons between responders (R) and non-respond-
ers (NR) were performed using the log-rank (Mantel–Cox)
test. PSA response, PFS, and OS were analyzed relative to
various pretreatment/treatment characteristics including
age, performance status, Gleason sum, primary or second-
ary failure toward docetaxel treatment, extraosseous meta-
static lesions (positive versus negative), number of previous
docetaxel-based cycles, hemoglobin (Hb), alkaline phos-
phatase (AP), lactate dehydrogenase (LDH), neuron-
speciWc enolase (NSE), chromogranin A (CgA), PSA at
castration-resistant status (PSA-CR), PSA at docetaxel-
resistant status (PSA-DR), interval from prior docetaxel-
based chemotherapy, and PSA Xare. Cox proportional
hazards regression modeling was used to investigate the
association of patient and disease characteristics with sur-
vival. Wald chi-square P values are reported. Multivariable
modeling implemented forward selection. Only P values
World J Urol (2010) 28:391–398 393

Table 1 Patient characteristics

No. (%) Median (range)
and prior therapy (n = 43)
Patient age (years) 68 (56–77)
ECOG performance status (%) 1 (0–3)
0 9 (20.9)
1 20 (46.5)
2 11 (25.6)
3 4 (9.3)
Gleason score 9 (4–10)
Number of organs involved
1 16 (37.2)
2 17 (39.5)
¸3 11 (25.6)
Sites of disease
Bone 40 (93.0)
Soft tissue 27 (62.8)
Lymph nodes 19 (44.2)
Lung 9 (20.9)
Liver 9 (20.9)
Brain 1 (2.3)
Meningeal 2 (4.7)
Laboratory data at baseline
Hemoglobin (g/dl) 10.9 (7.7–14.4)
PSA (g/l) at diagnosis of docetaxel-resistant status 329 (12.33–11,928)
Alkaline phosphatase (U/l) 208 (34–1,478)
Lactate dehydrogenase (U/l) 328 (166–4,191)
Neuron speciWc enolase (NSE) 13.0 (8–68)
Chromogranin A 42.0 (14–>700)
Cancer pain (%) 30 (69.8)
Requiring non-narcotic medication and/or 18 (41.9)
Requiring narcotic medication 19 (44.2)
Prior therapy
Prostatectomy 17 (39.5)
TUR prostate 9 (20.9)
Radiation therapy (prostate/pelvis) 21 (48.8)
Radiation therapy (bone) 19 (44.2)
Radiation therapy (soft tissue incl. brain) 3 (7.0)
Bisphosphonates 41 (95.3)
Osteonecrosis of jaw (ONJ) 12 (27.9)
Prior hormone therapy
LH-RH analog 41 (95.3)
Surgical castration 2 (4.7)
Antiandrogens (bicalutamide/Xutamide) 41 (95.3)
Ketoconazol/hydrocortisone 2 (4.7)
5-Reductase inhibitor (Wnasteride) 1 (2.3)
Prior estramustine therapy 11 (25.6)
Duration of initial hormone therapy (mo) 27 (8–102)
Prior chemotherapy 1 (1–3)
1 35 (81.4)
2 6 (14.0)

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Table 1 continued
No. (%) Median (range)

¸3 2 (4.7)
Docetaxel/prednisone 39 (90.7)
Docetaxel/estramustine 9 (20.9)
Mitoxantrone/prednisone § etoposide 5 (11.6)
Satraplatin 1 (2.3)
No. of Wrst-line cycles docetaxel 8 (3–34)
Duration of Wrst-line docetaxel chemotherapy (mo) 6 (3–37)
Primary refractory toward docetaxel therapy 20 (46.5)
Secondary failure toward docetaxel therapy 23 (53.5)
Progression before entry
PSA only 10 (23.3)
Objective disease only 1 (2.3)
PSA and objective disease 32 (74.4)
Progression of objective disease 33 (76.7)
Bone 13 (30.2)
Soft tissue 5 (11.6)
Bone + soft tissue 15 (34.9)

of < 0.05 were considered statistically signiWcant for all A

comparisons. 150
Maximal PSA Response
(% from baseline)
100

50
Results 0

-50
Patient characteristics, treatment, and clinical outcomes
-100
Patients 1- 41
B
The patient characteristics are listed in Table 1. After a
Progression-free Survival (%)

