International Journal of Urology (2008) 15, 106–109
`
`doi: 10.1111/j.1442-2042.2007.01929.x,
`
`Short Communication
`
`Combination chemotherapy with weekly docetaxel and
`estramustine for hormone refractory prostate cancer in
`Japanese patients
`Atsushi Takenaka, Yuji Yamada, Toshifumi Kurahashi, Hideo Soga, Hideaki Miyake and Masato Fujisawa
`
`Division of Urology, Department of Organ Therapeutics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chu-ku, Kobe, Japan
`
`Abstract: The aim is to evaluate the efficacy and toxicity of weekly docetaxel and estramustine for Japanese men with hormone refractory
`prostate cancer who were treated at a single institution. Twenty eligible patients had histologically proven adenocarcinoma of the prostate with
`metastases that were progressing despite complete androgen blockade and antiandrogen withdrawal. All of the patients received docetaxel
`30 mg/m2 weekly (days 1, 8, 15, 22, 29, and 36). After a two week break, the treatment schedule was repeated. Patients were scheduled to
`receive daily oral estramustine 560 mg/day throughout the protocol. In the serum prostate specific antigen (PSA) response, three (15%) patients
`achieved a complete response, and 8 (40%) acheived a partial response. Overall survival and time to progression were 13.4 months and
`6.4 months, respectively, however sixty-seven percent of the patients had to discontinue treatment because of toxicity. The high toxicity of this
`protocol suggests that the regimen and/or the timing should be altered for Japanese patients.
`
`Key words: docetaxel, estramustine, hormone-refractory, prostate cancer, toxicity.
`
`Introduction
`
`Prostate cancer is the most commonly diagnosed cancer and the second
`leading cause of cancer-related deaths in men in the US.1 Although the
`incidence is lower in Japan than in the US, it is the most rapidly
`increasing cancer in recent years.2
`For patients with newly diagnosed metastatic prostate cancer, andro-
`gen deprivation therapy is initially effective in most patients. However,
`prostate cancer often becomes hormone independent (hormone refrac-
`tory prostate cancer, HRPC) and progresses after the first or second
`round of endocrine therapy. Recently, the introduction of taxanes has
`led to the development of more effective treatments for HRPC. Doc-
`etaxel (DTX) has been reported to have activity as a single agent and a
`favorable toxicity profile when administered on a low-dose weekly
`schedule.3 On the other hand , estramustine phosphate (EMP), which
`dysregulates normal microtubule assembly, is resulting in cell growth
`inhibition in human prostate cancer cell lines.4 Thus, in an attempt, to
`improve outcome, many trials of combination therapy with taxanes and
`EMP have been performed.
`This protocol combined weekly DTX and EMP for Japanese men
`with HRPC. The aims of this trial were to evaluate the efficacy and
`toxicity of this regimen for Japanese men with HRPC treated at a
`single institution.
`
`Methods
`
`Patient selection
`
`The median time from the first hormone therapy to the start of this
`protocol was 37.2 months (range: 8.1–174.3 months). All prior thera-
`pies had been discontinued for at least 1 month before the first cycle of
`treatment on this protocol. Patients were required to have an Eastern
`Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
`Written informed consent was obtained from all patients as well as
`institutional review board approval.
`
`Study design and treatment
`
`All patients received DTX 30 mg/m2 basically in the outpatient clinic
`by 90-minute intravenous infusion once a week (days 1, 8, 15, 22, 29,
`and 36). After a two week break, the treatment schedule was repeated
`every eight weeks. The median number of treatment courses received
`was 2 (range, 1–9 courses). Dexamethasone 24 mg, diphenhydramine
`50 mg, and ranitidine 50 mg were administered before the DTX infu-
`sion to prevent a hypersensitivity reaction. Patients were scheduled to
`receive daily oral EMP 560 mg/day throughout the protocol. Aspirin
`100 mg/day was administered to prevent thrombosis.
