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Asia-Pacific Journal of Clinical Oncology 2016
doi: 10.1111/ajco.12583
ORIGINAL ARTICLE
Efficacy of metronomic oral cyclophosphamide with low dose
dexamethasone and celecoxib in metastatic
castration-resistant prostate cancer
Yumun JEONG1 and Jae Lyun LEE1,2
1
Departments of Medicine, and 2 Oncology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea
Abstract
Aim: This study aimed to assess the efficacy and safety of oral metronomic chemotherapy in patients with
metastatic castration-resistant prostate cancer (mCRPC).
Methods: From January 2011 to February 2013, 60 patients with mCRPC received daily metronomic oral
cyclophosphamide (50 mg qd), dexamethasone (1 mg qd) and celecoxib (200 mg bid). Among them 49 patients who met the preset inclusion criteria were included in this retrospective study. Adverse events and
activity for reducing serum prostate-specific antigen (PSA) levels, Response Evaluation Criteria in Solid Tumor responses and symptomatic responses were reviewed. The primary endpoints were PSA response rate
and time to PSA progression (TTPSA).
Results: Twenty-two patients had previous exposure to docetaxel. The median age was 71 years (range, 49–
88) with a median Eastern Cooperative Oncology Group performance of 1 (range, 0–2). The Gleason score
was 8 or more in 41 patients (84%) with a median baseline serum PSA of 32.1 ng/mL (range, 1.2–743.0).
The PSA response rate was 39%. With a median follow-duration of 17.5 months, the median TTPSA was 5.2
months (95% CI: 3.1–7.4). The median time to composite progression was 3.9 months (95% CI: 2.2–5.6) and
a median overall survival was 13.3 months (95% CI: 9.5–17.1 months). There were no significant differences
in the TTPSA between the pre- and post-docetaxel groups. Grade 3–4 AEs occurred only in six patients.
Conclusion: Metronomic oral cyclophosphamide chemotherapy is safe, well-tolerated and shows promising
activity against mCRPC.
Key words: castration-resistant prostate cancer, celecoxib, cyclophosphamide, dexamethasone, metronomic
INTRODUCTION
Prostate cancer is the most common type of cancer in men in the western world and is the second
leading cause of cancer deaths in men.1 Currently,
the incidence of prostate cancer in Asian populations, including Koreans, is increasing rapidly.2 The
basis of treatment for metastatic prostate cancer is androgen deprivation. Most patients benefit from horCorrespondence: Jae Lyun Lee, MD, PhD, Department of
Oncology, Asan Medical Center, University of Ulsan College of
Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505,
South Korea. Email: [email protected]
Conflicts of interest: none
Accepted for publication 20 June 2016.
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monal manipulation, but eventually become resistant and
develop metastatic castration-resistant prostate cancer
(mCRPC). Docetaxel-based chemotherapy represents the
standard first-line treatment in mCRPC after the confirmation of a survival benefit for this drug in two large randomized trials.3 Although the effectiveness of docetaxel
is well established, it is not long lasting and nearly all
patients experience disease progression with a median
of 6–8 months.4–6
Cabazitaxel in combination with prednisone significantly prolonged the time to progression and overall survival compared to mitoxantrone and prednisone in the
TROPIC trial.7 However, in clinical practice, hematologic toxicity and the risk of life-threatening infection
were major concerns, especially in ethnic Asian patients.
In a study of Korean patients, the incidence of febrile
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Y Jeong and JL Lee
neutropenia was 31%, and the treatment-related death
rate was 5%, which was mainly associated with severe
infection.3 Abiraterone (with prednisone) and enzalutamide improved survival in patients with mCRPC who
have previously received docetaxel.8 Abiraterone (with
prednisone) and enzalutamide also showed superiority
over prednisone alone or a placebo, respectively, improving overall survival, PSA progression, time to clinical deterioration and time to the initiation of cytotoxic
chemotherapy in patients who had not received previous
chemotherapy.8 The United States Food and Drug Administration has approved abiraterone and enzalutamide
as first-line therapies for mCRPC since 2012 and 2014,
respectively. Nevertheless, the high-cost combined with
the limited funding structure of the National Health Insurance System (NHIS) in Korea and the eventual progression that occurs because of resistance to these agents
are challenges in clinical practice.