100 100
median of 8 courses of Wrst-line chemotherapy with doce-
80 80
taxel for CRPC, a median of 7 consecutive cycles of DC
60 60
salvage chemotherapy (range 2–45, total 405) were contin-
40 40
uously administered to each of the 43 docetaxel-resistant
20 20
patients. Reasons for stopping DC treatment were progres-
sive disease (PD) in 31 patients (72.1%) and early death 0 0
0 10 20 30 40 0 10 20 30 40
(<30 days) due to PD in 2 patients. Decline of PSA Time (months)
level ¸ 50% (=PSA response, PSAR) from baseline values C
100 100
Overall Survival (%)

was observed in 22/43 patients (51.2%, 95% CI, 35.5–66.7)

80 80
including PSA reduction ¸ 90% in 12 patients (Fig. 1;
60 60
Table 2). PSA non-response (PSANR) was observed in 21
40 40
patients including 2 early deaths (<30 days after DC) due to
20 20
disease progression. In 8/12 patients with a maximal PSA
0 0
response ¸90%, a PSA decline ¸50% was observed after
0 10 20 30 40 50 0 10 20 30 40 50
the Wrst DC cycle. In 15/22 PSAR, maximal PSA response Time (months)
(PSA nadir) was observed ·200 days after initiating DC
Fig. 1 PSA response (¸50% decline from baseline), progression-free
treatment (not shown). PSA Xare phenomenon after start of
survival (PFS), and overall survival (OS) (n = 43). a Waterfall plot
DC treatment was observed in 13 patients (median increase showing maximal prostate-speciWc antigen (PSA) post-therapy change
28.2%, range 4.4–60.6%; 8 PSAR and 5 PSANR). (%) from baseline (n = 41; Note: two patients died early). b PFS for all
Six patients died before staging of objective disease at patients (left), PSA responders (PSAR) (black line), and PSA non-
responders (PSANR) (gray line) (right). At the time of the current analy-
12 weeks after start of treatment due to disease progression.
sis, 33/43 patients had events. c OS for all patients (left), PSA responders
Of the remaining 21 patients with measureable disease, 8 (PSAR) (black line), and PSA non-responders (PSANR) (gray line)
patients exhibited partial remission (PR, all PSAR), 9 (right). At the time of the current analysis, 28/43 patients had died

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Table 2 Clinical outcome

No. (%)
(n = 43)
PSA response (change from baseline)
Not evaluable due to early death (PD) 2 (4.6)
PSA non-response (PSANR, <50%) 19 (44.2)
PSA response (PSAR, ¸50%) 22 (51.2)
Response of objective disease
Death due to PD before staging 6 (14.0)
Measurable extraosseous disease (RECIST) 27/43 (62.8%)
Evaluable for response 21 (100%)
PR 8/21 (38%, all PSAR)
SD 9/21 (42.9%, 6 PSAR)
PD 4/21 (19%, all PSANR)
Osseous disease (PCWG2) 40/43 (93%)
Evaluable for response 35 (100%)
No new lesions 29/35 (82.9%, 21 PSAR)
Including 4 improvements
¸2 new lesions (PD) 6/35 (17.1%, all PSANR)
Months (95% CI) Hazard ratio (HR) P

Overall survival (OS) and progression-free survival (PFS)

Median follow-up 10.4 (9.9, 16.1)
PFS
All 6.5 (4.1, 8.9)
PSAR 9.5 (8.2, 19.0)
PSANR 3.3 (2.6, 4.0) 0.108 <0.0001
P values were obtained from OS
univariable logistic regression All 15.8 (12.1, 18.5)
(PSA response) or Cox propor- PSAR 24.4 (19.5, 29.4)
tional hazards regression (PFS
PSANR 7.8 (5.2, 10.3) 0.232 0.001
and OS)