`Toxicity was assessed using the National Cancer Institute – Common
`Toxicity Criteria (Version 2.0). The subsequent therapy was withheld
`until grade 3–4 toxicity had recovered to at least grade 2. EMP was
`reduced in the eight cases due to severe gastrointestinal toxicity.
`Treatment was continued until disease progression, unacceptable
`adverse events or the patient’s refusal occurred.
`
`Outcome assessments
`
`From March 2003 to August 2006, 20 eligible patients had histologi-
`cally proven adenocarcinoma of the prostate with metastases that were
`progressing despite complete androgen blockade therapy and antian-
`drogen withdrawal (Table 1).
`
`Correspondence: Atsushi Takenaka MD, Division of Urology, Department of
`Organ Therapeutics, Kobe University Graduate School of Medicine, 7-5-1
`Kusunoki-cho, Chuo-ku, Kobe, Japan. Email: atake@med.kobe-u.ac.jp
`
`Received 2 July 2007; accepted 24 September 2007.
`
`The serum PSA was measured every two weeks. PSA response criteria
`are defined below. A complete response (CR) required the normaliza-
`tion of the serum PSA (defined as a serum PSA < 4 ng/mL, for patients
`without prior radical prostatectomy, and <1 ng/mL, for those with prior
`radical prostatectomy). A partial response (PR) was defined as a 50% or
`greater reduction but without normalization. Patients were considered
`to have no change (NC) if the PSA levels decreased by <50% or
`increased by <25%. Patients with progressive disease (PD) had an
`increase in the serum PSA concentration of >25% above the baseline
`
`106
`
`© 2008 The Japanese Urological Association
`
`Mylan Laboratories Limited v. Aventis Pharma S.A. IPR2016-00712 MYLAN - EXHIBIT 1046
`
`

`

`DTX and EMP for prostate cancer
`
`a)
`
`0
`
`5
`
`10
`
`15
`
`20
`month
`
`25
`
`30
`
`35
`
`40
`
`b)
`
`0
`
`2
`
`4
`
`6
`
`8
`month
`
`10
`
`12
`
`14
`
`c)
`
`1
`
`.8
`
`.6
`
`.4
`
`.2
`
`0
`
`1 .
`
`8
`
`.6
`
`.4
`
`.2
`
`0
`
`1
`
`.8
`
`.6
`
`.4
`
`.2
`
`0
`
`Proportion
`
`Proportion
`
`Proportion
`
`0
`
`2
`
`4
`
`6
`
`8
`month
`
`10
`
`12
`
`14
`
`Fig. 1 Kaplan-Meier curves for overall survival (OS, A), time to treatment
`progression (TTP, B), and time to treatment failure (TTF, C). The median OS
`was 13.4 months, and the one and two year survival rates were 79.8% and
`19.9%, respectively. The median TTP and TTF were 6.4 and 2.6 months,
`respectively.
`
`the PSA, and 5 (25%) had a 50–75% decrease. Overall, the PSA
`response rate was 55%. One of five patients with lymph node
`metastases achieved a PR, while a patient with lung metastases had
`NC.
`
`Table 1 Patient characteristics
`
`Total
`Median cycle (Range)
`Time (months) from first hormone therapy (Range)
`Median age, Year (Range):
`Median PSA (Range)
`Metastatic sites
`bone
`lymph node
`lung
`EOD
`0
`1
`2
`3
`4
`Prior treatment
`Hormone therapy
`LHRH-analog + antiandrogen
`Low dose steroid
`Estrogen
`Orchiectomy
`Chemotherapy
`EMP
`Cyclophosphamide
`Other
`Radiation
`Prostate
`Outside prostate
`Radical prostatectomy
`(+)
`(–)
`
`20
`
`2 (1–9)
`37.2 (8.1–174.3)
`70.5 (59–80)
`79.1 (4.1–1438)
`
`19 (95%)
`5 (25%)
`1 (5%)
`
`1 (5%)
`5 (25%)
`7 (35%)
`7 (35%)
`0 (0%)
`
`20 (100%)
`9 (45%)
`8 (40%)
`5 (25%)
`
`17 (85%)
`4 (20%)
`5 (25%)
`
`2 (10%)
`6 (30%)
`
`4 (20%)
`16 (80%)
`
`EMP, estramustine phosphate; EOD, extent of disease on bone scanning;
`LHRH, luteinizing hormone releasing hormone.