Metronomic chemotherapy is rhythmic, typically involving the daily administration of oral agents at doses
significantly lower than the maximum-tolerated dose,
with minimal or no drug-free intervals, over an extended
period of time.9 Recent studies showed that metronomic
chemotherapy with oral cyclophosphamide plus a variety of agents (e.g. prednisone, celecoxib, dexamethasone, methotrexate, uracil with tegafur or capecitabine)
showed significant effectiveness, as assessed by the kinetics of prostate-specific antigen (PSA) levels and pain
control without significant toxicity,10–19 even in heavily
pretreated patients.11,12,14,18 Thus, low-dose metronomic
cyclophosphamide may have the potential to be used as
an alternative therapeutic option in mCRPC, especially
in situation when accessibility to newer agents is limited. Among various regimen, triple combination of cyclophosphamide, celecoxib and dexamethasone, reported
in 2010, had shown best activity in terms of PSA response
and time to progression,14 and we started to employ this
regimen in clinical practice since 2011 for patients who
could not have an access to newer agents.
The current study aimed to evaluate the clinical efficacy
and tolerance of metronomic oral cyclophosphamide
with celecoxib and dexamethasone in Korean patients
with mCRPC.
METHODS
Patients evaluated in this study and
treatment protocol
From January 2011 to February 2013, 60 patients
with mCRPC received metronomic chemotherapy, which
consisted of oral cyclophosphamide (50 mg daily),
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dexamethasone (1 mg daily) and celecoxib (200 mg
twice daily) at the Asan Medical Center, Seoul, Korea.
Predetermined eligibility criteria were as follows: (i) histological diagnosis of adenocarcinoma of the prostate
with clinical or radiological evidence of metastatic disease; (ii) documented CRPC, indicated by two consecutive increases in serum PSA levels with at least 1-week
intervals and ongoing castrated levels of serum testosterone ࣘ50 ng/dL during hormonal treatment; (iii) a minimum of a 4- or 8-week lapse between the withdrawal
of flutamide or bicalutamide, respectively, to avoid the
possibility of antiandrogen withdrawal phenomenon; (iv)
Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; (v) PSA levels ࣙ2.0 ng/mL; (vi)
no evidence of CNS metastases; and (vii) no serious or
uncontrolled concomitant medical or psychological illnesses. Patients were excluded from analysis if they prematurely discontinued treatment without objective evidence of disease progression or intolerable toxicities or
if they had another active cancer that was being treated.
This study was reviewed and approved by the Asan Medical Center Institutional Review Boards, which waived the
informed consent due to the retrospective nature of study
design.
Response criteria and toxicity assessments
All medical records, and laboratory and imaging findings were retrospectively reviewed to evaluate the activity of treatment on serum PSA level reductions, soft tissue response with modified Response Evaluation Criteria
in Solid Tumor (RECIST), pain responses evaluated using a numeric rating scale (NRS), and assessments of adverse events. Patient appointments were scheduled every
4 weeks for the first 3 months and every 6 weeks thereafter; laboratory monitoring, including CBC, chemistry,
electrolytes and PSA, was performed upon each visit. For
those patients with measurable lesions on CT or bone
metastases on baseline bone scans, no fixed intervals were
applied, but a follow-up CT and bone scan was usually
carried out every 12 weeks or if clinical signs of disease progression developed. Lesions were evaluated based
on the guidelines of the Prostate Cancer Clinical Trials
Working Group 2 (PCWG2).20 Adverse events were reassessed using the National Cancer Institute Common
Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0).
