|Year : 2014 | Volume
| Issue : 2 | Page : 251-257
Treatment outcome of docetaxel plus prednisolone for metastatic castration-resistant prostate cancer in Korea
In-Chang Cho1, Jae Young Joung2, Ho Kyung Seo2, Jinsoo Chung2, Weon Seo Park3, Kang Hyun Lee2
1 Department of Urology, National Police Hospital, Seoul, Korea
2 Department of Urology, Center for Prostate Cancer, National Cancer Center, Goyang, Korea
3 Department of Pathology, Center for Prostate Cancer, National Cancer Center, Goyang, Korea
|Date of Web Publication||14-Jul-2014|
Kang Hyun Lee
Center for Prostate Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi, 410-769
Source of Support: None, Conflict of Interest: None
Aim: We retrospectively reviewed the treatment outcomes of docetaxel plus prednisolone chemotherapy in Korean men with metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods: This Study included 106 consecutive Korean patients with mCRPC who were treated with a 3-weekly regimen of docetaxel plus prednisolone chemotherapy between 2005 and 2011. The oncologic results and treatment-related adverse events were analyzed.
Results: The mean patient age was 66 years. Of the 106 patients, 70 (66.0%) received docetaxel as the first-line chemotherapy. A 50% reduction in prostate-specific antigen and objective response in measurable lesion were observed in 45 (48.9%) and 14 (17.9%) patients respectively. Fifteen (14.4%) patients experienced grade 3 or higher neutropenic fever. One patient had a treatment-related death. median follow-up time was 26.5 months. The median progression-free survival and overall survival (OS) were 6.0 and 16.0 months respectively. Of several factors examined, multivariate analysis Identified good performance status and first-line setting predict longer OS. The median OS of the patients in the first- and second-line setting was 23.0 versus 11.0 months (Hazard ratio 2.485, 95% confidence interval 1.558-3.966, P < 0.001). The survival rates in the first-line at 12 and 24 months were 73.8% and 47.2% respectively.
Conclusion: Korean castration-resistant prostate cancer patients that receive docetaxel chemotherapy have a relatively longer survival outcome compared with western countries in the first-line setting. In addition, good performance status and first-line setting predicts longer survival. A prospective study including genetic background associated with the prognosis of mCRPC patients might be required.
Keywords: Docetaxel, prostate cancer, survival, toxicity
|How to cite this article:|
Cho IC, Joung JY, Seo HK, Chung J, Park WS, Lee KH. Treatment outcome of docetaxel plus prednisolone for metastatic castration-resistant prostate cancer in Korea. J Can Res Ther 2014;10:251-7
|How to cite this URL:|
Cho IC, Joung JY, Seo HK, Chung J, Park WS, Lee KH. Treatment outcome of docetaxel plus prednisolone for metastatic castration-resistant prostate cancer in Korea. J Can Res Ther [serial online] 2014 [cited 2019 Dec 15];10:251-7. Available from: http://www.cancerjournal.net/text.asp?2014/10/2/251/136546
| > Introduction|| |
Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer-specific deaths in men in the Western industrialized countries. About 192,000 men were estimated to have PCa in 2009 in the United States.  Despite the lower incidence of PCa in Korea compared to the United States, the incidence has been increasing in Korea in the recent years. According to Cancer Statistics in Korea 2009, the five leading primary cancer sites in men include prostate and the mortality rates of PCa have also continued to increase.  Although hormone therapy is useful for advanced PCa, its effects are limited because castration-resistant progression ultimately occurs within a few years in the majority of these patients. , Patients with castration-resistant prostate cancer (CRPC) are candidates for chemotherapy, with the goals of prolonging survival and/or relieving, preventing, or delaying symptoms caused by the disease. Metastases, particularly to the bone and lymph nodes, are frequent in men with CRPC, leading to pain, other symptoms, and impairment in the quality of life (QOL). since 2004, the treatment of CRPC has considerably evolved with the reporting of two landmark studies, TAX 327 and Southwest Oncology Group ( SWOG) 99-16, which revealed that docetaxel-based chemotherapy not only improves the QOL and prostate-specific antigen (PSA) response, but also prolongs the survival of patients with CRPC. , Based on the results of these studies, docetaxel chemotherapy has become the first-line standard of care for men with CRPC. 