showed stable disease (SD) (6 PSAR), and 4 showed PD
(all PSANR) (Table 2). Of the remaining 35 patients with
bone metastasis at baseline, four patients showed an
improvement (all PSAR), 25 patients no change (17 PSAR
and 8 PSANR) and six showed disease progression (all
PSANR) (Table 2).
The median follow-up time was 10.4 months, median
PFS was 6.5 months (95% CI 4.1, 8.9), and median OS was
15.8 months (95% CI 12.1, 18.5) (Fig. 1; Table 2). At anal-
ysis, 28 patients had died due to PD (11 PSAR and 17
PSANR), 4 had PD disease and 11 patients continued DC
treatment without PD. PFS and OS were signiWcantly
longer in PSAR (9.5 months; 95% CI 8.2, 19.0) vs.
3.3 months (95% CI 2.6, 4.0) months, P < 0.0001, HR
0.108, and 24.4 months (95% CI 19.5, 29.4) vs. 7.8 months
(95% CI 5.2, 10.3) months, P = 0.001, HR 0.232, respec-
tively) (Table 2; Fig. 1).
In univariate analyses, lower LDH, lower NSE, lower
Gleason sum, and onycholysis were associated with PSA
response. NSE, higher Hb, lower LDH, lower PSA-CR, and
PSA response were associated with PFS and OS. Further-
more, lower NSE, lower PSA-DR, PSA Xare, prostatec-
tomy and absence of measurable disease and TUR prostate
were associated with OS (Table 3). In multivariable analy-
ses, lower Gleason sum and onycholysis remained statisti-
cally signiWcant for the PSA response (each P < 0.05).
Furthermore, low PSA-CR, LDH, and PSA response
remained statistically signiWcant for PFS and lower NSE,
PSA-CR, PSA-DR, PSA response, and absence of extraos-
seous metastasis for OS (Table 3). In contrast, ECOG
score, pain, body mass index, age, and chromogranin A
level were not associated with PSA response, PFS, or OS.
Adverse events
No patient discontinued treatment because of toxicity
(Table 4). However, dose reductions by omission of d8 and/
or d15 docetaxel were common (in 193 cycles, 47.7%) and

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Table 3 Association of patient and disease characteristics with PSA Table 4 Major toxicities (n = 43)
response, PFS, and OS
Grades 1 + 2 Grades 3 + 4 Total
Characteristic HR (95% CI) P
No. (%) No. (%) No. (%)
PSA response
Hematologic
LDH >400 U/l 6.90 (1.70;27.7) P = 0.007
Anemia 33 (76.7) 9 (20.9) 42 (97.7)
NSE >20 g/l 4.76 (1.12;20.0) P = 0.034
Leukopenia 18 (41.9) 18 (41.9) 33 (83.7)
Gleason sum ·8* 0.14 (0.02;0.78) P = 0.025
Neutropenia 8 (18.6) 17 (39.5) 25 (58.1)
Onycholysis* 0.14 (0.03;0.61) P = 0.006
Thrombocytopenia 23 (53.5) 10 (23.3) 32 (76.7)
PFS
Febrile neutropenia – 0 0
Hb >10.5 mg/dl 0.327 (0.15; 0.71) P = 0.005
Transfusions 26 (60.5)
LDH* 1.001 (1.0; 1.002) P = 0.001
Non-Hematologic
LDH >400 U/l 2.89 (1.41; 5.94) P = 0.004
Fatigue/asthenia 28 (65.1) 1 (2.3) 29 (67.4)
NSE 1.03 (1.01;1.06) P = 0.014
Neurologic 18 (41.9) 0 18 (41.9)
PSA response ¸50%* 0.08 (0.03; 0.22) P < 0.001
Dyspnea 18 (41.9) 0 18 (41.9)
PSA (CR) >100 g/l* 2.13 (1.02; 4.46) P = 0.045
Nausea/anorexia 15 (34.9) 0 15 (34.9)
OS
Nail changes 15 (34.9) 0 15 (34.9)
Hemoglobin 0.69 (0.48; 1.00) P = 0.05
Constipation 6 (14.0) 0 6 (14.0)
Hb >10.5 mg/dl 0.33 (0.15; 0.73) P = 0.007
Thrombosis/embolism 0 6 (14.0) 6 (14.0)
LDH 1.001 (1.0; 1.002) P < 0.001
Infection 0 4 (9.3) 4 (9.3)
NSE 1.05 (1.02; 1.08) P < 0.001
Dysuria 2 (4.7) 2 (4.7) 4 (9.3)
NSE >20 g/l* 15.14 (1.40;164.2) P = 0.025
Bleeding 0 1 (2.3) 1 (2.3)
PSA response ¸50%* 0.20 (0.07; 0.52) P = 0.001
Hyperglycemia 0 1 (2.3) 1 (2.3)
PSA (CR) >100 g/l* 3.43 (1.44; 8.20) P = 0.006
Syncope – 1 (2.3) 1 (2.3)
PSA (DR) >100g/l* 4.92 (1.67; 14.51) P = 0.004
Carboplatin allergy – 1 (2.3) 1 (2.3)
PSA Xare 0.36 (0134;0.963) P = 0.042
Pleural eVusion 1 (2.3) 0 1 (2.3)
Measurable disease* 2.28 (1.00; 5.18) P = 0.049
Therapy-related deaths – – 0
Prostatectomy 0.36 (0.16;0.83) P = 0.017
Osteonecrosis 0 12/41 (29.3) 12/41(29.3)
TUR prostate 2.64 (1.05; 6.67) P = 0.04 of jaw (ONJ)*
P values were obtained from univariable logistic regression (PSA * Osteonecrosis of jaw was observed in 12 of 41 patients treated with
response) or Cox proportional hazards regression (PFS and OS). bisphosphonates (zoledronate); ONJ occurred before (n = 5) and dur-
Variables that were conWrmed in multivariable analyses with P
ing DC treatment (n = 7)
values < 0.05 are marked with *