Endpoints
The primary endpoints were the PSA response rate and
time to PSA progression (TTPSA) in all eligible patients
Asia-Pac J Clin Oncol 2016
3
Metronomic therapy for CRPC
Figure 1 A waterfall plot of the
percentage changes in PSA from
baseline. Maximum reduction (a)
and the reduction at 12 weeks (b)
from baseline following metronomic
chemotherapy. The area marked
with the dotted line shows patients
who discontinued treatment before
12 weeks because of adverse events
or disease progression.
and separately in pre-docetaxel and post-docetaxel setting. The PSA response was defined according to the
guidelines of the PCWG1,20 namely a ࣙ50% reduction
from the baseline PSA level on two consecutive tests.
PSA progression was defined as a ࣙ25% increase from
the nadir (confirmed by a second value obtained 2–3
weeks later). When no significant reduction from baseline was documented, PSA progression was defined as a
ࣙ25% confirmed increase from the baseline value. The
Asia-Pac J Clin Oncol 2016
secondary endpoint was to document the pain response,
adverse events, time to composite progression (TTP) and
OS. The pain response was defined as a reduction in NRS
score ࣙ2 on two consecutive assessments at least 2 weeks
apart. Composite progression was defined as the occurrence of one or more of the following criteria according
to PCWG2: PSA progression, progression of soft tissue
disease per modified RECIST, disease progression on a
bone scan (defined as the appearance of two or more le-
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Y Jeong and JL Lee
sions attributable to prostate cancer), a skeletal event (defined as a fracture or bone pain resulting in the need for
radiotherapy or surgery) or symptomatic progression (defined as a worsening of ECOG performance status and/or
increased pain).
Statistical analysis
Descriptive statistics were used to analyze patient characteristics (mean, median and 95% confidence intervals).
Time-to-event variables, such as TTPSA, TTP and OS,
were calculated using the Kaplan–Meier method. Quantitative variables were compared using the Student t-test,
and categorical variables were analyzed using the chisquare or Fisher’s exact test, as appropriate. All statistical analyses were performed using PASW statistics (version 18; IBM Co., Armonk, NY), and two-sided p value
<0.05 was considered statistically significant.
RESULTS
Patient characteristics and previous
treatments
A total of 49 patients fulfilled the eligibility criteria and
were included in this analysis. There were six patients
who prematurely discontinued treatment without objective evidence of disease progression or intolerable toxicities. There was one patient who was treated for another
active cancer and four patients who were lost to followup after treatment with no information on activity or
toxicities. Patient characteristics at baseline are listed in
Table 1. The median age was 71 years (range, 49–88) with
a median ECOG performance status of 1. The Gleason
score was 8 or more in 41 patients (84%), and the median baseline serum PSA level was 32.1 ng/mL (range,
2.1–743.0). Most patients (78%) had concomitant diseases (median age-adjusted Charlson Comorbidity Index
of 4).21 There were 16 patients who had visceral organ
involvement. A total of 31 patients (63%) had previous exposure to chemotherapeutic drug(s), and 22 (45%)
patients had received docetaxel-based regimens—a median of eight cycles were administered. Among patients
who stopped docetaxel, 12 patients stopped because of
progression and 10 patients stopped because of adverse
events. Finally, 14 patients (29%) received two or more
lines of chemotherapy, including docetaxel. No one had
prior exposure to abiraterone or enzalutamide.
Efficacy
Efficacy results were detailed in Table 2. The PSA response rate was 39% (95% CI: 25–52). Waterfall plots
show the maximal and initial PSA changes (during the
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Table 1 Baseline patient characteristics (n = 49)
Characteristics
No. (%)
Median age, years (range)
ECOG performance status
0
1
2
Gleason score ࣙ8
Serum PSA, median (ng/mL, range)
Site of metastasis
Bone
Lymph node
Lung
Liver
Presence of pain
Mild, NRS 1–3
Moderate, NRS 4–6
Severe, NRS 7–10
Anemia
Alkaline phosphatase, median (IU/L,
range)
Lactate dehydrogenage, median (IU/L,
range)
Prior secondary hormonal agents
(excluding abiraterone and
enzalutamide)
Bicalutamide
Flutamide
Cyproterone acetate
Ketoconazole
Prior chemotherapy
Docetexel
Estramustine
Cabazitaxel
Mitoxantrone
Median cumulative dose of docetaxel,
mg/m2 (range)
Prior palliative radiotherapy
Type of progression
PSA progression, n (%)
RECIST progression, n (%)
Bone scan progression, n (%)
Symptomatic progression, n (%)
71 (49–88)
12 (25%)
35 (71%)
2 (4%)
41 (84%)
32.1 (2.1–743.0)
47 (96%)
18 (37%)
12 (25%)
5 (10%)
26 (53%)
14 (29%)
10 (20%)
2 (4%)
37 (76%)
104 (35–812)
214 (88–658)
49 (100%)
25(51%)
19 (39%)
12 (25%)
31 (63%)
22 (45%)
16 (33%)
7 (14%)
2 (4%)
600 (75–1350)
8 (16%)
46 (94%)
11 (22%)
14 (29%)
8 (16%)
ECOG, Eastern Cooperative Oncology Group; NRS, numeric rating
scale; PSA, prostate-specific antigen.