The metabolism of docetaxel is affected by ethnicity and age. , in addition, long-term treatment might lead to toxicity increasing with additional treatment, and discontinuation of treatment has the possibility of triggering disease progression. However, until now, there has been no equivalent standard for Korean patients with CRPC and few reports of long-term treatment with docetaxel in CRPC because of the limit of maximum of ten and twelve cycles in the TAX 327 and SWOG protocol respectively.
We undertook this study to evaluate the efficacy and tolerability of the combination of docetaxel and prednisolone in Korean patients with CRPC. The study is meaningful because of the larger number of patients and a longer follow-up period in Korean patients with CRPC than any other study reported to date.
| > Patients and methods|| |
The study protocol was approved by the Institutional Review Board of our institution. One hundred-thirteen CRPC patients who received docetaxel plus prednisolone chemotherapy fulfilled the eligibility criteria for enrollment into the study between January 2005 and December 2011 at a single institution. Seven patients were excluded for other concomitant malignancies. Finally, this study was performed with a total of 106 Korean patients with metastatic castration-resistant prostate cancer (mCRPC) who received docetaxel plus prednisolone chemotherapy. Patient records were retrospectively reviewed to determine the baseline characteristics of patients and the clinical efficacy and tolerability of docetaxel. All the patients had histologically confirmed adenocarcinoma of the prostate, evidence of metastasis, and progressive disease despite complete androgen blockade therapy, anti-androgen withdrawal, and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. Progressive disease was defined by an increase in PSA levels as determined by two consecutive measurements at least 2 weeks apart, an increase in the size of a measurable lesion by computed tomography (CT), or any newly developed bony metastasis with hot uptake by bone scan. Bone scan was considered non-progressive if there were no new lesions in two scans at least 2 months apart. Androgen suppression was confirmed by serum testosterone measurements. Informed consent for toxicity was obtained prior to each therapy.
Treatment and data collection
Pretreatment evaluation included a complete medical history-taking, a physical examination, complete blood cell (CBC) count, serum chemistry profile, serum PSA, bone scan, CT of the pelvis and abdomen, and chest X-ray. Patients were treated with 75 mg/m 2 intravenous docetaxel every 3 weeks and 5 mg of prednisone twice daily, following premedication with 8 mg of dexamethasone. Patients who had not undergone orchiectomy were required to continue androgen blockade with a luteinizing hormone-releasing hormone analog. Patients underwent physical examination, CBC count, liver function test, and renal function test before docetaxel administration, and 7 days after each docetaxel administration. Patients were followed up by 3-weekly PSA determinations before docetaxel administration. In patients with measurable disease, tumor assessments were performed every three cycles until progression or sooner, if possible. Chemotherapy was continued until disease progression or unacceptable adverse events occurred. All patients received docetaxel treatment as an in-patient each cycle.
End points and statistical analyses
All patients were evaluated for PSA response, objective measurable disease response, time to progression, and survival. A PSA response was defined as a reduction of ≥50% from the baseline maintained for at least 3 weeks. For patients with measurable disease, the best response also determined based on the modified response evaluation criteria in solid tumors (RECIST) criteria, version 1.0. PSA progression was defined as a 25% increase in the serum PSA level (to at least 5 ng/ml) over the nadir. Treatment with docetaxel was continued until disease progression, unacceptable adverse events, or patient refusal occurred. The progression-free survival (PFS) and OS were defined as the time between first docetaxel administration and events. Then, they were determined by the Kaplan-Meier method. For univariate and multivariate analyses, Cox proportional hazards regression model was used. SPSS® for Windows®, version 12.0 (SPSS, Chicago, IL, USA) was used for statistical analysis with 2-sided P> 0.05 were considered significant.