`
`measurement. A therapeutic response in a lymph node or lung
`was defined as CR, PR, NC, and PD in the sum of the diameters
`of a bidimensionally measurable lesion by CT as well as PSA
`response.
`Time to treatment failure (TTF), time to treatment progression (TTP)
`and over all survival (OS) were calculated. The TTF and TTP were
`measured from the start of chemotherapy to the date of the end and PD,
`respectively. OS was measured from the initiation of therapy to death or
`the last follow-up.
`The correlation between each toxicity and patient’s age, the number
`of the treatment, the prior chemotherapy, and the time from the first
`hormone therapy was examined.
`
`Statistical analysis
`
`The Kaplan-Meier product limit estimator was used to estimate the
`TTF, TTP and OS. Significant factors found to affect the toxicities
`were further analyzed using the Mann–Whitney test.
`
`Results
`
`PSA and objective response
`
`Three (15%) patients achieved a CR, 8 (40%) achieved a PR, and 4
`(20%) had NC. Of the PR patients, 3 (15%) had a >75% decrease in
`
`© 2008 The Japanese Urological Association
`
`107
`
`

`

`Two patients continue on the present protocol currently, and 12 out of
`the remaining 18 patients had to discontinue treatment because of
`toxicity including grade 1–2 fatigue and anorexia in three patients.
`
`Discussion
`
`We used combination therapy with DTX and EMP for Japanese outpa-
`tients with HRPC in order to assess both its efficacy and safety. The
`PSA response rate was 55%. In previous reports that used DTX and
`EMP as a treatment for HRPC, the PSA response rate ranged from 45%
`to 68%.5–7 The OS and TTP were 13.4 months and 6.4 months, respec-
`tively. Previous studies found an OS from 13.3 to 33 months and a TTP
`from 4 to 18.0 months, respectively.8 Consequently, our outcomes did
`not surpass the previous reports.
`Although one patient died from grade 4 febrile neutropenia, overall
`myelotoxicity was moderate in intensity and hospitalization was not
`generally needed. Twelve out of 18 (67%) patients, however, had to
`discontinue treatment because of toxicity including unusual toxicities,
`i.e. nail changes, pneumonitis, and fluid collection, and even grade 1–2
`fatigue and anorexia. Then, the TTF was only 2.6 months.
`We have shown the only correlation between nail changes and the
`time from the first hormone therapy, and edema and the cycle of the
`present chemotherapy using univariate analysis (Table 2), but multi-
`variate analysis couldn’t prove these correlations, because this was a
`very small study. We couldn’t demonstrate any other correlations
`except for the above two combinations.
`The ultimate goal of a treatment for HRPC is a demonstration of a
`prolongation of disease-related survival without affecting a patient’s
`quality of life, not a high response rate. This is a preliminary study and
`it might be hard to evaluate the efficacy of the regimen, however the
`short TTF suggests that the regimen and/or the timing of the chemo-
`therapy should be altered for Japanese patients.
`DTX-induced fluid collection is a peculiar but well-known adverse
`effect. Semb et al.9 observed this in more than half of the patients who
`received a total DTX dose of at least 400 mg/m2. The mechanism is due
`to endothelial inflammation followed by abnormal capillary permeabil-
`ity. In this study, fluid collection depended upon the cumulative dose of
`DTX, although two patients who received less than 400 mg/m2 of DTX
`developed pretibial edema. Pleural effusion occurred after the cumu-
`lative dose exceeded about 1000 mg/m2. Of course, EMP also might be
`concerned with fluid collection. Indeed , all four patients who met with
`grade 3–4 fluid collection, had taken EMP without dose reduction.