first 12 weeks after starting treatment) from the baseline
PSA levels (Fig. 1). The PSA response rates were not significantly different between the pre- and post-docetaxel
groups (41% vs 36%, P = 0.771). The RECIST responses were evaluated in 20 patients with measurable
disease. One patient achieved a complete response and
another patient achieved a partial response. There were
Asia-Pac J Clin Oncol 2016
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Metronomic therapy for CRPC
Table 2 Efficacy of oral metronomic chemotherapy
Response criterion
Result
Treatment duration, median (months)
5.7
PSA response, n (%)
19 (39%)
Pre-docetaxel group (n = 27)
11 (41%)
Post-docetaxel group (n = 22)
8 (36%)
RECIST response, n (%)
2 (10%)
Complete response
1 (5%)†
Partial response
1 (5%)†
Stable disease
13 (65%)†
Progressive disease
5 (25%)†
TTPSA, median (months)
5.2
Pre-docetaxel group
5.5
Post-docetaxel group
4.9
OS, median (months)
13.3
Pre-docetaxel group
15.0
Post-docetaxel group
9.7
TTP, median (months)
3.9
Pain response, n (%)
10 (42%)‡
95% CI
4.3–7.1
25–52
0–23
3.1–7.4
3.2–8.9
2.8–6.9
9.5–17.1
14.1–15.9
7.5–11.8
2.2–5.6
22–61
95% CI, 95% confidence interval; OS, overall survival; PSA, prostatespecific antigen; TTP, time to composite progression; TTPSA, time to
PSA progression.
†
Out of 20 patients who had measurable lesion(s) and evaluable followup CT scan during treatment.
‡
Out of 24 patients who had pain and an assessable recording of the
serial NRS score during treatment.
13 patients (65%) who achieved stable disease and five
patients (25%) who demonstrated progressive disease as
the best response. With a median follow-up duration of
17.5 months (95% CI: 12.2–22.9), the median treatment
duration was 5.7 months (95% CI: 4.3–7.1). The median
TTPSA was 5.2 months (95% CI: 3.1–7.4), and the median composite TTP was 3.9 months (95% CI: 2.2–5.6)
with a median OS of 13.3 months (95% CI: 9.5–17.1;
Fig. 2). There was no significant difference in the TTPSA
between the pre- and post-docetaxel groups. The median
TTPSA was 5.5 months (95% CI: 3.2–8.9) in the predocetaxel group versus 4.9 months (95% CI: 2.8–6.9) in
the post-docetaxel group (P = 0.591; Fig. 3). However,
as expected, the overall survival was significantly longer
in the pre-docetaxel group (15.0 vs 7.9 months, P =
0.024). There were 26 patients who had bone pain before
treatment, and among them 24 had an assessable recording of pain levels during treatment; 10 of these 24 patients (42%) achieved a pain response. After disease progression, 27 patients (55%) received other chemotherapy
regimens.