| > Results|| |
The patient and disease characteristics of the 106 patients are summarized in [Table 1]. A total of 1180 cycles of treatment were administered to 106 patients (median 11 cycles; range, 2-32 per patient). The mean age and PSA at the beginning of docetaxel plus prednisolone treatment were 66.0 ± 7.3 years and 93.0 ± 60.2 ng/ml respectively. In this population, 70 (66.0%) patients received docetaxel plus prednisolone as the first-line chemotherapy, and 36 (34.0%) as the second-line chemotherapy. Fourteen (13.2%), 2 (1.9%), and 19 (17.9%) patients were treated with estramustine alone, mitoxantrone alone, and estramustine plus mitoxantrone, respectively, before the introduction of docetaxel plus prednisolone chemotherapy. The site of metastasis was bone only in 50 (47.2%) patients, lymph node only in 3 (2.8%) patients, and vital organ (s) in 11 (10.4%) patients. In the first-line group, the patients received more cycles of docetaxel therapy than second-line (P = 0.003).
|Table 1: Characteristics of patients with metastatic castration - resistant prostate cancer who received docetaxel plus prednisolone chemotherapy|
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PSA decline was observed in 69 (75.0%) of the 92 patients. Forty-five patients (48.9%) experienced PSA response, considered to be a PSA decline of 50% from baseline that lasted for 4 weeks. Stable disease and progression disease were presented by 35 (38.0%) and 27 (29.3%) of the study subjects respectively [Table 2]. In the first-line group, there were many PSA responders compared with second-line (P = 0.003).
|Table 2: Responses of serum prostate-specific antigen and measurable disease to docetaxel plus prednisolone chemotherapy|
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Responses of measurable lesions
Responses of measurable lesions to the treatment are shown in [Table 2]. Seventy-eight (73.6%) study subjects had measurable metastasis, revealed by radiographic examinations, which included CT and magnetic resonance imaging. The overall tumor response rate according to the RECIST criteria was 17.9%; all responses were partial responses (PRs). In these patients, the median number of cycles to PR was three. Stable disease was observed in 25 patients (32.0%). No difference was found in measurable tumor response according to chemotherapy setting. With a median follow-up of 26.5 months, the median duration of response was 8.0 months, with a maximum duration of response of 52 months.
During the treatment with docetaxel plus prednisolone chemotherapy, dose reduction of docetaxel was necessary in 67 patients (64.4%). Toxicity profiles are summarized in [Table 3]. Adverse events were reported for 68 patients (65.4%). In terms of hematologic toxicities, leukopenia and neutropenia were common, and were found in 35 (33.6%) and 34 (32.7%) respectively. Grade 3-4 neutropenia occurred in 18 patients (17.3%) and 15 (14.4%) developed neutropenic fever. Most of the patients recovered with supportive care that included hydration and antibiotics. However, one patient (1.0%) had a treatment-related death for neutropenic fever during the observation period. In terms of non-hematologic toxicities, grade 1-2 sensory neuropathies were most frequently found in 41 patients (39.4%). However, no patient developed a grade 3-4 non-hematologic toxicity, and all patients who developed a non-hematologic toxicity recovered with conservative management. There were no statistical differences between first and second-line in terms of toxicity profile.
Survival and predictive factors
Median follow-up was 26.5 months (range, 2.0-107.0 months). Time to PSA progression and the OS curve are presented in [Figure 1]. Median time to PSA progression for the study population was 6.0 months (95% confidence interval [CI], 4.0-8.0 months). At the end of the follow-up period, 33 out of 106 patients were alive. Median survival was 16.0 months (95% CI, 12.1-20.0 months). OS rates at 6, 12, and 24 months were 82.8%, 64.3%, and 32.7% respectively. To identify parameters associated with OS in patients treated with docetaxel plus prednisolone chemotherapy, univariate and multivariate analyses were performed using the Cox proportional hazard model [Table 4]. Of the several factors examined, ECOG PS, biopsy Gleason score, cycles of docetaxel, chemotherapy setting (first- or second-line), and PSA response were identified as significant factors associated with OS on univariate analysis. Of these five factors, only PS and chemotherapy setting appeared to be independent predictors of OS on multivariate analysis. As shown in [Figure 2], there were significant differences in OS of the 106 patients with respect to these two independent predictive factors of OS (log rank, P = 0.006 and P < 0.001, respectively). Only in the first-line setting, median OS was 23.0 months (95% CI, 12.0-34.0 months). OS rate at 6, 12, and 24 months were 88.5%, 73.8%, and 47.2% respectively [Table 5].