mainly due to hematotoxicity. Delays or interruptions of Discussion

the continuous DC regimen were due to chemotherapy holi-
day (n = 3), surgery (n = 3) or toxicity (n = 2).
Hematologic grade 3/4 toxicities included leukopenia/
neutropenia (41.9/39.5%), anemia (20.9%), and thrombo-
cytopenia (23.3%). Of 43 patients, 26 received blood trans-
fusions. Non-hematologic grade 3/4 toxicities included
thrombosis/embolism (6/43; 14%), infection (4/43; 9.3%),
dysuria (2/43; 4.7%), bleeding, syncope, and hyperglyce-
mia (each 1/43; 2.3%). As docetaxel-induced onycholysis
were common (15/43 patients), frozen hypothermia socks
and gloves (Elasto-Gel™, Velo-Medizinprodukte, Germany)
were subsequently oVered to all patients to reduce the
incidence of these toxicities [23]. Osteonecrosis of the jaw
(ONJ) was observed in 12/41 patients receiving zoledronate
treatment (9 PSAR and 3 PSANR; 29.2%). In 7 cases, ONJ
occurred under DC treatment.
Docetaxel represents an eVective anticancer drug for
CRPC. However, the majority of patients discontinue Wrst-
line treatment with docetaxel because of progressive dis-
ease or unacceptable side eVects. Treatment options for
patients with DRPC are limited. Only a small number of
retrospective or prospective trials with second-line treat-
ment of patients with DRPC have been reported to date.
Several lines of evidence suggest that carboplatin, which
has only moderate activity as a single agent in CRPC, pro-
vides additional beneWt when combined with taxanes in
chemotherapy-naïve CRPC as Wrst-line [16] or as second-
line [17–21] treatment in DRPC. For example, a pooled
analysis of seven prospective clinical trials of carboplatin–
taxane combinations as Wrst-line chemotherapy in CRPC
demonstrated signiWcant clinical activity with a PSA