Toxicity profiles
Clinically significant (CTCAE 4.0 grade 3 or greater), AEs
only occurred in six patients (12%; including cases of
Asia-Pac J Clin Oncol 2016
Figure 2 Time to PSA progression (a) and overall survival (b).
anemia [2], thrombocytopenia [2], nausea/vomiting [1],
asthenia [1] and abdominal pain [1], Table S1). Although
grades 3 and 4 anemia and thrombocytopenia occurred,
they seemed to be related to myelophthisic anemia resulting from extensive bone marrow metastases, that is,
disease per se, based on peripheral blood smears and
responses to transfusion, rather than metronomic agents.
Therefore, none of these patients required dose reduction
or modification of cyclophosphamide because of toxicities. A total of six patients required dexamethasone dose
reduction (to a half dose) because of peripheral edema or
minor infections (such as cellulitis or otitis media).
DISCUSSION
In our present study, metronomic oral cyclophosphamide
plus low-dose dexamethasone and celecoxib resulted in
notable activity with minimal toxicity. The PSA response
rate was 39% with a median TTPSA of 5.2 months,
and no patients required dose reduction or dose delay
of cyclophosphamide. Although indirect comparison of
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Figure 3 Time to PSA progression (a) and overall survival (b)
in the pre- versus post-docetaxel groups.
different studies is not recommended, our results are comparable with those studies that administered metronomic
chemotherapy with oral cyclophosphamide.10–13,15–19
As shown in Table S2, previous studies included a variety of agents along with oral cyclophosphamide, and
had small sample sizes, which usually used retrospective
analysis on heterogeneous patients’ population. Nevertheless, the efficacies of metronomic cyclophosphamide
combination regimens have been consistently reported to
be favorable. When restricted to a regimen of cyclophosphamide plus corticosteroid and celecoxib, similar to our
study, the PSA response rate, median TTPSA and OS
were 45%, 7.7 months and 19.7 months, respectively.14
Slightly shorter survival outcomes in the current study cohort might be explained by the more advanced stage of
disease, represented by the higher frequency of exposure
to prior chemotherapy (63% vs 34% for any cytotoxic
chemotherapy and 45% vs 31% for prior docetaxel) and
visceral metastasis (35% vs 7%). Although 32% of patients in the post-docetaxel group previously received
cabazitaxel and 9% had received mitoxantrone, the efficacy of metronomic therapy, in terms of the PSA response
and TTPSA, was comparable to that of cabazitaxel (39%,
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6.4 months) and was even better than those of mitoxantrone (18%, 3.1 months), which were reported in the
TROPIC study. Similarly, the PSA response and TTPSA
of the current regimen in the post-docetaxel group were
also comparable to those of abiraterone phase II study,
which didn’t exclude patients with prior exposure to ketoconazole (36%, 5.6 months).22
Generally, the outcomes of subsequent therapy are affected by a prior therapy, especially when the mechanism of action of the subsequent agents is at least partially related to that of the prior agents. For example,
abiraterone showed only a modest response and a brief
duration of effect after docetaxel and enzalutamide.23,24
Enzalutamide also showed limited activity in patients
with mCRPC who previously received docetaxel and
abiraterone.25 Similarly, second-line treatment with mitoxantrone after first-line docetaxel has shown only modest activity; the PSA response rates ranged from 9.8%
to 18.0% and were associated with a TTPSA of 1.4–
3.2 months.7,26 Interestingly, the activity of metronomic
oral cyclophosphamide did not differ between patients
with prior exposure to docetaxel and docetaxel-naive
patients. Indeed, patients in the post-docetaxel group
had already been heavily treated; 14 (64%) of 22 patients had previously been exposed to two or more
lines of chemotherapy, such as mitoxantrone, etoposide
or cabazitaxel, after failure to respond to docetaxel.
However, in the pre-docetaxel group, only 9 (33%) of
27 patients had previous exposure to estramustine. Our
study showed that oral metronomic cyclophosphamide
might have comparable activity, as indicated by the PSA
response and TTPSA, to those of prior studies, even in
patients who failed prior docetaxel or other subsequent
cytotoxic chemotherapies.
In terms of toxicity profiles, this combination regimen
was highly tolerable and lacked serious adverse events.