|Figure 1: (a) Progression-free survival of 106 patients with metastatic castration-resistant prostate cancer who received docetaxel plus prednisolone chemotherapy, (b) overall survival of 106 patients with mCRPC who received docetaxel plus prednisolone chemotherapy. (median follow-up duration: 26.5 months, range: 2.0-107.0 months)|
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|Figure 2: Overall survival of 106 patients with metastatic castration-resistant prostate cancer who received docetaxel plus prednisolone chemotherapy according to ECOG performance status (a), and chemotherapy setting (b)|
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|Table 4: Univariate and multivariate analyses of association between various parameters and overall survival|
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|Table 5: Comparison of overall survival rate at 6, 12, and 24 months according to parameter|
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| > Discussion|| |
Two landmark phase III trials, TAX 327 and SWOG 99-16, showed that docetaxel plus estramustine or prednisone improves OS versus mitoxantrone plus prednisone. ,, Thus, docetaxel has been strongly advocated as a standard treatment for metastatic CRPC. However, these studies mainly included patients from Western countries. Based on the results of TAX 327, ten cycles of docetaxel is generally used as the standard duration of therapy globally.  However, in clinical practice, docetaxel treatment is often continued until the appearance of unacceptable toxicity, disease progression, or until a few cycles beyond the best response.  Only three reports in the English literature have addressed the efficacy and safety of docetaxel-based chemotherapy in patients with Asian ethnicity; one Japanese Phase II study on reduced dose of docetaxel and two Korean retrospective studies including a preliminary report of our institution with a short follow-up duration. ,
The present study was conducted to explore the feasibility of long duration of treatment with 3-weekly administration of docetaxel (more than ten cycles) in combination with daily prednisolone, and to demonstrate the feasibility of this regimen in Korean patients with CRPC who appear to be responding to the treatment. The PSA response rate in the first-line group was 52.8%, which was similar to those found in the previous studies performed in Western countries. ,,,,, Tannock et al. reported that the rates of PSA response were 45% in the group given docetaxel every 3 weeks and 48% in the group given weekly docetaxel in the TAX 327 trial,  while Petrylak et al. reported a PSA response in approximately 50% of patients treated with docetaxel and estramustine in the SWOG 99-16 trial. 
In terms of toxicity, the present results show that the adverse events (predominantly leukopenia, neutropenia, nausea/vomiting, and paresthesia of the extremities) were acceptable and predictable. In the TAX 327 study, the 3-weekly docetaxel regimen was associated with grade 3/4 neutropenia in 32% of patients.  In the Japanese Phase II trial, the incidences of grade 3/4 neutropenia and leukopenia were 93.0% and 81.4%, respectively, and seven of 43 patients (16.3%) had febrile neutropenia.  In our study, the incidence of grade 3/4 neutropenia, leukopenia, and neutropenic fever were 16.3%, 17.3%, and 14.4% respectively. The Japanese and Korean subjects had a similar incidence of neutropenic fever. Other hematologic toxicity has been shown to be generally better than that of Japanese patients.  However, one patient with neutropenic fever and subsequent pneumonia experienced treatment-related death, despite aggressive treatment in our institution, emphasizing the need for careful management of neutropenic fever and use of granulocyte colony-stimulating factor.