`Consequently, fluid collection might be one of the dose-limiting tox-
`icities of this regimen for HRPC.
`
`A TAKENAKA ET AL.
`
`TTP, TTF and OS
`
`The median follow-up at the time of analysis was 12.2 months. During
`the follow-up period , 10 patients died of prostate cancer, and one died
`of an adverse effect. The median OS was 13.4 months, and the one and
`two year survival rates were 79.8% and 19.9%, respectively Fig. 1A).
`The median TTP (Fig. 1B) and TTF (Fig. 1C) was 6.4 and 2.6 months,
`respectively.
`
`Toxicity
`
`Most events were moderate in intensity and were managed medically.
`On the other hand , grade 3–4 toxicities included leukocytopenia in
`25% of patients, anemia in 20% and thrombocytopenia in 5%. There
`was one treatment-related death due to grade 4 febrile neutropenia.
`Other grade 3–4 toxicities included fatigue (10%), pneumonitis (10%),
`fluid collection, i.e. pleural effusion (10%) and edema of the limb
`(10%). Nail changes with grade 2 toxicity was observed in 10%,
`because grade 3–4 were not provided in the criteria. Overall, a fluid
`collection was observed in 11 (55%) patients, 7 with edema in the limbs
`and 4 with a pleural effusion. Figure 2 demonstrates the relationship
`between the proportion of those with a fluid collection and the cumu-
`lative dose of DTX. Edema increased in proportion to the cumulative
`chemotherapy dose. Pleural effusion occurred after the DTX exceeded
`about 1000 mg/m2.
`
`Edema: Limb (n = 7)
`
`Pleural effusion (n = 4)
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`
`Proportion
`
`0
`
`1200 1400 1600 1800
`200 400 600 800 1000
`Cumulative dose of DXT (mg/m2)
`
`Fig. 2 Docetaxel-induced fluid collection. Edema increased in proportion
`to the cumulative dose. Pleural effusion occurred after the cumulative
`docetaxel dose exceeded about 1000 mg/m2.
`
`Table 2 Incidence of drug related toxicities of grade 3/4 and the predictors
`
`Grade 3–4 toxicities
`
`Anemia
`
`Incidence
`Patient’ age
`No. chemotherapy
`Time from first hormone
`therapy
`Prior chemotherapy
`
`4 (20%)
`0.1857
`0.3823
`0.2986
`
`Leuko-
`penia†
`
`5 (25%)
`0.5703
`0.5307
`0.3594
`
`Thrombo-
`cytopenia
`
`1 (5%)
`0.34
`NA
`0.3402
`
`Fatigue
`
`2 (10%)
`0.8501
`0.4007
`0.0588
`
`Nail
`change‡
`
`2 (10%)
`0.5286
`0.4007
`0.0438
`
`Pleural
`effusion
`
`2 (10%)
`0.2567
`0.518
`NA
`
`Edema
`
`Pneumonitis
`
`2 (10%)
`0.8997
`0.0386
`0.6143
`
`2 (10%)
`0.5286
`0.4007
`0.8997
`
`0.5492
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`0.1474
`
`0.5211
`
`†Including one treatment-related death by febrile neutropenia with grade 4. ‡Because grades 3/4 are not provided in the criteria, grade 2 cases are
`described.
`
`108
`
`© 2008 The Japanese Urological Association
`
`

`

`In conclusion, this study of combination chemotherapy with weekly
`docetaxel and estramustine revealed a PSA response rate of 55%, with
`an OS and TTP of 13.4 and 6.4 months, respectively. However, 67%
`had to discontinue treatment because of toxicity and TTF was only
`2.6 months. Although it is a small study, this protocol might need to be
`modified including the regimen and the most appropriate time to start
`therapy for Japanese HRPC patients.
`
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`DTX and EMP for prostate cancer
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`© 2008 The Japanese Urological Association
`
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