Dose interruptions or modifications were not required
for cyclophosphamide. This favorable toxicity profile is
in accord with the previously reported well-known tolerability of metronomic therapy, even in elderly, heavily
treated and unfit patients.13,14,18,19 However, edema and infections were problematic, as six patients required dexamethasone dose reduction because of peripheral edema,
and at least temporary dose interruption was required
in three patients because of infections, such as cellulitis
or upper respiratory infections. Additionally, one patient
discontinued celecoxib because of epigastric soreness.
Although the exact mechanism remains to be defined,
the metronomic administration of cyclophosphamide
has been associated with antiangiogenic effects,9 and
immune-stimulation by reducing circulating regulatory T
Asia-Pac J Clin Oncol 2016
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Metronomic therapy for CRPC
cells and promoting natural killer cell cytotoxicity.27 In
accord with recently reported promising results of tests of
antianginogenic agents (e.g. cabozantinib) and immunestimulating agents (e.g. ipilimumab), metronomic oral
cyclophosphamide, which targets both angiogenesis and
immunity, warrants further investigation in mCRPC.8
The concurrent use of dexamethasone or celecoxib
contributed to the antitumor response and in part to managing pain control. The high pain response rate (42%)
indicates the palliative role of this combination. Celecoxib showed suppressive effects in vitro on androgen receptor expression, angiogenesis and prostate cancer cell
proliferation.28 However, in British STAMPEDE study,29
celecoxib failed to show meaningful benefit in terms of
failure-free survival in patients with hormone-sensitive
prostate cancer. But its effect on CRPC is not fully explored, and further studies are needed to establish an optimal regimen for administering metronomic chemotherapies for various cancers.
In this present study, we observed the limited accessibility of newly approved agents in mCRPC patients. Over
the last 5 years, the available treatments for mCRPC have
expanded significantly because of the approval of several new drugs. Androgen pathway inhibitors, such as
abiraterone and enzalutamide, demonstrate PFS and OS
benefits in mCRPC patients, not only after docetaxel
failure, but also in pre-docetaxel settings.8 Additionally,
radium-223 improves quality of life, prevents clinical
skeletal-related events and prolongs OS.8 Cabazitaxel
also improved PFS and OS in post-docetaxel settings.7
Although these agents have been approved for use in
Korea, none of the costs of these drugs has been reimbursed by the NHIS, which significantly limits their accessibility. In this present study, no patient had an opportunity to receive abiraterone or enzalutamide and patients
could only receive cabazitaxel through the Compassionate Use Program.3 A nationwide discussion about how to
implement affordable cancer care under the pressure of
limited resources is urgently needed. Recently, NHIS decided to reimburse enzalutamide only in post-docetaxel
setting.
There were several notable limitations to this study,
which included a small sample size, nonhomogeneous
disease status, imperfect data collection by retrospective review, the absence of preset radiological reassessments and limited patient-reported outcomes such as pain
responses.
CONCLUSION
Metronomic oral cyclophosphamide could be used as a
viable option in pre- and post-docetaxel settings with the
Asia-Pac J Clin Oncol 2016
advantages of convenient oral administration, a promising response rate and its duration, high tolerability and
a very affordable cost, especially when newer androgen
pathway inhibitors could not be employed. Prospective
randomized trial with potential laboratory biomarker
will be needed to draw firm conclusion on survival benefit
or improvement in quality of life.
ACKNOWLEDGMENTS
Presented in part at 6th European Multidisciplinary
Meeting on Urologic Cancers 13–16 November 2014
in Lisbon, Portugal. This study was supported by a
grant (HI12C1788, HI14C1931, HI14C1731) from the
Korean Health Technology R&D Project, Ministry of
Health and Welfare, Korea.
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SUPPORTING INFORMATION
Additional Supporting Information may be found in the
online version of this article at the publisher’s web-site:
Table S1 Treatment emergent adverse events
Table S2 A review of the literature on metronomic cyclophosphamide chemotherapy in metastatic castrationresistant prostate cancer
Asia-Pac J Clin Oncol 2016