In the overall population of this study, the median PFS and OS were 6.0 and 16.0 months respectively. Identification of factors predicting the prognosis of men with mCRPC treated with docetaxel-based chemotherapy are needed, as are subgroup analyses comparing survival data with those of western countries. In the present study, biopsy Gleason score, cycles of docetaxel, and PSA response were statistically significant only in the univariate analysis. These findings indicate that lower biopsy Gleason score and more than ten cycles of docetaxel and prednisolone does not statistically enhance survival, supporting an earlier suggestion.  However, the continuation of docetaxel and prednisolone chemotherapy beyond the initial ten cycles is still debatable. The benefit of this strategy should be reviewed even after this study. Finally, ECOG PS and chemotherapy setting were revealed to be independently associated with OS and PSA response had a marginal statistical power in our survival analysis. Also, in data from TAX 327 trials, PS was identified by multivariate analysis as an independent prognostic factor.  In our subgroup analyses, the first-line treatment group had a longer median survival (23.0 vs. 11.0 months, P < 0.001) than the second-line group. This OS outcome in the first-line setting was favorable compared with those of previous studies in other countries. Furthermore, we estimated 6, 12, and 24-month survival rates for each subgroup. About half of the patients in the first-line setting were still alive at 24 months. In the TAX 327 and SWOG 99-16 trials, the median survival in the groups assigned to docetaxel-based chemotherapy were less than 20 months. , Also in Japan, Wada et al.  reported that docetaxel-based chemotherapy (combination with estramustine) had a median OS of 19.4 months. One Japanese retrospective study showed long median OS of 25.4 months in patients receiving docetaxel-based chemotherapy.  However, 46.7% of their study population had a combined use of estramustine with docetaxel. A Japanese Phase II trial for docetaxel plus prednisolone chemotherapy published 4 years ago involved injection with a reduced dose of docetaxel; OS data were not reported because of the short follow-up period (median, 5.8 months).  The reports on the survival of docetaxel plus prednisolone chemotherapy in patients with Korean are very rare. Lee et al.  reported that median OS in their patients was 22.8 months with a median follow-up duration of 23.1 months. However, patient demographics showed a large number of prior estramustine (63%) and secondary hormonal treatment (cyproterone acetate, 31%).
This study targeted patients in a single-racial country. The study populations were native Korean. Koreans are a homogenous ethnic group. As far as we know, our study has the longest follow-up duration (median, 26.5 months) and includes the most homogenous population (especially in the subgroup analysis) of docetaxel plus prednisolone chemotherapy in Korean CRPC patients. The studies for inter-individual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians were conducted by researchers in Singapore several years ago. They found that the response rate to docetaxel plus carboplatin chemotherapy was significantly higher in Asian patients than Caucasian patients.  Further studies conducted on the pharmacology of docetaxel in Asian patients indicated a slower plasma clearance than in Caucasians,  suggesting this was the main determinant of the higher toxicity. It is, therefore, possible that the observed difference in response rate reflects differences in response assessment between different races. Thus, studies of the differences of treatment outcome according to the race or ethnicity are necessary and important.
Certain limitations must be considered when conclusions are drawn from our results. First is the inherent selection bias and potential data imperfection of the retrospective study design. Second, a sample size of 106 patients in such a common disease like mCRPC is not large enough. However, this is fairly large number in Korea when considering the low national incidence of PCa. Third, this study enrolled patients with variable degree of metastasis (from bone or lymph node only to vital organ) compared with TAX 327. In the future, more homogenous population should be enrolled. The fourth limitation is the lack of examination of the validity of molecular markers in predicting disease prognosis in addition to conventional clinicopathologic parameters, since mCRPC Is characterized by unique biological features as well as heterogeneous genetic backgrounds. ,
| > Conclusions|| |
Korean CRPC patients that receive docetaxel chemotherapy have a relatively longer survival outcome compared with western countries in the first-line setting. In addition, good performance status and first-line setting predicts longer survival. A well-designed prospective study including genetic background associated with the prognosis of mCRPC patients is required.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]