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response rate (RR) of 69% (95% CI 56–80%) and a pooled
12-month survival estimate of 79% (95% CI 71–84%) [16].
Furthermore, the double-blind, randomized, placebo-
controlled SPARC (satraplatin and prednisone against
refractory cancer) phase III trial with 950 patients who
failed prior chemotherapy (including docetaxel) showed
33% improvement in PFS (11.1 vs. 9.7 weeks, HR 0.67,
95% CI 0.57–0.77). Additionally, a signiWcant improve-
ment in pain, tumor, and PSA-RR was reported [2, 15].
Satraplatin did not improve OS, and the manufacturer sub-
sequently withdrew the FDA application in July 2007.
A phase II trial of second-line DC in patients with DRPC
demonstrated only limited clinical activity with 18% PSA-
RR, 3 months median PFS, 12.4 months median OS and a
high withdrawal rate [18]. Similar results were reported in a
retrospective analysis of three-weekly DC in patients with
DRPC [17]. In both studies, DC was given on a 3–4 week
schedule (e.g., carboplatin AUC4-6 plus docetaxel 50–
70 mg/m2 i.v. q3w). The limited eYcacy of DC q3w sug-
gests that the optimal DC dosage and regimen is still
unclear. The q3w DC regimen has some disadvantages: (1)
administration of DC dosage on 1 day requires dose reduc-
tions for either docetaxel or carboplatin or both; (2) a 1-day
regimen might cause higher grades of hematotoxicity; and
(3) might be disadvantageous in the case of high tumor cell
growth.
In order to limit hematopoietic toxicity, we applied
carboplatin AUC5 in combination with weekly docetaxel
35 mg/m2 d1, 8, (15) q4w in a dose-dense approach. Taxane
eYcacy can be increased and the risk of neutropenia
reduced by adapting dose-dense drug administration sched-
ules [24]. Our regimen was very active (PSA-RR > 50%)
and reasonably well tolerated in these heavily pretreated
patients. The most common and limiting toxicity was
hematotoxicity with 41.9/39.5% grade 3/4 leukopenia/neu-
tropenia, a rate similar to the 58.8/26.5% reported in the
second-line DC q3w phase II trial and the 32% grade 3/4
neutropenia in the TAX327 trial [1, 18]. Febrile neutrope-
nia was not observed, but more than half (26/43) of the
patients required one or more blood transfusions for ane-
mia. In contrast to the phase II DC trial [18] which had 17%
withdrawal because of fatigue, we observed no withdrawal
from treatment, although fatigue was common (26/42
patients). A high incidence of bisphosphonate-induced ONJ
was observed in our study after a median treatment time of
25 months (12/41, 29.3%), especially in PSAR (9/12 ONJ),
suggesting that ONJ may be more common in PC than pre-
viously reported (6–15%). ONJ occurs after 6–60 months
of bisphosphonate treatment usually after teeth extractions
and is associated with duration of therapy, presence of
metastasis (odds ratio of 27) and zoledronate use (odds
ratio of 32) [25]. These factors were all present in our
patient population and thus might explain our Wnding. Five
397
cases occurred before and 7 cases while receiving DC treat-
ment, suggesting that ONJ was not directly linked to the
DC regimen. However, two patients showed an ONJ
relapse after resuming zoledronate treatment following a
pause during the Wrst ONJ.
Median PFS for all patients was 6.5 months and median
OS 15.8 months and thus superior to most reported second-
line regimens [3–13, 15, 17–21]. In PSAR median PFS and
OS were even longer. Furthermore, some established prog-
nostic factors were associated with survival [1, 16]. The
mechanisms of the clinical synergy between docetaxel/car-
boplatin in this weekly regimen in DRPC are unclear. Plati-
num compounds display moderate in vitro cytotoxicity
against prostate carcinoma cells with IC50 values in the
micromolar range [26–29]. In vitro assessment of cytotoxic
agent combinations for CRPC treatment demonstrated
antagonistic eVects of taxane–platinum combinations in
human CRPC cell lines [26, 27]. Furthermore, docetaxel-
resistant PC cell lines demonstrated slight cross-resistance
with carboplatin [29]. However, recent in vitro data suggest
that platinum may be beneWcial in CRPC due to interfer-
ence with testicular steroid biosynthesis [30]. In conclu-
sion, treatment with carboplatin plus weekly docetaxel is a
reasonably well tolerated and active regimen in DRPC and
may be an important therapeutic option for these patients.
ConXict of interest statement None declared.
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